K. G. Baker

Distribution, morphology and number of monoamine-synthesizing and substance P-containing neurons in the human dorsal raphe nucleus

The distribution, morphology and number of serotonin-, catecholamine- and substance P-containing neurons in the human dorsal raphe nucleus were studied. Parallel series of sections were prepared from 10 human brainstems obtained at autopsy from patients without neurological disease aged between 42 and 88 years. The neurons were identified using immunohistochemistry with antibodies raised against phenylalanine hydroxylase (tryptophan hydroxylase-containing, serotonin neurons), tyrosine hydroxylase (catecholamine neurons) and substance P. A reference series of Nissl-stained sections was also prepared and data published separately were used to delineate the subnuclear divisions of the dorsal raphe nucleus and to establish the total number of neurons in each subnucleus. The following principal findings emerged. (1) Serotonin-synthesizing neurons are present in all regions of the dorsal raphe nucleus and their total number is 165,000 +/- 34,000. The same types of neurons as those seen in Nissl material characterize each of the five subnuclei (caudal, dorsal, ventral, ventrolateral and interfascicular). (2) Substance P-containing neurons mostly occupy the rostral part of the nucleus and their number is 74,600 +/- 17,600. (3) Catecholamine cells are only found in the rostral part of the dorsal raphe nucleus and their number is 5600 +/- 3400. (4) In the ventral and interfascicular subnuclei the combined number of serotonin-synthesizing and substance P-containing neurons exceeds the total number of Nissl-stained neurons suggesting that serotonin and substance P co-exist in a substantial part of the cell population of the dorsal raphe nucleus. This is further supported by the highly similar morphology and size of these neurons. It is concluded that there are demonstrable chemical differences between the various subregions of the human dorsal raphe nucleus. These differences are in harmony with the results of hodological studies in animals, which have demonstrated differential projection pathways emerging from this nucleus.

Neuronal loss in functional zones of the cerebellum of chronic alcoholics with and without Wernicke's encephalopathy

This study examines the effect of chronic alcohol consumption on the human cerebellum using operational criteria for case selection [Caine D. et al. (1997) J. Neurol. Neurosurg. Psychiat. 62, 51-60] and unbiased stereological techniques. We describe, for the first time, structural changes in different functional zones of the cerebellum of chronic alcoholics and correlate these changes with specific clinical symptoms. No consistent changes in the number of neurons or the structural volume for any cerebellar region were observed in the chronic alcoholics without the clinical signs of Wernickes encephalopathy. In all cerebellar measures, these chronic alcoholics did not differ significantly from the non-alcoholic controls, suggesting that chronic alcohol consumption per se does not necessarily damage human cerebellar tissue. However, several cerebellar changes were noted in the thiamine-deficient alcoholics studied. There was a significant decrease in Purkinje cell density (reduced on average by 43%) and molecular layer volume (reduced by 32%) in the cerebellar vermis in all thiamine-deficient chronic alcoholics. A decrease in cell density and atrophy of the molecular layer, where the dendritic trees of the Purkinje cells are found, without significant cell loss suggests loss of cellular dendritic structure and volume. These thiamine-deficient alcoholics also had a significant decrease (36% loss) in the estimated Purkinje cell number of the flocculi, disrupting vestibulocerebellar pathways. These results indicate that cerebellar Purkinje cells are selectively vulnerable to thiamine deficiency. There is evidence that this damage contributes significantly to the clinical signs of Wernickes encephalopathy. There was a 36% loss of Purkinje cells in the lateral lobe in alcoholics with mental state signs and 42% atrophy of vermal white matter in ataxic alcoholics. The finding of a 57% loss of Purkinje cells and a 43% atrophy of the molecular layer of the vermis in alcoholics with cerebellar dysfunction supports previous findings highlighting the importance of spinocerebellar pathways to these symptoms.

The human locus coeruleus complex: an immunohistochemical and three dimensional reconstruction study.

SummaryThe CA (catecholamine/catecholaminergic) cell populations of the locus coeruleus (LC) and subcoeruleus (SubC) were studied using serial sections of the human brainstem immunostained with an antibody against tyrosine hydroxylase. The tyrosine hydroxylase-immunoreactive (TH-IR) neurons were plotted in a computer reconstruction system and their number and soma size determined. Serial section computer analysis was then used to create a three dimensional reconstruction of the LC complex. The number of cells containing neuromelanin pigment was also determined and compared with the number of TH-IR cells. In our sample there were 53,900 TH-IR cells in the LC and a further 6260 cells in the SubC. These numbers were very similar to our estimates of the number of cells containing neuromelanin pigment and we concluded that virtually all of these cells were also tyrosine hydroxylase positive. The average soma size of the TH-IR cells of the LC was 37 μm and in the SubC 34 μm. In addition to these quantitative observations the morphology of the TH-IR and the Nissl stained cells is described in some detail. We also compared the groups of immunoreactive cells in the human pons with the noradrenergic groups A5–A7 described in the rat. Although in the human these groups are contiguous, A5 is not part of the LC complex. However we did find that the A7 group is equivalent to the rostroventral part of SubC while the remainder of SubC is formed by ventral A6.

Serotonin and alcohol-related brain damage.

Preliminary results from the immunohistochemical examination of the brainstems of chronic alcoholics, suggest that alcohol may have a role in damage to the principal serotonergic (5HT) nuclei. This view is reinforced by evidence from previous animal experiments which demonstrated a reduction in 5HT neurons in the brains of alcohol-preferring rats and selective neurotoxicity to 5HT neurons following 5,6-dihydroxytryptamine-induced increased ethanol intake. It is speculated that, like other neurotoxins, alcohol or its metabolites cause degeneration of 5HT axons and axon terminals. It is possible that if axonal damage is sufficiently severe and chronic, the eventual consequence is cell death. This could be due to insufficient opportunity for repair and regrowth under repeated and sustained insults of high alcohol consumption.

Chronic alcoholism in the absence of Wernicke-Korsakoff syndrome and cirrhosis does not result in the loss of serotonergic neurons from the median raphe nucleus

Previous studies have identified alcohol, thiamine deficiency and liver disease as contributing to the neuropathology of alcohol-related brain damage. In order to examine the effects of alcohol toxicity and thiamine deficiency on serotonergic neurons in the median raphe nucleus (MnR), alcoholic and previously published Wernicke-Korsakoff syndrome (WKS) cases without liver disease, were compared with age-matched non-alcoholic controls. While there was no difference between the estimated number of serotonergic neurons in either controls or alcoholics without WKS (means of 63,010±8,900 and 59,560±8,010 respectively), a substantial loss of serotonergic neurons was previously found in WKS cases (mean of 19,050±13,140). Further analysis revealed a significant difference in the maximum daily alcohol consumption between these groups. However, analysis of covariance showed that the number or serotonergic neurons in the MnR did not correlate with the amount of alcohol consumed. Therefore, our results suggest that cell loss in the MnR can be attributed to thiamine deficiency rather than alcoholper se.

Ascending Noradrenergic and Serotonergic Systems in the Human Brainstem

Together with Istvan Tork, we have examined the morphology and distribution of noradrenergic (Baker et al., 1989) and serotonergic neurons in the human brain (Tork and Hornung, 1990; Baker et al, 1991a; Baker et al., 1991b). As in other species, these neurons are confined to anatomically distinct regions. In rats, histofluorescent and immunohistochemical studies have shown that both noradrenergic (Morrison et al., 1978; Levitt et al., 1984) and serotonergic (Lidov et al., 1980) fibers project diffusely to all regions of the cerebral cortex. Although there is variation in the pattern of cortical arborization (Levitt and Moore, 1978; Morrison et al., 1978; Lidov et al., 1980; Steinbusch, 1981), both systems have uniform density of fibers which does not vary substantially across neocortical regions (Morrison et al., 1978; Lidov et al., 1980; Levitt et al., 1984). However in primates, noradrenergic and serotonergic afferents to the cortex show regional and laminar innervation patterns which have a high degree of specificity not found in the rat (Lewis et al., 1986). It has been postulated that these two systems are counteractive (Brodie and Shore, 1957). Noradrenergic neurons have been shown to fire frequently during watchfulness and vigilance whereas serotonergic neurons are quiescent during the same activity in cats (Jacobs and Azmitia, 1992).

Een overzicht van therapeutisch ultrageluid: studies naar de effectiviteit

A review of therapeutic ultrasound: effectiveness studies [Physical Therapy 2001;81:1339-50]