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Biomedical subjects

L B Geffen

Publications and source records attributed to L B Geffen.

At least 37 records · Page 2Linked to original sources
PubMed1990

Galanin immunoreactive neurons in the human hypothalamus: colocalization with vasopressin-containing neurons.

Galanin (GA) is a recently described neuropeptide that has been demonstrated to be widely distributed in the hypothalamus of experimental animals. So far there is no immunohistochemical description of GA in the human hypothalamus and, in particular, no studies of the colocalization of this neuropeptide with other transmitter candidates in the human hypothalamus. We have now investigated this question immunohistochemically by using human brains fixed by vascular perfusion within 24 hours of death. Nerve cell bodies and fibers stained for GA were observed throughout the hypothalamus. Major populations of GA-ir cell bodies were found in the suprachiasmatic, intermediate, supraoptic, paraventricular, arcuate, tuberomammillary, and supramammillary nuclei. Scattered positive neurons were found in the periventricular preoptic area, the posterior hypothalamic nucleus, the lateral hypothalamic area, and zona incerta. A few positive cells were located in the dorsomedial and ventromedial hypothalamic nuclei. The number of GA-ir neurons estimated from three brains was 11,100 +/- 2,400 for the intermediate nucleus, 57,800 +/- 9,100 for the supraoptic nucleus and 47,400 +/- 13,900 for the paraventricular nucleus. GA-ir fibers were widely distributed in the hypothalamus. They were more dense in the periventricular and medial hypothalamic zones, whereas the lateral tuberal nuclei and the dorsolateral part of the supraoptic nucleus contained sparse positive fibers. The mammillary complex contained almost no GA-ir fibers. In the ventromedial tuberal region, GA-ir axons formed bundles travelling down in the infundibular stem. In the median eminence the vascular plexus was wrapped by GA-ir fiber networks. The coexistence of GA with arginine vasopressin (AVP), oxytocin (OXY), and tyrosine hydroxylase (TH) was examined in the supraoptic, paraventricular, and suprachiasmatic nuclei in adjacent paraffin sections. Neurons containing both GA and AVP were very common in the supraoptic nucleus and also occurred in the paraventricular and suprachiasmatic nuclei. The supraoptic and paraventricular nuclei also contained some neurons immunoreactive for both GA and OXY. Neurons positive for GA and TH were rare. The topographic distribution of GA-ir neuronal structures in the hypothalamus and the colocalization of GA, principally with AVP and to a lesser extent with OXY, in some hypothalamic nuclei constitute anatomical evidence that this neuropeptide may be involved in the regulation of endocrine, autonomic, and behavioural homeostatic responses.

Aged↗
PubMed1990

Loss of brainstem serotonin- and substance P-containing neurons in Parkinson's disease.

Using postmortem immunohistochemical analysis, we have identified degeneration of several different neuronal cell groups in the brainstem of patients dying with idiopathic Parkinson's disease. We report the first chemically identified loss of presumed serotonin neurons in the median raphe nucleus of the pons and of substance P-containing preganglionic neurons in the dorsal motor vagal nucleus. This evidence is concordant with other evidence that the primary neuropathological process is not confined either to a single pathway or to neurons containing a particular transmitter. Rather it appears that Parkinson's disease affects several classes of neurons in localized areas of the brainstem.

Antibodies, Monoclonal↗
PubMed1990

Neuropathology of immunohistochemically identified brainstem neurons in Parkinson's disease.

Regional loss of immunohistochemically identified neurons in serial sections through the brainstem of 4 patients with idiopathic Parkinson's disease was compared with equivalent sections from 4 age-matched control subjects. In the Parkinson brains, the catecholamine cell groups of the midbrain, pons, and medulla showed variable neuropathological changes. All dopaminergic nuclei were variably affected, but were most severely affected in the caudal, central substantia nigra. The pontine noradrenergic locus ceruleus showed variable degrees of degeneration. There was also a substantial loss of substance P-containing neurons in the pedunculopontine tegmental nucleus. However, the most severely affected cell group in the pons was the serotonin-synthesizing neurons in the median raphe. In the medulla, substantial neuronal loss was found in several diverse cell groups including the adrenaline-synthesizing and neuropeptide Y-containing neurons in the rostral ventrolateral medulla, the serotonin-synthesizing neurons in the raphe obscurus nucleus, the substance P-containing neurons in the lateral reticular formation, as well as the substance P-containing neurons in the dorsal motor vagal nucleus. Lewy bodies were present in immunohistochemically identified neurons in many of these regions, indicating that they were affected directly by the disease process. These widespread but region- and transmitter-specific changes help account for the diversity of motor, cognitive, and autonomic manifestations of Parkinson's disease.

Aged↗
PubMed1990

Covert orientation of visual attention in Parkinson's disease: an impairment in the maintenance of attention.

Covert orientation of attention was studied in a group of patients with idiopathic Parkinson's disease and compared to a matched control group using a cued reaction time task which measured disengagement, covert movement and engagement of attention. Parkinson patients had an increased response latency and disengaged from attended locations more readily than controls. This impairment in the maintenance of attention in Parkinson's disease was comparable to that produced in a previous study by pharmacological blockade of brain catecholamines in normal subjects. It is suggested that an impairment in the maintenance of oriented attention may underlie some of the cognitive deficits reported in Parkinson's disease.

Aged↗
PubMed1990

Substance P-containing neurons in the pontomesencephalic tegmentum of the human brain.

We have employed immunohistochemical and computerized morphometric procedures to study substance P-containing neurons in the tegmentum of adult humans. An estimated 192,500 +/- 40,500 substance P-containing neurons were found in three main cytoarchitectural regions: the mesencephalic reticular formation, the central gray, and the pontine reticular formation. The morphology of the immunoreactive neurons varied according to the region in which they were found. On the basis of size alone two types of substance P-containing neurons, large and small, were readily distinguishable by eye and measurement. Within each of the three main regions it was possible to distinguish distinct subgroups using cell size, morphology and position. Large neurons were concentrated in the caudal midbrain (pedunculopontine tegmental nuclei), in the oral pontine reticular nucleus and in the lateral dorsal tegmental nucleus. In contrast, small neurons were concentrated in the rostral mesencephalic reticular formation (cuniform nuclei). Both small and large neurons were found in the midbrain and pontine raphe nuclei. In addition, small neurons were concentrated in discrete midline regions (the periaqueductal gray, the tegmental nuclei of the pontine central gray, and the interpeduncular nucleus). The findings suggest that the majority of neurons in the brainstem tegmental nuclei previously identified as cholinergic also contain substance P in humans.

Aged↗
PubMed1989

Catecholamines and the covert orientation of attention in humans.

The role of brain catecholamines in covert orienting was tested in normal subjects using a cued reaction time paradigm which measures the directional engagement, disengagement and movement of attention. Droperidol and clonidine were administered intravenously to suppress central dopamine and noradrenaline transmission. Both drugs produced reductions in the cost of invalid cueing without change in the benefit of valid cueing suggesting that both noradrenaline and dopamine are involved in facilitating the disengagement of attention. These results are relevant to the slowed disengagement observed with parietal lesions in monkeys and humans since this region of the cortex associated with visuospatial analysis receives a dense innervation by both dopamine and noradrenaline projections in primates.

Adolescent↗
PubMed1988

Tyrosine hydroxylase-containing neurons in the supraoptic and paraventricular nuclei of the adult human.

We have studied the distribution of tyrosine hydroxylase-containing neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the adult human hypothalamus. Large numbers of these neurons were seen in these hypothalamic nuclei; approximately 40% of all the cells within the SON and PVN were immunoreactive for tyrosine hydroxylase (TH-ir). Most of these cells were magnocellular. Their distribution was compared to that of arginine-vasopressin-immunoreactive (AVP-ir) cells. In the SON a greater proportion of magnocellular TH-ir cells was found caudally compared to AVP-ir cells. In the PVN the magnocellular TH-ir cells were larger in mean diameter compared to AVP-ir cells. In double-immunofluorescence experiments some TH-ir cells contained oxytocin immunoreactivity but none contained AVP-ir. In the adult human a large number of PVN and SON magnocellular cells appear to synthesize a catecholamine. A subclass of these neurons also synthesize oxytocin but most cells are distinct from the classically described neurosecretory neurons.

Aged↗
PubMed1988

Distribution of monoamine-synthesizing neurons in the human medulla oblongata.

We have employed immunohistochemical and morphometric procedures to study the distribution of monoamine-synthesizing neurons in the medulla oblongata of the adult human, utilizing antibodies to tyrosine hydroxylase (TH), phenylethanolamine N-methyltransferase (PNMT), and phenylalanine hydroxylase (PH8). In the human brain, the antigen with which PH8 reacts occurs within neurons that presumably synthesize serotonin (Haan et al., '87). Neurons containing these antigens were mapped and counted in successive coronal sections with the aid of a computer-assisted procedure. The results indicate that monoamine-synthesizing neurons are distributed in the human brain in patterns broadly similar to those described for other species. TH-immunoreactive cells extended caudorostrally for approximately 32 mm commencing at the spinomedullary junction and ending 8 mm caudal to the pontomedullary junction. In coronal sections these TH-immunoreactive neurons were seen in the lateral medulla dorsal to the inferior olive extending in a continuous band to the dorsomedial medulla. Above the obex the majority of these cells apparently synthesize adrenaline since many PNMT-immunoreactive cells were also found in this region. There were few or no PNMT-immunoreactive cells caudal to the obex, indicating that the TH-immunoreactive cells in this region synthesize either noradrenaline or dopamine. Approximately 65% of these TH-immunoreactive neurons contained melanin pigment, whereas few or no PNMT-immunoreactive cells contained melanin pigment. PH8-immunoreactive cells extended throughout the rostrocaudal extent of the medulla oblongata (approximately 40 mm). In coronal sections the majority were found in the medullary raphe nuclei. However, many cells throughout the rostrocaudal extent of the medulla were found laterally intermingled with catecholamine-synthesizing neurons. Occasional neurons in the lateral medulla appeared to contain both PH8- and TH-immunoreactivity.

Aged↗
PubMed1988

Distribution of substance P-like immunoreactive neurons in the human medulla oblongata: co-localization with monoamine-synthesizing neurons.

The raphe nuclei also contained SP-like immunoreactivity (up to 30%) while few monoamine-synthesizing neurons in the lateral and dorsomedial medulla contained SP-like immunoreactivity (approximately 5% of presumed serotonin-, noradrenaline-, and adren- the adult human. The majority of SP-like immunoreactive neurons were found in four main regions: the lateral medulla, the dorsomedial medulla, the spinal trigeminal nucleus, and the raphe nuclei. The morphology of immunoreactive cells varied according to the region in which they were found. In contrast to previous studies, we found large numbers (90,000) of SP-like immunoreactive neurons throughout the adult human medulla oblongata. The distribution of these SP-like immunoreactive neurons appears to be significantly different from those described in the rat and cat. These results were compared to the distributions of monoamine-synthesizing and neuropeptide Y (NPY)-like immunoreactive neurons in the human medulla previously reported (Halliday et al.: Neuroscience, in press, 1988a; J. Comp. Neurol., in press, 1988b). Colocalization studies revealed that many presumed serotonin-synthesizing neurons in the raphe nuclei also contained SP-like immunoreactivity (up to 30%) while few monoamine-synthesizing neurons in the lateral and dorsomedial medulla contained SP-like immunoreactivity (approximately 5% of presumed serotonin-, noradrenaline-, and adrenaline-synthesizing neurons). The distributions of SP- and NPY-like immunoreactive neurons were similar, although SP-like immunoreactive neurons were concentrated in the lateral regions of the same structures. We have found that the distributions of monoamine-synthesizing, NPY-, and SP-like immunoreactive neurons significantly overlap, particularly in the lateral medulla of the adult human. There is a large increase in the number of these cells in this region compared to other species, emphasizing the neuroanatomical differences between humans and other species.

Aged↗
PubMed1988

Event-related potentials in autistic and healthy children on an auditory choice reaction time task.

Event-related potentials (ERPs) were recorded from midline (Fz, Cz, Pz) and lateral sites (F3, F4, P3, P4) in autistic children (n = 7) and age-matched controls (n = 9) on an auditory choice reaction time task. Subjects were asked to press a button to an infrequent target (500 Hz, P = 0.14) and to ignore higher pitched infrequent (2000 Hz, P = 0.14) and frequent (1000 Hz) non-targets. Autistic subjects made twice as many errors of omission as controls and showed a higher criterion (beta) for targets. Maximum ERP peak amplitudes showed a more varied scalp distribution in the autistic group. N1 latencies were consistently shorter in the autistic group and in 3 subjects the target P3 latencies were markedly longer than for the controls. Compared to controls, the N1 amplitude of the autistic response was larger to the rare stimuli (particularly to non-targets). The amplitude of the P3 component was smaller in the autistic group (particularly to the target). The stimuli were also presented in a passive condition requiring no response. After subtraction of the waveform obtained in the passive condition from that obtained in the active condition or subtraction of the waveform elicited by the rare non-target from that elicited by the target, N1 target amplitude was larger in control than in autistic children. Autistic subjects showed more early negativity to the rare non-target at left frontal and a larger P3 to the target at right parietal sites. ERPs of autistic children are more responsive to stimulus features (e.g. high/rare non-target tone) and less responsive to their associations or meaningfulness (e.g. target P3). Attention-related ERPs of autistic children show signs of precocious (right dominance for P3) and delayed development (P3 not maximal at parietal sites).

Adolescent↗
PubMed1988

The distribution of neuropeptide Y-like immunoreactive neurons in the human medulla oblongata.

We have described the distribution of neuropeptide Y-like immunoreactive neurons in the medulla oblongata of the adult human. The majority of neuropeptide Y-like immunoreactive cells were found in four regions of the medulla: the ventrolateral reticular formation, the dorsomedial medulla, the secondary sensory nuclei and the rostral raphe nuclei. The morphology of neuropeptide Y-like immunoreactive cells varied in each of these regions. In the ventrolateral reticular formation, the labelled neurons were round and pigmented caudal to the obex but elongated and non-pigmented rostral to the obex; in the dorsomedial medulla, they were triangular and pigmented caudal to but not rostral to the obex; in the secondary sensory nuclei, they were multipolar, non-pigmented and significantly smaller than in the other areas; in the rostral raphe nuclei, they were bipolar and non-pigmented. Colocalization studies revealed that many neuropeptide Y-like immunoreactive cells also synthesize monoamines, consistent with conclusions based on a quantitative comparison of their distributions. Neuropeptide Y-like immunoreactivity was present in about 25% of presumed noradrenaline-synthesizing cells in the caudal ventrolateral medulla (corresponding to the A1 region); about 50% of adrenaline- and 70% of presumed serotonin-synthesizing cells in the rostral ventrolateral medulla (C1 and B2-3 regions); 90-100% of presumed noradrenaline-synthesizing cells in the dorsomedial medulla at and above the obex (A2 region); about 50% of adrenaline-synthesizing cells in the rostral dorsomedial medulla (C2 region); about 5% of presumed serotonin-synthesizing cells in the rostral raphe nuclei (B2-3 region). The largest of these groups was the presumed serotonin-synthesizing cells that contained neuropeptide Y-like immunoreactivity in the rostral ventrolateral medulla. This is the first report of such a cell group in the medulla of any mammal, and emphasizes the neuroanatomical differences between humans and other species.

Aged↗
PubMed1987

Catecholamines and attention. I: Animal and clinical studies.

One important function of the catecholamine innervation of the cerebral cortex may be the control of attention. Of particular interest are the catecholamine projections to the cerebral cortex from the reticular formation, namely the dopamine neurons of the ventral tegmentum of the midbrain and the noradrenergic neurons of the locus coeruleus in the upper pons. Animal studies implicate noradrenaline and dopamine in a wide range of attention-related behaviours involving search and exploratory activity, distractibility, response rate, discriminability and the switching of attention. Most human studies come from the clinical literature relating to schizophrenia, Parkinson's disease and attention deficit disorder. An association has been claimed in each of these conditions between abnormal catecholamine activity (in particular dopamine) and attentional dysfunction. In particular, difficulty with the attachment of appropriate responses to environmental stimuli, akin to those observed in animals with lesions to central dopamine pathways, indicates a role for dopamine in response selection processes. Overall, the animal and human studies reviewed indicate a role for central noradrenaline and dopamine in the early and late processing of information, respectively.

Animals↗
PubMed1987

Catecholamines and attention. II: Pharmacological studies in normal humans.

Part I of this review [17] found evidence from animal and clinical studies of a role for catecholamines in the control of attention. This part of the review examines the results of a systematic study of the acute effects of a number of catecholamine active drugs on measures of attention in normal adults. The results are interpreted within the context of a general capacity model of information processing in which level of arousal determines the capacity to process stimulus information and level of activation the capacity for processing response demands. Whilst the dopamine antagonist, droperidol, and the alpha agonist, clonidine, had similar effects on behavioural indices of processing capacity and reports of the degree of effort required to carry out processing, they differentially affected subjective state and measures of activation and arousal. These differences provide some support for the hypothesis that central noradrenaline and dopamine modulate the capacity for early and late processing of information, respectively, in humans.

Adolescent↗
PubMed1986

Role of monoamine pathways in the control of attention: effects of droperidol and methylphenidate in normal adult humans.

Methylphenidate (0.65 mg/kg), droperidol (15 micrograms/kg) or placebo were administered to normal adult males undertaking a dichotic auditory attention task. Performance following placebo, as measured by the ability of subjects to detect nominated target words and discriminate them from phonemically distracting words, was superior when attention was focused on one ear than when divided between the ears. Following droperidol, target detection and discrimination were reduced for both divided and focused attention and in the latter case responses were also slowed. However, these effects were small compared to the striking withdrawn behaviour of the subjects, who reported an unwillingness to attend to external events. Methylphenidate reversed all of these effects when administered following droperidol. Administered alone, methylphenidate had no effect on dichotic measures of attention but had marked effects on spontaneous behaviour, when most subjects reported a substantial increase in both the field and distractibility of attention. These results are interpreted as implicating central dopaminergic pathways in the regulation of attention without precluding a role for other neurotransmitter systems including ascending noradrenaline and serotonin pathways to cerebral cortex. The disparity between these objective and subjective assessments of the effects of the drugs on attention is discussed in terms of the degree of mental effort voluntarily brought to bear by subjects in the selective allocation of their attentional capacity.

Adolescent↗
PubMed1986

Role of monoamine pathways in attention and effort: effects of clonidine and methylphenidate in normal adult humans.

Methylphenidate (0.65 mg/kg), clonidine (200 micrograms) or placebo were administered to normal adult males undertaking a dichotic monitoring task in which they were required to detect nominated target words and discriminate them from phonemic distractors. Following placebo, performance was better when attention was focused than when divided. Following clonidine, subjects were poorer and slower at discriminating targets during both divided and focused attention and subjectively were withdrawn and reported difficulties with concentration. Methylphenidate had no effect on target discrimination or response time but raised the rate of response and had marked effects on spontaneous behaviour in which an increased attention capacity was generally reported. The effects on attention of the pharmacological agents employed in this study are attributed to their effects on central monoamines. The disparity noted between objective and subjective assessments of attention is discussed in terms of the voluntary allocation of effort.

Adolescent↗
PubMed1981

Phentolamine increases neuronal binding and retrograde transport of dopamine beta-hydroxylase antibodies.

When 125I-labelled antibodies against dopamine beta-hydroxylase (DBH) were injected into the anterior eye chamber of guinea-pigs they bound to sympathetic nerve terminals, were internalized into the axons and retrogradely transported to the ipsilateral superior cervical ganglion (SCG). This process was demonstrated to depend on specific binding sites since neutralized antibodies were not taken up and transported. The alpha-receptor antagonist phentolamine caused a 2.5-fold increase in binding in the iris and a 2.1-fold increase in accumulation of [125I]anti-DBH in the SCG. The results demonstrate that retrograde axonal transport of synaptic vesicle components is coupled to their turnover in nerve terminals.

Afferent Pathways↗
PubMed1980

Dopamine beta-hydroxylase in health and disease.

DBH is a copper-containing oxygenase that catalyzes the hydroxylation of the beta carbon of a wide variety of phenylethylamine derivatives using molecular oxygen ascorbate as cofactors. It is a glycoprotein with a molecular weight of 290,000 and consists of four identical subunits, each with a single copper atom and 5% carbohydrate by weight. The enzyme is a constituent of catecholamine storage vesicles in chromaffin cell and adrenergic neurons in the peripheral and central nervous system where it functions to synthesize noradrenaline from dopamine. Although endogenous inhibitors have been isolated, they have not been demonstrated to have a physiological function, and the kinetics of the enzyme in vitro and in vivo suggest that the enzyme is not a rate limiting step in catecholamine synthesis under normal conditions. DBH exists in both a soluble form within vesicles and as a constituent of their membranes with its active site directed inward. The significance of the partition of the enzyme into soluble and membrane forms is not understood, although the soluble form has a fivefold greater homospecific activity. DBH has been one of the most intensively investigated enzymes in neurochemistry for several reasons. It is a readily assayable constitutent of catecholamine storage vesicles and, as such, provides a convenient biochemical marker for subcellular fractionation work and studies of the cellular regulation of catecholamine synthesis, storage, and release. The adrenal medulla is a rich source of the enzyme for purification, and the purified enzyme is highly antigenic, thereby enabling the use of several immunological techniques to study the cellular dynamics of the enzyme and the organelles in which it is located. These include radioimmunoassay, immunohistochemistry, and cytochemistry. This review firstly summarizes the present state of knowledge concerning the molecular properties of DBH. It then describes the tissue, cellular, and subcellular localization of the enzyme and its physiological regulation. The remainder of the review concentrates on those aspects of research on DBH in which the authors have participated that have led to general advances such as the development of the concept of homospecific activity, the introduction of immunohistochemistry for the localization of enzymes involved in transmitter metabolism, the release of macromolecules from synaptic vesicles during the process of exocytosis, the use of antibodies to DBH administered in vivo to study the fate of synaptic vesicle membranes and to produce specific immunological lesions of noradrenergic nerves in the peripheral and central nervous system, the genetic, environmental, and physiological determinants of serum DBH activity as an index of sympathetic function in animals and man, and the question of its diagnostic value in disease.

Animals↗