The effect of MLC speed and acceleration on the plan delivery accuracy of VMAT.

OBJECTIVE: To determine a new metric utilizing multileaf collimator (MLC) speeds and accelerations to predict plan delivery accuracy of volumetric modulated arc therapy (VMAT). METHODS: To verify VMAT delivery accuracy, gamma evaluations, analysis of mechanical parameter difference between plans and log files, and analysis of changes in dose-volumetric parameters between plans and plans reconstructed with log files were performed with 40 VMAT plans. The average proportion of leaf speeds ranging from l to h cm s(-1) (Sl-h and l-h = 0-0.4, 0.4-0.8, 0.8-1.2, 1.2-1.6 and 1.6-2.0), mean and standard deviation of MLC speeds were calculated for each VMAT plan. The same was carried out for accelerations in centimetre per second squared (Al-h and l-h = 0-4, 4-8, 8-12, 12-16 and 16-20). The correlations of those indicators to plan delivery accuracy were analysed with Spearman's correlation coefficient (rs). RESULTS: The S1.2-1.6 and mean acceleration of MLCs showed generally higher correlations to plan delivery accuracy than did others. The highest rs values were observed between S1.2-1.6 and global 1%/2 mm (rs = -0.698 with p < 0.001) as well as mean acceleration and global 1%/2 mm (rs = -0.650 with p < 0.001). As the proportion of MLC speeds and accelerations >0.4 and 4 cm s(-2) increased, the plan delivery accuracy of VMAT decreased. CONCLUSION: The variations in MLC speeds and accelerations showed considerable correlations to VMAT delivery accuracy. ADVANCES IN KNOWLEDGE: As the MLC speeds and accelerations increased, VMAT delivery accuracy reduced.

Evaluation of a commercial orthopaedic metal artefact reduction tool in radiation therapy of patients with head and neck cancer.

OBJECTIVE: To assess the image quality and dosimetric effects of the Philips orthopaedic metal artefact reduction (OMAR) (Philips Healthcare System, Cleveland, OH) function for reducing metal artefacts on CT images of head and neck (H&N) patients. METHODS: 11 patients and a custom-built phantom with metal bead inserts (alumina, titanium, zirconia and chrome) were scanned. The image was reconstructed in two ways: with and without OMAR (OMAR and non-OMAR image). The mean and standard deviation values of CT Hounsfield unit (HU) for selected regions of interest of each case were investigated for both images. Volumetric modulated arc therapy plans were generated for all cases. Gamma analysis of each dose distribution pair in the patient (1%/1 mm criteria) and phantom (2%/2 mm and 3%/3 mm criteria) images was performed. The film measurements in phantom for two metal beads were conducted for evaluating the calculated dose on both OMAR and non-OMAR images. RESULTS: In the OMAR images, noise values were generally reduced, and the mean HU became closer to the reference value (measured from patients without metal implants) in both patient and phantom cases. Although dosimetric difference was insignificant for the eight closed-mouth patients (γ = 99.4 ± 0.5%), there was a large discrepancy in dosimetric calculation between OMAR and non-OMAR images for the three opened-mouth patients (γ = 91.1%, 94.8% and 96.6%). Moreover, the calculated dose on the OMAR image is closer to the real delivered dose on a radiochromic film than was the dose from the non-OMAR image. CONCLUSION: The OMAR algorithm increases the accuracy of CT HU and reduces the noise such that the entire radiation treatment planning process can be improved, especially for contouring and segmentation. ADVANCES IN KNOWLEDGE: OMAR reconstruction is appropriate for the radiotherapy planning process of H&N patients, particularly of patients who use a bite block.

Effects of ibogaine on acute signs of morphine withdrawal in rats: independence from tremor.

Because of the claim that ibogaine suppresses the symptoms of "narcotic withdrawal" in humans, the effect of ibogaine on naltrexone-precipitated withdrawal signs in morphine-dependent rats was assessed. Morphine was administered subcutaneously through implanted silicone reservoirs for 5 days. Ibogaine (20, 40 or 80 mg/kg, i.p.) or saline was administered 30 min prior to challenge with naltrexone (1 mg/kg, i.p.) and withdrawal signs were counted for the following 2 hr. Ibogaine (40 and 80 mg/kg) significantly reduced the occurrence of four signs (wet-dog shakes, grooming, teeth chattering and diarrhea) during naltrexone-precipitated withdrawal; three other signs (weight loss, burying and flinching) were unaffected. Ibogaine induces head and body tremors lasting for 2-3 hr and the tremors might have interfered with the expression of opioid withdrawal. To examine this issue, another experiment was conducted in which ibogaine (40 mg/kg) or saline was administered 4 hr prior to challenge with naltrexone. Although there was a complete absence of tremors, ibogaine still significantly reduced the occurrence of the same four signs of withdrawal.

Differential immune responses in mice with left- and right-turning preference.

Humoral and cell-mediated immune responses of inbred BALB/c male mice were assayed for differential reactivities associated with behavioral sidedness, which was evaluated by spontaneous rotational behavior in a circular cage model system. Mice with left-turning preference had lower in vivo primary IgM and IgG anti-Keyhole Limpet Hemocyanin (KLH) antibody responses, delayed-type hypersensitivity (DTH) responses, and host-resistance against the intracellular bacteria, Listeria monocytogenes, than mice with right-turning preference. The only immune parameter not shown to be associated with turning preference was the secondary humoral immune response to KLH. The weak innate immune response of left-turners for clearance of Listeria showed close intercorrelation with elevated serum IL-6 levels. Serum corticosterone and splenic norepinephrine levels were differentially increased and decreased by infection, respectively. We suggest that the observed differential immune reactivities of individual animals with same age, gender, and genetic background are associated with functional asymmetries within the brain, that the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic innervation are involved in the regulatory brain: immune interconnection after infection, and that the HPA axis and sympathetic nervous system are involved in the brain laterality effects on immune responses.

Exposure to low doses of the environmental chemical dieldrin causes behavioral deficits in animals prevented from coping with stress.

Experiments were conducted which assessed the effects of low doses of an environmental contaminant in conjunction with various forms of stress. Rats were given acute doses (0, 0.5, 1.5, 4.5 mg/kg) of the chemical dieldrin and subsequently exposed to a series of 40 escapable shocks, identical inescapable shocks, or no shock in an operant chamber. Eight hours later, the subjects were re-exposed in a shuttlebox to footshock which was escapable upon performance of an FR-2 shuttle response. Escape deficits which were related in magnitude to the size of the dieldrin dose were found in the inescapable shock group but not in the escapable shock or no shock groups. The data suggest that experience with the lack of control over stress is critical in determining the behavioral effects of the agent and that the behavioral effects caused by uncontrollable stress may be exacerbated by concurrent exposure to such compounds. These results are discussed in terms of previous studies on the behavioral actions of dieldrin, the response to uncontrollable stress and the common neuronal systems that may be involved.

Dose-dependent and baseline-dependent conditioning with d-amphetamine in the place conditioning paradigm.

The place conditioning paradigm was used to evaluate the positively reinforcing effects of d-amphetamine. During conditioning, female rats were injected (IP) with saline or one of five doses (0.625-5 mg/kg) of d-amphetamine (d-A) and confined to the initially non-preferred side of the testing apparatus. The highest dose of d-A failed to produce a significant preference. The four middle doses of the drug induced a similar preference. A significant increase from baseline was observed on the 4th post-conditioning test day in the five drug groups and controls when given an injection of 1.5 mg/kg d-A 15 min prior to placement in the chamber. Control and drug groups were separated into high and low initial preference sub-groups. Place preferences were more readily induced by d-A in the subgroups with initially high baseline preferences. These findings as well as those of others led us to conclude that the place conditioning paradigm is a somewhat problematic way of measuring drug reinforcement and that the effects observed may not solely be the result of the conditioning of the drug's reinforcing properties to a particular environment.

Food deprivation and stimulant self-administration in rats: differences between cocaine and d-amphetamine.

The effects of food deprivation (24 h) on response rates of rats self-administering d-amphetamine and cocaine were compared. Food deprivation clearly increased rates of responding for both drugs but did so to a significantly greater extent for cocaine than for d-amphetamine. Consistent with other findings, the results suggest that the neural substrates underlying cocaine and d-amphetamine reinforcement are not identical.

Regional changes in brain dopamine and serotonin metabolism induced by conditioned circling in rats: effects of water deprivation, learning and individual differences in asymmetry.

Rats were trained, using water reinforcement, to turn in circles (rotation) during 1 h daily test sessions. After achieving criterion performance (100 full turns per hour) for at least 10 consecutive sessions, rats were sacrificed 20 min after starting a session and levels of dopamine, DOPAC (3,4-dihydroxyphenylacetic acid), serotonin, and 5-HIAA (5-hydroxyindoleacetic acid) were assayed in nigrostriatal (corpus striatum), mesolimbic (nucleus accumbens) and mesocortical (medial prefrontal cortex) brain regions. Other control groups of rats were comparably water deprived or satiated at the time of sacrifice. Although, as previously reported, evidence of 'two populations' of rats was again apparent with respect to the relationship between direction of spontaneous turning and asymmetry in striatal dopamine levels, there were no lateralized effects of operant rotational training on striatal dopamine and DOPAC levels nor on the DOPAC/dopamine ratio. There were, however, bilateral neurochemical effects of both rotational training and water deprivation in striatum: an increase in the 5-HIAA/serotonin ratio in both sexes was attributable to learning whereas an increase in the DOPAC/dopamine ratio in males was attributed to water deprivation. A bilateral decrease in the DOPAC/dopamine ratio in the mesolimbic and mesocortical regions of both sexes was also induced by water deprivation. The only lateralized neurochemical changes associated with learning to rotate in the operant task occurred in the medial prefrontal cortex: in both sexes, dopamine levels were higher in the ipsilateral than in the contralateral cortex and the DOPAC/dopamine ratio was greater in the contralateral than in the ipsilateral cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain laterality as a determinant of susceptibility to depression in an animal model.

Rats exposed to stressors that cannot be controlled may develop a deficit in their ability to subsequently learn to control a new stressor. This phenomenon is known as 'learned helplessness' and is a well-accepted animal model of depression. Evidence is presented showing that rats having different directional biases of brain laterality, as indicated in tests of rotational behavior, differ greatly in their response to stressors and to the lack of stressor control. Differences in brain laterality appear to be an important source of variability within the animal model of depression. As with humans, only some rats are vulnerable to depression-like symptoms. These findings are relevant to biological theories of depression that are based upon lateralized specialization of the human brain for affect.

Selective enhancement of dopamine utilization in the rat prefrontal cortex by food deprivation.

Previous studies have indicated that food deprivation exerts various effects on brain neurotransmitters and that mild stress causes a selective enhancement of dopamine activity in the rat medial prefrontal cortex. In the present study it was found that in rats 24 h of food deprivation produced an increase in levels of the dopamine metabolite 3,4-dihydroxyphenylacetic acid in the medial prefrontal cortex but not in the nucleus accumbens or caudate-putamen. This selective increase in mesocortical dopamine activity is comparable to that found with mild footshock stress exposure and indicates that food deprivation may function as a stressor.

Basal and amphetamine-induced asymmetries in striatal dopamine release and metabolism: bilateral in vivo microdialysis in normal rats.

In vivo microdialysis was used to monitor bilaterally the release of dopamine and its metabolites 3,4-dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid (HVA) in the striata of both anesthetized and awake, freely moving female rats. Under baseline conditions, an asymmetry in dopamine release was reciprocally related to an asymmetry in DOPAC. Baseline dopamine and DOPAC asymmetries were predictive of the preferred direction of amphetamine-induced rotation: the striatum having higher dopamine and lower DOPAC was contralateral to the preferred direction of rotation. Amphetamine (D-amphetamine sulfate, 1.25 mg/kg) enhanced dopamine release and decreased DOPAC and HVA; the increase in dopamine was greater in the ipsilateral striatum. Effects in anesthetized and awake rats were similar. Variations in rotation and in the dopamine asymmetry after amphetamine were correlated across time within individual awake rats.

Food deprivation alters dopamine utilization in the rat prefrontal cortex and asymmetrically alters amphetamine-induced rotational behavior.

The effects of 24 and 48 h of food deprivation on changes in the activity of dopaminergic (DAergic) neurons and D-amphetamine-induced rotational behavior were studied in male and female Long-Evans rats. Food deprivation selectively altered 3,4-dihydroxyphenylacetic acid (DOPAC) in the medial prefrontal cortex (PFC) but not in the nucleus accumbens or striatum: PFC DOPAC was significantly increased and decreased bilaterally after 24 and 48 h of food deprivation, respectively. Left greater than right hemispheric asymmetries were seen for DOPAC and DOPAC/DA in the control animals. In a separate experiment, 24 h of food deprivation enhanced right rotational behavior, while 48 h significantly increased left rotational behavior. The results are discussed in terms of food deprivation's effects on mesocortical DAergic neurons, previous work on cortical modulation of striatal function and how these effects on rotational behavior may be determined by brain asymmetry.

Effects of prenatal cocaine exposure on the mesocorticolimbic dopamine system: an in vivo microdialysis study in the rat.

Microdialysis studies were conducted on prenatally saline-treated and prenatally cocaine-treated rats, either as pups (10-30 days old) or young adults (40-190 days old), to study the effects of prenatal cocaine exposure on the mesolimbic dopamine (DA) system. In the n. accumbens of saline-treated rats, basal dialysate concentrations of DA were similar in pups and adults; however, the levels of DA metabolites, DOPAC, HVA, and the serotonin metabolite, 5-HIAA, were markedly lower in pups. In pups, prenatal cocaine exposure led to basal dialysate levels of DA in the n. accumbens that were twice control levels; however, there was no difference in response to a period of intermittent tail pinch or an acute injection of cocaine (20 mg/kg). In the adult, basal levels of DA, DOPAC, HVA and 5-HIAA in n. accumbens did not differ across prenatal treatments. However, in prenatally cocaine-treated adults a cocaine injection led to an enhanced rise in extracellular DA compared to controls. In frontal cortex of adult rats, basal levels of DA, DOPAC and HVA did not differ across prenatal treatments; however, basal levels of 5-HIAA in this region were significantly elevated in prenatal-cocaine rats. No group differences were observed in the frontal cortex in response to either tail pinch or cocaine. Thus prenatal cocaine exposure produces an increase in basal extracellular DA in the n. accumbens of pups which returns to normal with aging. While this initial difference normalizes, prenatal cocaine exposure induces other persistent changes in adulthood.

Left and right 6-hydroxydopamine lesions of the medial prefrontal cortex differentially alter subcortical dopamine utilization and the behavioral response to stress.

The effects of left and right prefrontal cortical dopamine (DA) depletion on circling behavior, stress-escape behavior and subcortical DA function were examined in rats exhibiting left or right turning biases. 6-Hydroxydopamine lesions of the medial prefrontal cortex (PFC) caused significant DA depletions when assessed in separate studies at 3 days and 3-4 weeks. However, depletions were smaller at 3-4 weeks and there was a significant increase in DA concentration on the left side following right lesions. Significant increases in striatal DA content were observed following lesions of either side at 3-4 weeks, but not at 3 days. No changes in DA concentration were observed in the nucleus accumbens septi (NAS). Left circling rats significantly increased their circling behavior following right sided lesions and showed disrupted footshock-escape behavior following left sided lesions. Performance of the footshock-escape task exerted an effect on striatal and NAS DA utilization as indicated by the ratio of 3,4-dihydroxyphenylacetic acid (DOPAC) to DA. The effects of footshock on NAS DA utilization were greater following left PFC lesions as compared to the right lesion and sham conditions. These lesion effects were also greater in left- than in right-turning animals. The data indicate that an intrinsic asymmetry in brain DA systems interacts with left and right PFC lesions to differentially determine subcortical DA function and behaviors that it subserves.

Chronic antidepressant drug treatment reduces turning behavior and increases dopamine levels in the medial prefrontal cortex.

The effects of chronic administration of the antidepressant drugs desipramine, nortryptiline and paroxetine (PAR) (10 mg/kg/day, 21 days) on changes in turning (circling) behavior and on norepinephrine (NE), dopamine (DA) and serotonin and their metabolites 3,4-dihydroxyphenylacetic acid and 5-hydroxyindole acetic acid (5-HIAA) in the medial prefrontal cortex (PFC), nucleus accumbens and striatum were evaluated in rats. All three drugs eliminated turning biases in right turning rats. All drugs increased DA concentrations in the PFC while PAR increased NE in the PFC and reduced 5-HIAA in all three structures. The results are discussed with reference to previous findings involving brain asymmetry in depression.

Effects of prenatal cocaine exposure on the nigrostriatal dopamine system: an in vivo microdialysis study in the rat.

Pregnant rats were given injections of saline (0.5 ml/kg) or cocaine (10 mg/kg, 20 mg/ml, s.c.) twice daily between gestational days 7-21. Offspring were examined by microdialysis between postnatal days 10-125 to study the effects of prenatal cocaine exposure on the nigrostriatal dopamine (DA) system. Twenty-min dialysis samples were collected and assayed for DA, DOPAC and HVA. After four baseline samples, the rat was exposed to 20 min of intermittent tail pinch and monitored for four samples; then each rat received an acute injection of cocaine (20 mg/kg, i.p.) and six additional samples were collected. Basal dialysate concentrations of all DA markers, estimated from pre-implantation calibration of the probes, were markedly reduced in young rats ('pups', 10-30 days old) as compared with adult rats (40-125 days old). Compared to control pups, basal DA, as well as DOPAC and HVA, were elevated in the prenatal-cocaine pups. Tail pinch (a mild stressor) produced a significant increase in DA only in the pups prenatally exposed to cocaine. The increase in basal DA induced by an acute cocaine injection (20 mg/kg) was also greater and more prolonged in the prenatal-cocaine pups. In older rats (40-125 days) there were no group differences in any of the DA parameters. Thus prenatal exposure to cocaine produces an activation of the DA system which persists after birth but returns to normal in older rats.

Side and region dependent changes in dopamine activation with various durations of restraint stress.

Exposure to various mild stressors has been shown to result in the activation of dopamine containing neuronal systems projecting to the medial prefrontal cortex (PFC), to a lesser extent the nucleus accumbens septi/olfactory tubercle (NAS) and, in a few studies, the striatum. It has also been shown that dopamine (DA) systems on different sides of the PFC are successively activated as stressors are prolonged. We have therefore examined the effects of variation in the duration of a restraint stressor (15, 30 and 60 min) on region and side dependent alterations in DA utilization in the PFC, NAS and striatum. Increases in the concentrations of the DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and/or homovanillic acid (HVA) or in their ratios with DA were seen in all regions examined with the largest effects occurring in the PFC and lesser effects in the NAS and striatum. In each region, the magnitude of these effects varied with time of restraint exposure. In the PFC, lateralized alterations in HVA and DA were seen over time with effects progressing from a left greater than right involvement at 15 min to a right greater than left involvement at 60 min. These results are discussed with reference to side and region dependent effects on brain DA systems as stressors are prolonged and the implications they may have for lateralized regional brain activity associated with stressor precipitated psychiatric disease.

Neurochemical predisposition to self-administer morphine in rats.

Using in vivo microdialysis, this study attempted to determine whether a neurochemical predisposition to self-administer morphine could be identified. Extracellular levels of dopamine and its metabolites were measured bilaterally in the mesocorticolimbic and nigrostriatal systems of naive rats that were subsequently trained to self-administer morphine intravenously. There were several significant relationships between dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels and rates of morphine self-administration during both acquisition and asymptotic phases of testing. DOPAC and HVA levels in the striatum were inversely correlated with self-administration rates during the asymptotic phase whereas hemispheric asymmetries in striatal metabolite levels were inversely correlated with self-administration during the acquisition phase. DOPAC and HVA levels in in the right but not in the left side of the medial prefrontal cortex were positively correlated with self-administration rates during the acquisition phase; right/left asymmetries in cortical metabolite levels were also correlated with acquisition rates. There were no significant relationships between neurochemical indices and rates of bar-pressing for water. These results suggest that the normal variability in drug seeking behavior is at least in part attributable to individual differences in the organization and activity of brain dopamine systems. Furthermore, different mechanisms appear to be responsible for the initiation and maintenance of morphine intake: DA release in the nucleus accumbens appears to be a critical component of both mechanisms; DA release in the striatum appears to modulate maintenance and, in relationship to striatal lateralization, modulate initiation; DA release in the right but not in the left medial prefrontal cortex appears to be an important predictor of initiation.

Lateralized changes in prefrontal cortical dopamine activity induced by controllable and uncontrollable stress in the rat.

Exposure to stressors that are not controlled results in a variety of changes in behavior and in brain chemistry. Among these is the activation of dopamine-containing neuronal systems projecting to the medial prefrontal cortex (PFC), to a lesser extent the nucleus accumbens (NAC) and, in a few studies, the striatum. Previous data have shown that stressor evoked PFC activation is asymmetrical. The present experiments were designed to assess the effects of controlled and uncontrolled stressors on these DA systems using the procedures of the learned helplessness (LH) model. In a first experiment, 80 trials of either a controllable (ESC) or identical uncontrollable footshock stressor (YOK) caused an activation, as indicated by increased metabolite concentrations of DA in the PFC, NAC and striatum. In the PFC, YOK caused a bilateral DA depletion, relative to ESC and control animals, and a right > left increase in DOPAC/DA which was not seen in ESC animals. These findings suggested a preferential effect of YOK in the right PFC. A second experiment used rats that had been grouped according to their turning behavior, YOK right-biased rats showed an increase in DOPAC on the right side of the PFC and YOK left-biased rats displayed a similar increase on the left side in response to a brief (5 min) controllable footshock stressor. Since right-turning rats had been shown to be more sensitive to a LH behavioral phenomenon, the data suggested that right PFC activation is responsible for the greater LH sensitivity. A final experiment evaluated the neurochemical and behavioral responses to a prolonged footshock stressor 24 h after uncontrolled footshock. Right-biased YOK animals displayed depressed footshock escape behavior and a right > left depletion in PFC DA and HVA. Across-groups footshock escape performance was correlated with DA and HVA concentrations on the right but not on the left side of the PFC. Thus a disturbance of right PFC DA utilization was again associated with compromised coping behavior. The data suggest that the inability to control a stressor causes a lateralized alteration of PFC DA and this results in a disruption of the ability to respond to a new stressor. These findings indicate that the two sides of the PFC are differentially specialized for responding to a stressor.

Neurochemical predisposition to self-administer cocaine in rats: individual differences in dopamine and its metabolites.

Using in vivo microdialysis, this study attempted to determine whether a neurochemical predisposition to self-administer cocaine could be identified. Estimated extracellular levels of dopamine and its metabolites were measured bilaterally in the mesocorticolimbic and nigrostriatal systems of naive rats that were subsequently trained to self-administer cocaine intravenously. There were several significant relationships between dopamine and dopamine metabolite (3,4-dihydroxyphenylacetic acid and homovanillic acid) levels and rates of cocaine self-administration during both acquisition and asymptotic phases of testing. Dopamine levels in the nucleus accumbens were non-monotonically related to rates of self-administration during both phases: low to moderate dopamine levels were positively correlated with self-administration rates whereas moderate to high dopamine levels were negative correlated with self-administration rates. Dopamine, DOPAC (3,4-dihydroxyphenylacetic acid) and HVA (homovanillic acid) levels in the striatum were inversely correlated with self-administration rates during the acquisition phase. DOPAC and HVA levels in the left and right sides of the medial prefrontal cortex were positively and negatively correlated, respectively, with self-administration rates during the asymptotic phase; left/right asymmetrics in cortical metabolite levels were also correlated with asymptotic rates. There were no significant relationships between any neurochemical indices and rates of bar-pressing for water. These results suggest that the normal variability in drug seeking behavior is at least in part attributable to individual differences in the activity of brain dopamine systems.(ABSTRACT TRUNCATED AT 250 WORDS)