Long-term complications in adult spinal deformity patients having combined surgery a comparison of primary to revision patients.

STUDY DESIGN: This is a comparison of primary (N = 18) to revision (N = 26) combined (anterior and posterior surgery) adult spinal deformity patients with regard to late (>6 months) complications and radiographic/functional outcomes at a minimum 2-year follow-up. OBJECTIVES: To determine whether revision status increases the risk of late complications or offers a poor prognosis for functional outcome in adult deformity patients. SUMMARY OF BACKGROUND DATA: It is known that patients who have combined surgery for adult deformity have a high incidence of perioperative complications. Long-term complications and the effect of revision status have not been clarified in the literature. The functional outcomes for these patients are unclear as to whether or not there is a difference between primary and revision patients. Outside the arena of adult spinal deformity the functional outcomes for revision cases have been disappointing. METHODS: A consecutive series of 44 patients who underwent combined procedures for adult spinal deformity were followed for a minimum of 2 years (average follow-up 42 months). Clinical data were obtained by chart and radiographic review. Major complications were considered to be deep wound infection, pseudarthrosis, transition syndrome, neurologic deficit, and death. Minor complications considered were asymptomatic instrumentation failure (without loss of correction), instrumentation prominence requiring removal, and proximal or distal junctional segmental kyphosis (5-10 degrees ) or subsequent disc space narrowing of 2-5 mm without clinical symptoms. The patients also completed the AAOS Lumbar/Scoliosis MODEMS questionnaires aimed at assessing pain, function, and satisfaction. RESULTS: Minor complications were comparable in both groups: 4 of 18 (22%) in the primary group and 6 of 26 (23%) in the revision group. Major complications were slightly more frequent in the primary group with five complications in 4 patients (4 of 18 patients) (22%) compared with 3 of 26 patients (12%) in the revision group. The incidence of pseudarthrosis was 22% (4 of 18) for the primary group and 4% (1 of 26) for the revision group (P< 0.14). Forty of 44 patients completed the questionnaires. The primary patients functioned at a slightly higher level after surgery than the revision group. The level of pain was also slightly lower at final follow-up in the primary group. Despite these differences, the revision group had a higher level of patient satisfaction. CONCLUSION: At a minimum 2-year follow-up the late complications were not higher in the revision patients than in the primary group. The rate of major long-term complications, specifically pseudarthroses, was higher in the primary group. Patient satisfaction was higher in the revision patients, probably because they were experiencing a greater level of perceived pain and dysfunction at the time of their reconstruction.

The effect of variation in arm position on sagittal spinal alignment.

STUDY DESIGN: A prospective radiographic analysis of sagittal alignment in patients with and without previous spinal fusion. OBJECTIVES: To evaluate the effect of variation of arm position on the segmental, regional, and global sagittal radiographic spinal alignment. In addition, to determine whether spinal fusion has any influence on the effect of variation in arm position on the sagittal spinal alignment. SUMMARY OF BACKGROUND DATA: Importance of segmental, regional, and global sagittal alignment has been widely promoted. However, no mention has been made of arm positioning during a lateral spinal radiograph and the resultant effects it may have on sagittal alignment and balance. METHODS: Prospective evaluation of 40 consecutive patients with and 40 consecutive patients without a previous spinal fusion was performed. The patients had lateral long cassette radiographs performed in a standardized fashion with the first radiograph obtained with the patient's arms raised horizontally forward at 90 degrees of flexion at the shoulder, and the second radiograph obtained with arms raised horizontally forward at 30 degrees of flexion at the shoulder. Standard segmental, regional, and global sagittal alignments were measured and statistically compared. RESULTS: In comparing group 1 (patients with spinal fusion) to group 2 (patients without spinal fusion), there was no statistically significant difference in segmental and regional sagittal alignments. However, positioning the arms at 90 degrees versus 30 degrees resulted in a negative shift of the sagittal vertical axis (SVA) in patients that was statistically significant (P = 0.038) for those with (-6 mm at 90 degrees vs +4 mm at 30 degrees ), but not (P = 0.119) for those patients without (-8 mm at 90 degrees vs -4mm at 30 degrees ) a previous spinal fusion. CONCLUSIONS: Based on the findings in this study, the authors recommend positioning the arms at 30 degrees of forward flexion from the vertical when obtaining a long cassette lateral radiograph of the entire spine.

Comparison of push-prone and lateral-bending radiographs for predicting postoperative coronal alignment in thoracolumbar and lumbar scoliotic curves.

STUDY DESIGN: A comparative evaluation of supine right and left lateral-bending radiographs and push-prone radiographs in patients with thoracolumbar and lumbar scoliosis to determine postoperative correction of the curve. OBJECTIVES: To determine the difference in the ability of the push-prone radiograph and the supine lateral-bending radiograph to predict postoperative coronal alignment for primary thoracolumbar and lumbar curves managed with an anterior spinal instrumentation and fusion. SUMMARY OF BACKGROUND DATA: Right and left supine side-bending radiographs are the standard means of evaluating curve flexibility before surgery in idiopathic scoliosis. A push-prone radiograph also has been obtained at the authors' institution as a single dynamic radiographic assessment of forced correction of the primary curve and resultant effects on compensatory curves above and below the fusion. METHODS: Preoperative standing, supine right and left lateral-bending, and push-prone radiographs were performed in 40 patients who underwent anterior spinal instrumentation and fusion. Postoperative standing radiographs of the spine were obtained at 3 months after surgery. Measurements on all the radiographs included the coronal Cobb angle, the angle of the lowest instrumented vertebra to the horizontal, the rotation of the lowest instrumented vertebra, and the distance of the midpoint of the lowest instrumented vertebra from the center sacral line. RESULTS: The lateral-bending and the push-prone radiographs predicted less correction of the Cobb angle and the angle of the lowest instrumented vertebra to the horizontal than was achieved after surgery. However, the push-prone radiograph was superior to the lateral-bending radiograph in accurately predicting the postoperative correction of the rotation of the lowest instrumented vertebra as well as the translation of the lowest instrumented vertebra from the center sacral line. CONCLUSIONS: The push-prone and lateral-bending radiographs are similar in predicting less correction of the Cobb angle after anterior spinal surgery. The push-prone radiograph helps in determining the effects that correction of the primary curve has on the curves above and below the level of fusion by better predicting the translational correction of the lowest instrumented vertebra and the rotation of the lowest instrumented vertebra.

A prospective evaluation of pulmonary function in patients with adolescent idiopathic scoliosis relative to the surgical approach used for spinal arthrodesis.

STUDY DESIGN: A prospective evaluation of pulmonary function in patients with adolescent idiopathic scoliosis undergoing surgical correction. OBJECTIVES: 1) To evaluate prospectively, at regular intervals, the changes in pulmonary function after surgical arthrodesis of primary thoracic and double primary thoracic-lumbar (double major) types of adolescent idiopathic scoliosis in a homogeneous population; 2) to compare the changes in pulmonary function after surgical correction relative to the surgical approach used for spinal arthrodesis; and 3) to determine if short- to midterm morbidity with respect to pulmonary function is associated with the type of surgical approach used for spinal arthrodesis. SUMMARY OF BACKGROUND DATA: The effect of surgical correction on the pulmonary function of patients with adolescent idiopathic scoliosis is controversial. Studies have shown improvement, decline, or no change in pulmonary function after surgical correction of idiopathic scoliosis. METHODS: Ninety-eight patients with adolescent idiopathic scoliosis undergoing surgical treatment at the authors' institution were prospectively evaluated with pulmonary function tests assessing volume (forced vital capacity and total lung capacity) and flow (forced expiratory volume in 1 second). Pulmonary functions were evaluated before surgery and after surgery at 3 months, 1 year, 2 years, and at the final follow-up visit. All patients were divided into four groups depending on the surgical approach used for spinal fusion: Group 1 (n = 47) underwent a posterior spinal fusion with iliac crest bone graft; Group 2 (n = 33) underwent a posterior spinal fusion with rib resection thoracoplasty; Group 3 (n = 7) underwent an anterior spinal fusion with a rib resection thoracotomy; and Group 4 (n = 11) underwent a combined anterior and posterior spinal fusion with autogenous rib and iliac crest graft used, respectively. RESULTS: Patients in Group 1 had improved pulmonary function values at 3 months after surgery, whereas patients in Groups 2, 3, and 4 showed a decline at 3 months after surgery. Two years after surgery, Group 1 had significantly improved pulmonary function values (P < 0.0001), whereas the pulmonary function values of patients in Groups 2, 3, and 4 had returned to preoperative values. CONCLUSIONS: 1) Patients with chest cage disruption during surgical treatment showed a decline in pulmonary function at 3 months after surgery. 2) In contrast, patients without chest cage disruption showed an improvement in pulmonary function at 3 months after surgery. 3) Irrespective of the surgical approach used for spinal arthrodesis, postoperative pulmonary function tests (absolute values) returned to preoperative values at 2 years after surgery. 4) Patients who had no chest cage disruption experienced a significantly greater improvement in two of their pulmonary function values at 2 years after surgery than patients with chest cage disruption.

Complications in the adult spinal deformity patient having combined surgery. Does revision increase the risk?

STUDY DESIGN: A comparison of short-term complications (within 6 months after surgery) between primary combined adult spinal deformity (multilevel scoliosis, kyphosis, fixed coronal-sagittal imbalance) surgeries (n = 18) and combined adult spinal deformity revision surgeries (n = 26). OBJECTIVES: To analyze the short-term complications and to determine whether revision status increases the risks of short-term complications in this group of patients. SUMMARY OF BACKGROUND DATA: There is no peer-reviewed article comparing complications of revision to those in primary patients in a group of patients undergoing combined surgery for adult spinal deformity. METHODS: Major and minor complications were analyzed for both patient groups, and demographic data were collected. The demographic data of the two groups were very similar. RESULTS: The major (11.1% vs. 7.8%) and minor (11.1% vs. 11.5%) complications for the two groups (primary vs. revision) were very similar. All patients had combined procedures and all were patients with adult spinal deformity. The wound complications were less in those receiving total parenteral nutrition (2 of 31) than in those without (2 of 13). The group receiving parenteral nutrition was thought to be at higher risk for wound complications. CONCLUSIONS: The risk of major and minor complications within the first 6 months after surgery is not necessarily greater in the revision group than in the primary group of patients with adult spinal deformity who have combined surgeries. Total parenteral nutrition does appear to have a role in many of these patients.

Cholinergic basal forebrain projections to nitric oxide synthase-containing neurons in the rat cerebral cortex.

Stimulation of basal forebrain neurons elicits regional cerebral blood flow increases which are reportedly mediated by acetylcholine and nitric oxide. However, the modality of interaction between these two mediators remains unclear. Particularly, little is known about the source, i.e. endothelial, glial and/or neuronal, of the potent gaseous vasodilator nitric oxide. In the present study, we examined, by double immunocytochemical labelling of nitric oxide synthase and choline acteyltransferase at the light and electron microscopic level, the existence of morphological relationships between cortical nitric oxide synthase-containing neurons and cholinergic cells or nerve fibres. Using anterograde tract tracing and selective basal forebrain lesions, we further investigated the origin of the cholinergic input to cortical nitric oxide synthase neurons. The results confirm that cortical nitric oxide synthase-immunoreactive neurons are often associated with the local microvascular bed, show that intracortical neurons immunostained for nitric oxide synthase and choline acetyltransferase belong to two distinct neuronal populations and, further, that a subset of nitric oxide synthase-containing cell bodies and their proximal dendrites receive a cholinergic input which originates primarily from basalocortical projections. Altogether, these findings suggest that cholinergic basal forebrain neurons could increase cortical blood flow partly via a local nitric oxide relay neuron whereby the freely diffusing gas would be the direct smooth muscle vasodilator agent. It is concluded that this interaction might contribute to the complex relationships between the basal forebrain and the cortical microcirculation, interactions which result in fine regulation of cortical perfusion.

Pharmacological characterization of muscarinic acetylcholine binding sites in human and bovine cerebral microvessels.

The aim of this study was to investigate the presence of muscarinic receptors in human brain microvessels (MVs) and capillaries (CAPs) and, further, to pharmacologically characterize these receptors as well as those in bovine cerebral microvascular beds. For this purpose, the binding of [3H]N-methyl scopolamine ([3H]NMS) was assessed in isolated human and bovine cerebral MVs and CAPs and competition studies were performed against [3H]NMS binding with several well characterized muscarinic antagonists. The antagonist cerebrovascular affinity constants (pKD) were determined with the computer-fitting software LIGAND and then compared by correlation analyses to their reported affinities (pKi) at the five cloned muscarinic receptors. The specific binding of [3H]NMS to human and bovine MVs and CAPs was saturable, of high affinity and competitively inhibited by muscarinic antagonists. Heterogeneous populations of muscarinic binding sites were found in the microvascular tissues from both species. In human cortical MVs, the pharmacological binding profile obtained from various muscarinic receptor antagonists was best correlated to that of the cloned ml (r = 0.95; p < 0.001) and less so m5 (r = 0.77; p = 0.025) receptor subtypes while in bovine MVs, the presence of the m1 subtype was strongly suggested. Cerebrovascular affinities obtained for selected muscarinic antagonists in single preparations of human and bovine CAPs were suggestive of the presence of M1/m1 and M3/m3 receptor subtypes, and possibly the m5 subtype in bovine CAPs. The detection of M1/m1, M3/m3 and possibly m5 muscarinic receptor subtypes in brain microcirculation is consistent with reports where these receptors have been shown to mediate vasoconstriction, vasodilatation, and activation of nitric oxide synthase, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Cholinergic dilatation and constriction of feline cerebral blood vessels are mediated by stimulation of phosphoinositide metabolism via two different muscarinic receptor subtypes.

The muscarinic receptors involved in phosphoinositide (PI) hydrolysis have been pharmacologically characterized in cat cerebral blood vessels. Carbachol elicited a concentration-dependent increase in inositol phosphate accumulation [inositol monophosphate, bisphosphate, trisphosphate (IP3) and tetrakisphosphate] in both major cerebral arteries and small pial vessels, which reached 140-280% of baseline at 10(-3) M carbachol (referred to as maximal effect). However, the inositol phosphate accumulation response was found to be biphasic with a submaximal effect (30-50% of the maximal stimulation) obtained at low carbachol concentrations (< 10(-5) M). Endothelial denudation induced a virtual disappearance of the submaximal PI response without affecting that elicited by high concentrations of carbachol. The pharmacology of the two carbachol-induced PI responses was investigated by comparing the potency of selected muscarinic antagonists to block the IP3 accumulation induced by 10(-7) M (endothelium-dependent submaximal effect) and 10(-4) M (endothelium-independent near-maximal effect) carbachol. In both major arteries and pial vessels, the activation of IP3 production by 10(-4) M carbachol was similarly inhibited by muscarinic antagonists with the following averaged rank order of potency (in -log IC50): 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP; 8.65) > pirenzepine (8.28) > 6-chloro-5,10-dihydro-5-[(1-methyl-4-piperidinyl)acetyl]-11H- dibenzo[b,e][1,4]diazepine-11-one (UH-AH 371; 7.87) > 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,-11- dihydro-6H-pyridol[2,3-b][1,4]benzodiazepine-6-one (AF-DX 116; 6.62), a pharmacological profile compatible with an M1 receptor subtype.(ABSTRACT TRUNCATED AT 250 WORDS)

Nicotinic agonists modulate basal forebrain control of cortical cerebral blood flow in anesthetized rats.

Previous studies have indicated that electrical microstimulation of the cholinergic (basal forebrain, BF) elicits profound increases in cortical cerebral blood flow (CBF) that are selectively attenuated by nicotinic receptor antagonists. This study sought to determine whether nicotinic receptor agonists such as (-)-nicotine, and related agents, can enhance the increases in CBF elicited by electrical stimulation of the BF of urethane-anesthetized rats. The magnitude of cortical CBF responses, measured by laser-Doppler flowmetry, increased progressively with higher frequencies (range = 6.25-50 Hz) to a maximum of 248% of control. (-)-Nicotine and (-)-lobeline each further enhanced the responses to BF stimulation, with (-)-nicotine having the most potent effect (up to 350%). (+)-Nicotine and (-)-cotinine were without effect, suggesting stereoselectivity and that the effects were not mediated by the major metabolite of (-)-nicotine. In contrast, (-)-cystisine, another nicotinic receptor agonist, modestly inhibited the BF-elicited increase in CBF suggesting nicotinic receptor subtype selectivity in mediating the response. Arecoline, a potent muscarinic agonist, was without effect suggesting that muscarinic mechanisms are not involved in the mediation of this response. None of the nicotinic agents had overt effects on heart rate or blood pressure in the dose ranges examined. In experiments targeting the site of action of the nicotinically mediated enhancement, (-)-nicotine microinjections into the BF elicited profound increases in cortical CBF, whereas similar injections into the cerebral cortex were without effect suggesting that nicotine receptors mediating CBF increases are localized to the BF.(ABSTRACT TRUNCATED AT 250 WORDS)

Basal forebrain control of cortical cerebral blood flow is independent of local cortical neurons.

To determine whether intrinsic cortical neurons participate in mediating increases in cortical cerebral blood flow (CBF) in response to electrical stimulation of the basal forebrain (BF), cortical CBF was assessed by laser-Doppler flowmetry in rats before and after unilaterally removing local cortical neurons with the excitotoxin ibotenic acid (IBO). On the first day of testing, CBF responses to right and left BF stimulation were nearly identical in right and left frontal cortices, corresponding to the frequency of stimulation, up to a maximum at 25 Hz (+180%). Subsequently, animals received a unilateral microinjection of IBO and a contralateral microinjection of phosphate-buffered saline (PBS) into the responsive cortical sites. After five days, responses in lesioned cortices were remarkably intact both in comparison to the contralateral PBS-injected site and to the same site tested prior to lesioning on day 1. IBO lesions of the response sites were histologically confirmed to extend through the entire depth of the frontal cortex and to encompass a large surface area (7.7 +/- 0.5 mm2). These results indicate that local cortical neurons are not critical to the mediation of increases in cortical CBF as elicited by BF stimulation. This study further supports the role of the BF as a distinct intracerebral neurogenic regulator of cortical CBF.

Expression of mRNA for the serotonin 5-hydroxytryptamine1D beta receptor subtype in human and bovine cerebral arteries.

Serotonin [5-hydroxytryptamine (5-HT)] has been implicated in the pathophysiology of migraine, and the clinical efficacy of the 5-HT1B/5-HT1D receptor agonist sumatriptan points to neural and/or vascular 5-HT1D receptors as relevant targets in migraine therapy. We characterized the human and/or bovine 5-HT1D receptor subtype in cerebral blood vessels pharmacologically by correlation analysis and molecularly by Northern blot hybridization of cerebrovascular RNA extracts. Pharmacological analysis showed that sumatriptan was less potent than 5-HT in inducing contraction in freshly isolated human cerebral arteries and revealed an overall pharmacological profile positively and significantly correlated with that published for the 5-HT1D alpha (r = 0.746, p = 0.021) and 5-HT1D beta (r = 0.942, p = 0.0001) cloned human receptor subtypes. These results are suggestive of a contractile 5-HT1D beta receptor subtype but are not conclusive. However, Northern blots revealed the presence of mRNA transcripts for the 5-HT1D beta subtype, but not the 5-HT1D alpha subtype, in bovine (approximately 2.2 kilobases) and human (approximately 4.5 kilobases) cerebral blood vessels. Expression of either subtype could not be detected in intraparenchymal microvessels or capillaries isolated from bovine or human cerebral cortex. These results clearly indicate that the beneficial effect of sumatriptan in migraine attack, if vascularly related, is mediated by contractile 5-HT1D beta receptors most likely located on cerebral blood vessels at the surface of the brain. This study points to the 5-HT1D beta receptor subtype as the putative cerebrovascular target for migraine therapeutic agents.

Nitric oxide synthase is critical in mediating basal forebrain regulation of cortical cerebral circulation.

This study sought to determine whether the activity of nitric oxide synthase (NOS) is an important physiological link required to mediate increases in cortical cerebral blood flow (CBF) elicited by electrical microstimulation of the basal forebrain (BF). Changes in cortical CBF were assessed in urethane anesthetized rats using laser-Doppler flowmetry. Microstimulation of the BF elicited stimulus-locked increases in CBF that were dependent on frequency and current intensity (up to 280% of control at 50 Hz). Infusion of the potent NOS inhibitor NG-nitro-L-arginine (L-NNA) resulted in significant dose-related reductions in the BF-elicited response at 50 Hz (3.75-60 mg/kg, i.v.), significant elevation in resting mean arterial pressure (MAP) from 106 to 160 mmHg, and modest 21% reductions in resting CBF. The stereoisomer NG-nitro-D-arginine (D-NNA) was without any effect on CBF, although at higher concentrations MAP was elevated to levels comparable to those obtained with L-NNA. Infusion of arginase was also without effect on resting or BF-elicited CBF responses. In contrast, L-arginine (100-400 mg/kg, i.v.) significantly potentiated the BF-elicited response up to an additional 38%, without affecting resting CBF or MAP. This study suggests that NO, or a related nitroso precursor formed by NOS, has a critical role in mediating regulation of cortical CBF by BF neurons.

Genetic alterations in the 61st codon of the H-ras oncogene isolated from archival sections of hepatic hyperplasias, adenomas and carcinomas in control groups of B6C3F1 mouse bioassay studies conducted from 1979 to 1986.

In order to better understand the molecular events in murine hepatocarcinogenesis, the frequency and types of mutations in the murine H-ras proto-oncogene isolated from 184 independent, spontaneously occurring hepatic lesions were determined. Hepatocellular foci, hyperplasias, adenomas and carcinomas were obtained from archival samples of control male (134 samples) and female (50 samples) B6C3F1 mice used in oncogenicity studies that were conducted at Lilly Research Laboratories from 1979 to 1986. The 61st codon region of the H-ras oncogene from these sections was amplified using the polymerase chain reaction. Mutation frequencies were determined by restriction fragment length polymorphism analysis. The types of mutations were characterized by allele-specific oligonucleotide hybridization and confirmed by DNA sequencing. Forty-two per cent of the carcinomas, 44% of the adenomas, 42% of the hyperplasias and 29% of the foci contained mutations at the 61 codon. The mutation spectra for the carcinomas, adenomas and hyperplasias consisted of mostly CAA-AAA transversions, followed by CAA-CGA transitions, followed by CAA-CTA transversions. These results demonstrate that: (i) the frequency of spontaneous mutations in the H-ras 61st codon is equivalent in murine hyperplasias, adenomas and carcinomas, and (ii) sex was not a determining factor in either the mutation frequency or mutation spectrum for the spontaneous lesions. If these lesions represent successive stages in the carcinogenic process, then these results suggest that mutations in the 61st codon of H-ras are early events in spontaneous murine hepatocarcinogenesis.

Heptyl-physostigmine enhances basal forebrain control of cortical cerebral blood flow.

This study sought to determine the effect of heptylphysostigmine (H-PHY), a reversible cholinesterase (ChE) inhibitor with greater lipophilicity and longer duration of action than physostigmine, on resting and basal forebrain (BF)-elicited increases in cortical cerebral blood flow (CBF). Laser-doppler flowmetry (LDF) was used to monitor changes in frontal cortical microvascular perfusion in urethane anesthetized rats. Responses were measured before, early after, and 1 hr following H-PHY, 3 mg/kg, i.m. Electrical stimulation (100 microA) of the BF elicited up to 220% increases in CBF at 50 Hz, an effect that was graded with frequency. At 15 min following H-PHY (3 mg/kg) resting cortical CBF was unchanged, whereas BF-elicited increases were potentiated 47% at 50 Hz. At 1 hour, resting cortical CBF remained unchanged, and the BF-elicited responses were remarkably potentiated by 354% at 10 Hz and 67% at 50 Hz. Acetylcholinesterase (AChE) activity measured in the tissue directly beneath the LDF probe was decreased by 84% at a time when these CBF responses were enhanced. These data suggest that H-PHY substantially enhances the regulation of cortical CBF by the BF, an effect that may be linked to inhibition of cortical AChE activity. This enhancement of cortical CBF may contribute to the efficacy of H-PHY as a treatment for Alzheimer's disease.

Cortical cerebral blood flow governed by the basal forebrain: age-related impairments.

This study sought to compare resting and evoked increases in cortical microvascular perfusion elicited by electrical microstimulation of the basal forebrain (BF) in young (4-6 months) and aged (22-26 months) Sprague-Dawley rats. Regional cerebral blood flow (rCBF) was measured in chloralose-anesthetized rats for twelve bilateral regions using 14C-iodoantipyrine with regional brain dissection, while second-to-second changes in tissue perfusion were concurrently assessed using laser-doppler flowmetry (LDF). In young animals, BF stimulation elicited significant ipsilateral increases in CBF in parietal (+123%) and frontal (+107%) cortices, caudate nucleus (+63%) and thalamus (+59%) (p less than 0.05). The BF-elicited increases were preserved in frontal cortex and thalamus, but not in parietal cortex or caudate nucleus of aged animals. No frequency- or current-specific attenuations were observed in the spared frontal cortex of aged animals. However, there was a significant (+70%) age-related increase in the latency to reach maximal blood flow increases (p less than 0.05), without any change in the total time of increased blood flow. These findings support the hypothesis that cortical CBF is in part governed by BF neurons, and suggest that regionally selective, age-related impairments of cortical coupling of neuronal to dynamic vascular responses exist. It remains to be determined whether the mechanism of this impairment relates to an age-related impairment in coupling of blood flow and metabolism.

Cholinergic influences on wall climbing and its ontogenetic decline.

Wall climbing is an age-specific behavior that is robustly elicited in rat pups during the 2nd postnatal week, but not thereafter, by a variety of stimuli including footshock and treatment with catecholamine agonists such as clonidine. This series of experiments examined the influence of the cholinergic antagonist scopolamine on footshock- and clonidine-induced wall climbing and its ontogenetic decline in infant to adult Sprague-Dawley rats. Scopolamine was observed to partially reinstate clonidine- and footshock-precipitated wall climbing following the ontogenetic decline in this behavior pattern after the 2nd postnatal week, effects that did not appear to be related to drug-induced alterations in general activity levels or to alterations in body temperature. In contrast, wall climbing induced by both stimuli during the 2nd postnatal week was conversely reduced by scopolamine, data consistent with a number of previous reports that anticholinergic agents may produce "paradoxical" responses early in development opposite to those observed later in ontogeny. These results provide evidence that the dramatic ontogenetic decline in wall climbing may be related in part to the maturation of cholinergic subsystems with an inhibitory influence on this behavior pattern. However, the only partial reinstatement of wall climbing by cholinergic blockade suggests that the ontogenetic decline of this behavior pattern may also be related to the development of other inhibitory systems or to the emergence of competing responses elicited by formerly effective wall climbing stimuli as the organism matures.

GABA and behavioral inhibition in the neonatal rat pup.

The effects of the GABA agonist muscimol and GABA antagonist picrotoxin were examined in 3-4-day-old deprived rat pups under conditions of low (absence of milk) and high (milk presence) activity baselines. A low dose of muscimol was observed to have activating effects under low baseline conditions, whereas higher doses of muscimol were observed to depress milk-induced activity and mouthing. Picrotoxin treatment was observed to increase activation of these neonates under both baseline conditions. Taken together, these results provide evidence for a functional GABAergic inhibition of behavior in the neonate.

Age-specific behaviors as tools for examining teratogen-induced neural alterations.

One approach to evaluate the impact of chemical insults during development is to examine teratogen-induced alterations in age-specific behaviors that appear to be modulated by activity of specific neurotransmitter systems. A number of age-specific behaviors appear to be useful candidates for neurobehavioral assessment batteries. During the first postnatal week, mouthing in numerous situations appears to be strongly related to serotonergic activity. Footshock- or pharmacologically-precipitated wall climbing behavior, which is seen specifically during the second postnatal week in rat pups, seems to be related to noradrenergic, and perhaps dopaminergic, activity. The rapid ontogenetic decline in wall climbing seen after the second postnatal week may be in part related to the maturation of a cholinergic inhibitory influence on this behavior pattern. The periadolescent period, an age associated in rats with a number of age-specific alterations in behavior and psychopharmacological responsivity, appears to be associated with age-related alterations in dopaminergic activity. Examination of teratogen-induced alterations in age-specific behaviors such as these may provide useful early markers of the neural substrates potentially affected by early insults.