Functional magnetic resonance imaging at 3T as a clinical tool in patients with intracranial tumors.

PURPOSE: To investigate the potential of functional magnetic resonance imaging (fMRI) at 3T as a clinical tool in the preoperative evaluation of patients with intracranial tumors. High magnetic field strength such as 3T is of benefit for fMRI because signal-to-noise ratio and sensitivity to susceptibility changes are field-strength-dependent. MATERIAL AND METHODS: Twenty patients with tumors close to eloquent sensorimotor or language areas were studied. Motor, sensory, and two language paradigms (word generation, rhyming) were used; their effectiveness was determined as the percentage of patients in whom the functional area of interest was activated. Activation maps were calculated and their quality rated as high, adequate, or insufficient. The influence of fMRI on the neurosurgical decision regarding operability, surgical approach, and extent of the resection, was assessed. RESULTS: Paradigm effectiveness was 90% for motor and 95% for sensory stimulation, and varied from 79% to 95% for word generation and rhyming in combination. Ninety percent of the activation maps held high or adequate quality. fMRI proved useful: in the decision to operate (9 patients), in the surgical approach (13 patients), and in extent of the resection (12 patients). CONCLUSION: fMRI at 3T is a clinically applicable tool in the work-up of patients with intracranial tumors.

Immunotreatment in patients with glioblastoma multiforme--a histopathological evaluation of reactive and inflammatory changes.

Glioblastoma multiforme (GBM) is the most common highly malignant brain tumor and is also one among the most therapy-resistant human neoplasias. At the University Hospital in Lund, a group of patients with GBM were treated with a new therapy form attempting immunization by glioma cells transfected to produce interferon-gamma. The purpose of this report was to evaluate tumor material from the first nine patients treated with this therapy, assessing the levels of inflammatory/reactive cells (lymphocytes and macrophages). Tumor biopsies from surgery performed at different time points during treatment were analyzed with conventional histotechnical methods and immunohistochemistry. A post-mortem neuropathological investigation with a whole brain assessment was achieved in 5 immunized patients. The results show that cytotoxic T lymphocytes exhibited a mild increase during immunotreatment. This increase indicates an invoked stimulation of a cytotoxic T cell reaction, which may prove beneficial when immunization is adequately manipulated in dosage and timing.

Cerebral physiological and biochemical changes during vasogenic brain oedema induced by intrathecal injection of bacterial lipopolysaccharides in piglets.

BACKGROUND: The objective of the study was to evaluate biochemical and physiological changes in an experimental model of vasogenic brain oedema utilising techniques also used in routine neurointensive care. METHOD: 32 piglets were randomised to control or experimental group. The latter received an intrathecal injection of lipopolysaccharide (LPS) from E. coli (LPS group). Intracranial pressure (ICP)and mean arterial pressure (MAP) were measured continuously. Intracerebral microdialysis was used for analysing interstitial levels of glucose, pyruvate, lactate, glutamate, glycerol and urea every 30 min. Repeated calculations of mean hemispheric CBF were performed utilising an extracranial scintillation detector and Intra-carotid injection of (133)Xe. Cerebral specific gravity was measured and the brains were fixed for histological examinations. FINDINGS: After LPS injection ICP increased reaching a plateau phase after 4-7 hours and CBF increased by 46%. Histological examination showed inflammation with pronounced extravasation of granulocytes. A significant decrease in brain specific gravity (p =0.022) was obtained. LPS caused a significant decrease in cerebral interstitial concentration of glucose (p = 0.0035), and significant increases in lactate concentration (p = 0.002) and lactate/pyruvate ratio (p = 0.0017). A small but significant increase in glutamate was obtained (p = 0.0219). Glycerol did not change significantly. INTERPRETATION: Intrathecal LPS caused an inflammatory reaction with extravasation of granulocytes, increased blood-brain barrier permeability and cerebral oedema. Biochemical analyses indicate increased glycolysis but no signs of cell membrane degradation.

Nitric oxide synthase in the hypothalamic paraventricular nucleus of the female rat; organization of spinal projections and coexistence with oxytocin or vasopressin.

We investigated the distributions and interrelations of neuronal nitric oxide (NO) synthase- (nNOS), oxytocin- (OT), and 8-arginine vasopressin- (AVP) immunoreactive (IR) neurons in the paraventricular nucleus (PVN), and the occurrence and distribution of nNOS spinally projecting neurons in the PVN of the female rat. Using double labelling immunohistochemistry, we mapped the distribution of nNOS-, OT- and AVP-immunoreactive (IR) neuronal cell bodies in the different parts of the PVN. About 80% of nNOS-IR cell bodies were magnocellular. About 30% of the nNOS-IR cell bodies were OT-IR, colocalization being most frequent in the rostral parts. In comparison, only approximately 3% of all nNOS-IR cell bodies were AVP-IR, evenly distributed throughout the PVN. True Blue (TB), administered unilaterally into the spinal cord, disclosed that most spinally projecting cell bodies in the PVN were localized in caudal parts. Combined TB tracing and nNOS immunohistochemistry showed that approximately 30% of spinally projecting neurons in the PVN were nNOS-IR, and that approximately 40% of these were magnocellular. Ipsilateral nNOS spinal projections were about eight times more frequent than the contralateral nNOS projections. The study describes the detailed neuroanatomical organization of nNOS neurons coexpressing OT or AVP, and of nNOS spinally projecting neurons within defined parts of the PVN. In contrast to the paraventriculo-spinal system in general, we show that the nNOS paraventriculo-spinal pathway to a large extent originates in magnocellular cell bodies. The results suggest that NO is an important messenger in the paraventriculo-spinal pathway that may in part act in concert with OT.

Detailed organization of nitric oxide synthase, vasopressin and oxytocin immunoreactive cell bodies in the supraoptic nucleus of the female rat.

The anatomical distribution and quantitative relations of cell bodies containing neuronal nitric oxide synthase (nNOS), 8-arginine vasopressin (AVP) and oxytocin (OT) were examined throughout the supraoptic nucleus (SON) of the female rat by means of immunocytochemical and NADPH-diaphorase (NADPH-d) histochemical techniques using a triple labelling methodology. Seven chemically defined populations of neurons containing all combinations of either nNOS, AVP or OT were identified. nNOS-containing (NADPH-d positive) neurons, amounting to about 40% of all neurons counted, were most frequent in central and dorsal regions, and were evenly distributed along the rostro-caudal axis. Two small nNOS-positive neuronal populations were preferentially located dorso-centrally in the nucleus: nNOS-positive neurons containing both AVP- and OT-immunoreactivity, and neurons only containing nNOS. Slightly less than half of all nNOS-positive neurons contained AVP, and a similar share of nNOS-positive neurons contained OT. The occurrence of nNOS-positive/AVP-containing neurons was highest in the caudal half, whereas that of nNOS-positive/OT-neurons was highest in the rostral half of SON. The data demonstrate new findings concerning the anatomical organization and co-localization patterns of nNOS-, AVP- and OT-containing neuronal populations in SON. We conclude that the absolute and relative occurrence of the identified neuronal populations vary markedly in different parts of SON. This is important to take into consideration when performing, and evaluating experimental investigations concerned with neurochemical changes in SON.

Proton MR spectroscopy and preoperative diagnostic accuracy: an evaluation of intracranial mass lesions characterized by stereotactic biopsy findings.

BACKGROUND AND PURPOSE: MR imaging has made it easier to distinguish among the different types of intracranial mass lesions. Nevertheless, it is sometimes impossible to base a diagnosis solely on clinical and neuroradiologic findings, and, in these cases, biopsy must be performed. The purpose of this study was to evaluate the hypothesis that proton MR spectroscopy is able to improve preoperative diagnostic accuracy in cases of intracranial tumors and may therefore obviate stereotactic biopsy. METHODS: Twenty-six patients with intracranial tumors underwent MR imaging, proton MR spectroscopy, and stereotactic biopsy. MR spectroscopic findings were evaluated for the distribution pattern of pathologic spectra (NAA/Cho ratio < 1) across the lesion and neighboring tissue, for signal ratios in different tumor types, and for their potential to improve preoperative diagnostic accuracy. RESULTS: Gliomas and lymphomas showed pathologic spectra outside the area of contrast enhancement while four nonastrocytic circumscribed tumors (meningioma, pineocytoma, metastasis, and germinoma) showed no pathologic spectra outside the region of enhancement. No significant correlation was found between different tumor types and signal ratios. MR spectroscopy improved diagnostic accuracy by differentiating infiltrative from circumscribed tumors; however, diagnostic accuracy was not improved in terms of differentiating the types of infiltrative or circumscribed lesions. CONCLUSION: MR spectroscopy can improve diagnostic accuracy by differentiating circumscribed brain lesions from histologically infiltrating processes, which may be difficult or impossible solely on the basis of clinical or neuroradiologic findings.

Frontal lobe dysfunction in patients with non-frontal malignant gliomas: a monoaminergic dysregulation?

Previous investigations concerned with the neuropsychological function of patients with intracerebral supratentorial malignant gliomas has revealed the frequent occurrence of signs suggestive of an inhibitory frontal lobe dysfunction regardless of the intracerebral localization of the tumor and before the diagnosis was known to either the investigator or the patient. Upon closer analysis, the frontal lobe dysfunction has been verified by the demonstration of reduced blood flow in frontal areas in these patients. Since many of the findings can be related to a dysfunction of dopaminergic neurotransmission, we hypothesize that abnormal astrocytes interfere with the metabolism, transport and release of various neurotransmitters of which dopamine may be the one responsible for the most striking neuropsychological abnormalities in patients with malignant gliomas.

Nitric oxide synthase and vasopressin in rat circumventricular organs. An immunohistochemical study.

The distribution of immunoreactivity to neuronal nitric oxide synthase (nNOS) and vasopressin (AVP) was studied in the circumventricular organs of the female rat. The occurrence of NOS immunoreactivity showed correspondence to nicotinamide dinucleotide phosphate diaphorase reactivity, a previously used but less specific marker for neuronal NOS. nNOS immunolabeling was detected in the two most rostrally located circumventricular organs - the organum vasculosum of the lamina terminalis and the subfornical organ. In the latter, AVP immunoreactivity was observed in some cell bodies, which also were nNOS-immunoreactive. In the median eminence and the neurohypophysis there were large amounts of nNOS- and AVP-immunoreactive nerve fibers, which often displayed similarities in distribution and morphology. Within the pineal gland, only very few nNOS-immunoreactive varicose terminals were observed, which ran along blood vessels. nNOS immunoreactivity was also seen in the epithelium of the choroid plexus, whereas no nNOS immunoreactivity could be found in the subcommissural organ or in the area postrema. The present demonstration of nNOS and AVP immunoreactivity in the subfornical organ, median eminence, and neurohypophysis, and the occurrence of nNOS immunoreactivity also in the choroid plexus and organum vasculosum of the lamina terminalis, provides a morphological background for a functional role for nitric oxide in water homeostatic mechanisms, both as executed through the hypothalamohypophyseal system and via the production of cerebrospinal fluid.

Effect of lesioning of medullary catecholamine neurons or the median eminence on the development of cerebral vasospasm in the squirrel monkey.

Injections of blood into the interpeduncular fossa and cisterna magna in the squirrel monkey produce an angiographically demonstrable, biphasic cerebral vasospasm with a maximal acute spasm at ten minutes and a maximal late spasm at six days after the subarachnoid haemorrhage (SAH). Selective lesioning of the A2 nucleus in the medulla oblongata or the median eminence in the hypothalamus prior to the SAH prevents the development of both the acute and late cerebral vasospasm. The present data indicate that the A2 nucleus and the median eminence participate in the development of vasospasm in the squirrel monkey.

Immunocytochemical demonstration of DSIP-like immunoreactivity in the hypothalamus of the rat.

The distribution of delta sleep-inducing peptide immunoreactivity (DSIP-IR) was studied in the rat diencephalon. Varicose nerve fibers exhibiting DSIP-IR were found throughout the mediobasal hypothalamus, most frequently in the hypothalamic arcuate nucleus and in the adjoining median eminence and pituitary stalk. This innervation provides a basis for the involvement of DSIP in neuroendocrine regulation at the hypothalamic level. In the hypothalamus, DSIP-IR innervation was also observed close to the third ventricle and within the mamillary complex. Despite pretreatment with colchicine, no evidence of immunoreactive cell bodies containing DSIP-IR could be found.

Central origins of preganglionic fibers to the sphenopalatine ganglion in the rat. A fluorescent retrograde tracer study with special reference to its relation to central catecholaminergic systems.

The brainstem origin of preganglionic fibers to the sphenopalatine ganglion in rat was revealed by the aid of the retrograde axonal tracer True Blue (which does not traverse to a second order neuron) applied deep in the sphenopalatine ganglion or the Vidian nerve on one side. The majority of fibers originate in the ipsilateral lacrimo-muconasal nucleus in the ventrolateral rostral medulla oblongata and caudal pons. A smaller number of fibers originate more dorsomedially and caudally in the medullary reticular formation. After application to the ganglion a third small group of labelled neurons was found more rostrally in the brainstem, in the reticular formation ventrolateral to the caudal part of the dorsal raphe nucleus. Simultaneous visualization of catecholaminergic nerves revealed that the labelled neurons in the lacrimo-muconasal nucleus were heavily innervated by catecholaminergic fibers. It appears from previous studies that the preganglionic neurons may not be cholinergic. None of the labelled neurons in the brainstem stained positively for catecholamines. Thus, further studies are required to elucidate the transmitter(s) used in these neurons.

Adrenergic innervation of the calvarium of the neonatal rat. Its relationship to the sagittal suture and developing parietal bones.

The presence and distribution of adrenergic nerves in the developing calvarium of the newborn rat documented by means of the formaldehyde-induced fluorescence technique in rats aged 2 or 7 days. Nerve fibres exhibiting catecholamine-specific fluorescence were seen within the developing calvarium of all animals. In coronal sections, these fibres could be seen in the developing bone, especially in the lamina interna, while in sagittal sections, they were seen to traverse the tissue to reach the central of the diploë. These fibres originate from a denser plexus within the dura mater. Especially in the younger age group, the fluorescent fibres often exhibited an immature appearance, being coarse and devoid of varicosities. In the older animals the fibres were often varicose. The sutural tissue proper was always found to be devoid of adrenergic innervation. The possible origin and functional significance of the adrenergic innervation in the developing bone in relation to skull growth and sutural closure are discussed.

Studies on dopamine-, tyrosine hydroxylase- and aromatic L-amino acid decarboxylase-containing cells in the rat diencephalon: comparison between formaldehyde-induced histofluorescence and immunofluorescence.

The morphology, number and distribution of catecholaminergic neurons, as visualized either with the aluminum-catalysed formaldehyde method for catecholamines or with the immunohistochemical method for the catecholamine-synthesizing enzymes tyrosine hydroxylase and aromatic L-amino acid decarboxylase, respectively, were analysed within the rat dorsal hypothalamus, ventral thalamus and adjoining regions (A11 and A13 cell groups). Both polyclonal rabbit and monoclonal mouse tyrosine hydroxylase antibodies were used in elution-restaining and double-staining experiments, respectively. Some of the animals also received spinal injections of the fluorescent tracer True Blue in order to retrogradely label cells projecting to the spinal cord. With respect to the number and distribution of catecholaminergic neurons in the A11 and medial A13 cell groups, including the spinal-projecting subpopulation, the results obtained with the two methods were very similar, indicating that within these regions of the CNS the two methods in principle visualize identical cell populations. However, the catecholaminergic cells were distinctly larger and their processes appeared more extensive with the immunohistochemical method. Animals processed for immunohistochemistry exhibited a lower total number of retrogradely labelled cells in the A11 area than those analysed with aldehyde-induced fluorescence despite the fact that both methods revealed similar numbers of retrogradely labelled tyrosine hydroxylase-positive and catecholamine-containing cells, respectively. The reason for these discrepancies, which are probably of methodological nature, are discussed. While this study shows that the results obtained with the two methods within the A11 and medial A13 cell group are very similar and thus strengthens the earlier proposed concept of the organization of the diencephalospinal dopaminergic system, it also documents that in intermingling and nearby CNS regions there are cell bodies which cannot be demonstrated with the aldehyde fluorescence method, but which still contain tyrosine hydroxylase and/or aromatic L-amino acid decarboxylase-like immunoreactivity. One explanation is low levels of enzyme and/or dopamine combined with a comparatively low sensitivity of the histochemical method. Thus, neurons containing both enzymes are probably dopaminergic, even if catecholamine fluorescence cannot be demonstrated. Neurons containing tyrosine hydroxylase, but lacking both aldehyde induced fluorescence and aromatic L-amino acid decarboxylase, may also still be dopaminergic.(ABSTRACT TRUNCATED AT 400 WORDS)

Projections from the ventral tegmental area and mesencephalic raphe to the dorsal raphe nucleus in the rat. Evidence for a minor dopaminergic component.

The origins of the dopaminergic innervation of the rat dorsal raphe nucleus (NRD) have been investigated using a combination of fluorescent retrograde tracing and fluorescence histochemistry. Stereotaxic microinjections of True Blue were placed in the central, caudal and lateral portions of the NRD, and after 6-12 days survival the brains were processed for fluorescence histochemical detection of catecholamines. Retrogradely labeled neurons were searched for in the diencephalic A11 and A13 dopaminergic cell groups, substantia nigra, ventral tegmental area (VTA) and the linear, central superior and dorsal raphe nuclei. The various NRD injections consistently resulted in retrograde labeling of a small number of catecholamine-containing, presumed dopaminergic cell bodies, confined mainly to three regions: the VTA, the linear and central superior raphe nuclei and the NRD itself. The present findings indicate that not only dopaminergic neurons in the VTA but also the system of catecholamine-containing cells, extending dorsally and caudally from the VTA within the midline raphe area, project to the NRD. Although often similar in size, shape and distribution to the catecholaminergic neurons the majority of retrogradely labeled cells in these regions were, however, found to be non-catecholaminergic.

Do tyrosine hydroxylase-immunoreactive neurons in the ventrolateral arcuate nucleus produce dopamine or only L-dopa?

Dopamine (DA) was early demonstrated in the arcuate nucleus by means of the formaldehyde-induced histofluorescence method. In the present study we have investigated the distribution of cell bodies in the arcuate nucleus with antisera against tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AADC) and DA. The results indicate that TH-immunoreactive cells in the dorsomedial part of the arcuate nucleus also contain immunoreactivity for both AADC and DA. However, TH-positive cells in the ventrolateral arcuate nucleus lacked AADC- and DA-immunoreactivity with the sensitivity of the present methods. The findings raise the question whether the ventrolateral cells synthesize L-DOPA or DA as endproducts.

Neuropeptide Y (NPY) in the area of the hypothalamic paraventricular nucleus activates the pituitary-adrenocortical axis in the rat.

Immunocytochemical studies have documented the presence of neuropeptide Y (NPY) in the hypothalamic paraventricular nucleus (PVN) which harbours a large number of neurones that contain corticotrophin-releasing factor (CRF). In this study the close morphological association between NPY fibres and CRF cell bodies in the PVN was confirmed. The localization of NPY terminals in the vicinity of CRF neurones forms a morphological basis for an action of NPY in the hypothalamic control of the pituitary-adrenocortical axis. We therefore microinjected NPY into the area of the PVN of both conscious, freely moving and anaesthetized rats and noted a powerful stimulatory effect on adrenocorticotropic hormone (ACTH) and corticosterone release as measured by radioimmunoassay. In experiments with conscious, freely moving rats, higher ACTH and corticosterone levels were detected following injection of NPY into the area of the PVN than following control injection (desamidated NPY). Intracerebroventricular injection of NPY produced a small, albeit significant, increase in circulating corticosterone levels as compared to control (saline-injected) rats. Anaesthetized rats responded to NPY (but not to saline) injected into the area of the PVN with elevated ACTH and corticosterone levels, while injection of NPY into the neocortex failed to affect the blood concentration of either ACTH or corticosterone. In conclusion, we have demonstrated an activating effect of NPY on the pituitary-adrenocortical axis both in conscious and anaesthetized rats which may reflect the anatomical relationship between NPY fibres and CRF neurones in the PVN.

Catecholamine innervation of the caudal spinal cord in the rat.

By means of the aluminum-formaldehyde (ALFA) fluorescence technique for monoamine visualization the distribution of catecholamines was studied in the caudal spinal cord, particularly in relation to motoneurons innervating pelvic structures. In the lumbosacral cord all parts of the spinal gray matter were found to contain catecholamines. In the dorsal horn the most intense fluorescence was seen in the superficial layers. The motoneuron neuropil exhibited the most prominent catecholamine-fluorescence of the ventral horn layers. In the sixth lumbar segment, which contains the motor nuclei that innervate the pelvic striated muscles as well as one innervating muscles in the lower limb, a differential distribution of the density of catecholamine fluorescence was presented by the individual nuclei. The catecholamine fibers in the motoneuron neuropil were seen closely surrounding the motoneuron somata, suggesting the existence of axosomatic contacts, and by utilizing the fluorescent retrograde tracer True Blue in combination with the ALFA method tentative axosomatic noradrenergic synapses on identified neurons innervating small striated pelvic muscles could be visualized in the light microscope. In the intermediate gray the intermediolateral nucleus in thoracic and upper lumbar segments was the most heavily innervated area, followed by the medial lumbar sympathetic group, which contains the majority of the sympathetic preganglionic neurons innervating the pelvic organs. The parasympathetic intermediolateral nucleus in the upper sacral segments received a catecholamine innervation of moderate density. The catecholamine innervation pattern is discussed in relation to the patterns of other putative transmitters. The distribution of catecholamine fluorescence in relation to nuclei that control the pelvic organs differs from the arrangement of other transmitters in this region. The complexity of the innervation of the pelvic organs and their related striated muscles is thus further stressed.

Organization of diencephalic dopamine neurones projecting to the spinal cord in the rat.

Using the aluminium-formaldehyde method for visualization of catecholamines in combination with injections of the fluorescent retrograde tracer True Blue we have studied those diencephalic dopamine (DA)-containing cell groups which have been proposed to give rise to the DA innervation of the spinal cord and investigated the organization of the diencephalospinal DA system in detail. The A13 cell group was found to contain 370, and the A11 cell group 140, DA-producing cells on each side, whereas only very few such cells were found in the paraventricular hypothalamic nucleus. Tracer injections into the spinal cord labelled only DA cells within the A11 group. The overall majority of labelled cells were found ipsilaterally but some cells were also found contralaterally indicating the existence of a minor crossed dopaminergic projection to the spinal cord. Large tracer injections which covered the hemicord at different levels generally resulted in very similar distributions and numbers of retrogradely-labelled DA cells. The labelled DA-containing cells constituted 30-50% of the total number of labelled neurones in the ipsilateral A11 area and about 20-40% of the total number of DA containing cells in this area were labelled. Small injections that did not extend into the nucleus reticularis or the adjacent part of the lateral funiculus failed to label any diencephalic DA cells but usually labelled some non-DA cells in the A11 area. It is concluded that the diencephalospinal DA neurones have long axons that extend over several segments and possibly traverse the entire length of the spinal cord, giving off collateral branches at various levels. From the anatomical data of the present study and previous pharmacological and electrophysiological findings it seems possible that diencephalospinal DA neurones could modulate both sympathetic activity and nociception.

Topographic principles in the spinal projections of serotonergic and non-serotonergic brainstem neurons in the rat.

The spinal projections from the raphe-associated brainstem areas containing serotonergic neurons were studied with aldehyde-induced fluorescence in combination with the retrograde fluorescent tracer True Blue in the rat. This technique makes it possible to determine simultaneously the projections of individual neurons and to detect whether serotonin is present in the same neurons. After tracer injections into the spinal cord retrogradely labeled serotonergic and non-serotonergic neurons were found in the medullary raphe nuclei and adjacent regions and to a lesser extent in association with the dorsal and median raphe nuclei in the mesencephalon. Large True Blue injections that covered one side of the spinal cord at mid-cervical level labeled about 60% of the ipsilaterally situated serotonergic neurons in the medullary raphe regions while the corresponding figure contralaterally was about 25%. On both sides a larger number of labeled non-serotonergic neurons were found; these were sometimes located dorsal to, but often intermingled with, the serotonergic cells. While the serotonergic projection from the mesencephalon could not be labeled from injections below cervical levels, the labeling in more caudal brainstem regions exhibited only minor variations depending on the rostrocaudal level of the spinal segment injected. Furthermore, quantitative data from injections at different levels indicate that the majority of the spinal-projecting neurons traverse most of the length of the cord. Summarizing the results obtained from small injections restricted to subregions of the cord we feel that it is possible to distinguish three fairly distinct pathways for spinal projections from the medullary raphe and adjacent regions: The dorsal pathway originates mainly from cells in the caudal pons and rostral medulla oblongata (rostral part of nucleus raphe magnus, nucleus raphe magnus proper, nucleus reticularis gigantocellularis pars alpha and nucleus paragigantocellularis). This pathway, which contains a large non-serotonergic component, descends through the dorsal part of the lateral funiculus and terminates mainly in the dorsal horn at all spinal cord levels. The intermediate pathway is largely serotonergic with its cell bodies located within the arcuate cell group (situated just ventral and lateral to the pyramids very close to the ventral surface of the brainstem) and in the nucleus raphe obscurus and pallidus and terminates in the intermediate grey at thoracolumbar and upper sacral levels.(ABSTRACT TRUNCATED AT 400 WORDS)