Biomedical subjects

P F Renshaw

Publications and source records attributed to P F Renshaw.

At least 19 recordsLinked to original sources

PubMed2006

MDMA use is associated with increased spatial BOLD fMRI visual cortex activation in human MDMA users.

Previous animal studies have demonstrated that 3,4-methylenedioxymethamphetamine (MDMA) exposure causes serotonin axotomy that is greatest in occipital cortex (including primary visual cortex) where serotonergic axons innervate neurons and blood vessels. Human MDMA users have altered serotonergic function and reduced gray matter density in occipital cortex. The fMRI BOLD method is potentially sensitive to both the neuronal and vascular consequences of MDMA-induced serotonin toxicity. To test the hypothesis that MDMA users have altered visual system function, we used the fMRI BOLD technique to assay visual cortical activation after photic stimulation in a group of adult MDMA users. Because MDMA users worldwide are polydrug users and therefore difficult to match to comparison groups in terms of polydrug exposure, we conducted a primary within-group analysis examining the correlation between lifetime episodes of MDMA exposure and measures of visual cortical activation. The within-group correlational analysis in the MDMA user group revealed that the degree of prior MDMA exposure was significantly positively correlated with the number of activated pixels for photic stimulation (r=0.582, p=0.007). A secondary between-group comparison of MDMA users with non-MDMA users found overall greater levels of polydrug exposure in the MDMA user cohort but no significant differences in visual cortical activation measures between the two groups. Additional research is needed to clarify the origin and significance of the current findings.

Adolescent↗

PubMed2006

Magnetic resonance spectroscopy for measuring the biodistribution and in situ in vivo pharmacokinetics of fluorinated compounds: validation using an investigation of liver and heart disposition of tecastemizole.

BACKGROUND AND OBJECTIVE: The study of biodistribution and in situ pharmacokinetics is a challenging, but sometimes very important, aspect of premarketing characterization of drugs. We aimed to develop a non-invasive fluorine magnetic resonance (MR) spectroscopic method for the absolute quantitation of a mono-fluorinated compound and of its metabolites in the heart and liver of healthy subjects for this purpose. METHOD: We used fluorine MR spectroscopy (MRS) at 4 T (Tesla) and external standardization in an open label multiple-dose study. Twenty-three healthy adult subjects were enrolled in the study. The surface coil localized fluorine MR spectrum was monitored in the heart and liver at baseline and after oral administration of multiple doses of tecastemizole. Steady-state measurements were made at set time points that depended upon dose, and washout measurements were made only on subjects in which in vivo fluorine signal was observed. RESULTS AND DISCUSSION: At 4 T, under the given experimental conditions, the method had a lower limit of quantitation (LLOQ) of about 2.6 microm and a limit of detection (LOD) of about 0.3 microm for solution state samples (linewidth approximately 15 Hz). The measurement reproducibility was 6.4% using a 50 microm phantom. The effect of MR operator and spectral analyst on the calculated calibration curve slope was small, with inter-rater correlation coefficients of 0.999 and 0.998 respectively. MR signal from fluorine-containing tecastemizole-related moieties was observed in situ only at day 8 in the liver of three of five subjects dosed at 270 mg/day. The average in situ concentration was estimated to be 58+/-22 microm, with an average test-retest reproducibility of 216%. Extrapolating the in vitro results to human measurements, with an approximate linewidth of 250 Hz, predicts in situ LOD and LLOQ values of approximately 6 and 44 microm respectively. However, the human study had a fluorine MRS LOD of approximately 20 microm. The decrease in sensitivity and the increase in variability of the in vivo, in situ measurements compared with the validation study most likely arose from coil placement and incomplete rephasing of the MR signal by the respiratory phase compensation method. CONCLUSION: The measured concentrations were the lowest ever recorded for a multi-dose exogenous mono-fluorinated compound in the human liver using a validated fluorine MR quantitation method. The proposed non-invasive MR method for studying the biodistribution and in situ pharmacokinetics of mono-fluorinated compounds in the liver and heart should have broader application to the development of non-invasive biomarkers.

Adult↗

PubMed2005

Mitochondrial dysfunction in bipolar disorder: evidence from magnetic resonance spectroscopy research.

Magnetic resonance spectroscopy (MRS) affords a noninvasive window on in vivo brain chemistry and, as such, provides a unique opportunity to gain insight into the biochemical pathology of bipolar disorder. Studies utilizing proton ((1)H) MRS have identified changes in cerebral concentrations of N-acetyl aspartate, glutamate/glutamine, choline-containing compounds, myo-inositol, and lactate in bipolar subjects compared to normal controls, while studies using phosphorus ((31)P) MRS have examined additional alterations in levels of phosphocreatine, phosphomonoesters, and intracellular pH. We hypothesize that the majority of MRS findings in bipolar subjects can be fit into a more cohesive bioenergetic and neurochemical model of bipolar illness that is both novel and yet in concordance with findings from complementary methodological approaches. In this review, we propose a hypothesis of mitochondrial dysfunction in bipolar disorder that involves impaired oxidative phosphorylation, a resultant shift toward glycolytic energy production, a decrease in total energy production and/or substrate availability, and altered phospholipid metabolism.

Biomarkers↗

PubMed2004

Brain T2 relaxation times correlate with regional cerebral blood volume.

We previously reported cerebellar and putaminal transverse relaxation time (T2) differences in children with ADHD and in adults with childhood trauma. As brain T2 can be altered by deoxyhemoglobin concentration ([dHb]) and because [dHb] is proportional to regional cerebral blood volume (rCBV), at steady state we attributed those differences to rCBV changes. Studies in other species have established a correlation between T2 and rCBV; however this has yet to be demonstrated in human brain. Echo planar imaging (EPI) T2 relaxometry and dynamic susceptibility-contrast (DSC) MRI were used to measure T2 and rCBV in 11 healthy adults. Significant T2-rCBV correlations were observed in both cerebellar vermis and putamen (r = 0.759,p = 0.007;r = 0.782,p = 0.004, respectively). These correlations predict 9 +/- 3% and 10 +/- 3% rCBV changes, respectively, for each 1-msec change in T2. Consequently, brain T2 measurements may be useful for estimating steady-state rCBV.

Adolescent↗

PubMed2002

Chronic citicoline increases phosphodiesters in the brains of healthy older subjects: an in vivo phosphorus magnetic resonance spectroscopy study.

RATIONALE: Phosphatidylcholine (PtdCho) in brain cell membranes decreases with age. Evidence from both animal and in vitro studies indicates that CDP-choline (citicoline) administration may increase phosphatidylcholine (PtdCho) synthesis and might reverse PtdCho loss. OBJECTIVES: We investigated whether oral citicoline can increase PtdCho synthesis in the brains of older subjects by measuring levels of phosphorus-containing metabolites using proton-decoupled phosphorus magnetic resonance spectroscopy ((31)P-MRS) before and after citicoline treatment. METHODS: All subjects took 500 mg citicoline once orally each day for 6 weeks, then took either citicoline or placebo once orally per day for a second 6-week period. Subjects underwent a (31)P-MRS scan at baseline and following 6 and 12 weeks of treatment. RESULTS: Treatment with citicoline for 6 weeks was associated with a 7.3% increase from baseline levels in brain phosphodiesters ( P=0.008), including an 11.6% increase in glycerophosphoethanolamine ( P=0.002) and a 5.1% increase in glycerophosphocholine ( P=0.137). Subjects who continued to take citicoline for the second 6-week period did not show significant additional increases in the levels of these metabolites. No changes were seen in other phosphorus-containing metabolites. There was a correlation between improvement on the California Verbal Learning Test and increase in phosphodiesters. CONCLUSIONS: The increases in phosphodiesters seen in this study indicate that phospholipid synthesis and turnover were stimulated by 6 weeks of oral citicoline. These results in humans support previous in vitro and animal studies and suggest that the administration of oral citicoline may be of use in reversing age-related changes in the brain.

Administration, Oral↗

PubMed2002

Biexponential transverse relaxation (T(2)) of the proton MRS creatine resonance in human brain.

Differences in proton MRS T(2) values for phosphocreatine (PCr) and creatine (Cr) methyl groups (3.0 ppm) were investigated in studies of phantoms and human brain. Results from phantom studies revealed that T(2) of PCr in solution is significantly shorter than T(2) of Cr. Curve-fitting results indicated that the amplitude-TE curves of the total Cr resonance at 3.0 ppm in human brain (N = 26) fit a biexponential decay model significantly better than a monoexponential decay model (P < 0.006), yielding mean T(2) values of 117 +/- 21 ms and 309 +/- 21 ms. Using a localized, long-TE (272 ms) point-resolved spectroscopy (PRESS) proton MRS during 2 min of photic stimulation (PS), an increase of 12.1% +/- 3.5% in the mean intensity of the total Cr resonance in primary visual cortex (VI) was observed at the end of stimulation (P < 0.021). This increase is consistent with the conversion of 26% of PCr in VI to Cr, which is concordant with (31)P MRS findings reported by other investigators. These results suggest a significantly shorter T(2) for PCr than for Cr in vivo. This difference possibly could be exploited to quantify regional activation in functional spectroscopy studies, and could also lead to inaccuracies in some circumstances when the Cr resonance is used as an internal standard for (1)H MRS studies in vivo.

Adult↗

PubMed2001

Effect of lithium on phosphoinositide metabolism in human brain: a proton decoupled (31)P magnetic resonance spectroscopy study.

BACKGROUND: The objective of our study was to evaluate whether lithium increases brain phosphomonoester (PME) levels in human subjects. METHODS: Proton decoupled (31)P magnetic resonance spectra were obtained from eight healthy volunteers before and after the administration of lithium carbonate, 450 mg b.i.d., for 7 and 14 days. RESULTS: Pairwise comparisons of the mole percent PME revealed a significant increase from baseline at day 7 and day 14 of lithium administration. CONCLUSIONS: An increase in PME concentration with 7 and 14 days of lithium administration in the human brain in vivo was observed. Because the inositol-1-monophosphate contributes to the PME peak, this result suggests that some of the initial actions of lithium may occur through a reduction of myo-inositol, which in turn may initiate a cascade of secondary changes at different levels of signal transduction process and gene expression in brain, effects that are ultimately responsible for the therapeutic benefits of lithium.

Adolescent↗

PubMed2001

Test-retest reliability of DSC MRI CBV mapping in healthy volunteers.

Dynamic susceptibility contrast magnetic resonance imaging (DSC MRI) can be used to generate high resolution maps of cerebral blood volume (CBV). To determine the test-retest reliability, CBV was measured in eight volunteers on two occasions, separated by 4 weeks. The mean ratio (scan 2/scan 1) for 72 cortical regions of interest (ROIs) was 1.03, with a coefficient of variation of 14%. The correlation between the first and second scans was 0.73 (p < 0.0001; 95%). In five hand-drawn ROIs, the mean ratio was 1.08, with a coefficient of variation of 12%. The correlation between scans was 0.84 (p < 0.0001). The data presented here support the hypothesis that DSC MRI CBV mapping has acceptable test-retest reliability.

Adult↗

PubMed2001

31P Nuclear magnetic resonance spectroscopy findings in bipolar illness: a meta-analysis.

Published literature comparing 31P MR brain spectra of bipolar patients to healthy controls was evaluated, focusing on phosphomonoester (PME)/phosphodiester (PDE) resonance areas because these metabolites are related to membrane phospholipids and membrane defects in bipolar disorder have been suggested. Studies comparing PME and/or PDE values of bipolar subjects to values observed in healthy controls were reviewed. Data from the studies meeting our inclusion criteria (8 reports involving 139 bipolar and 189 comparison subjects) were grouped according to the mood state of the subjects. Meta-analyses of data were performed to compare PME and PDE levels of euthymic bipolar patients to healthy controls, as well as comparing PME levels during euthymia in bipolar subjects to values observed during manic and depressed states. The PME values of euthymic bipolar patients were found to be significantly lower than PME values of healthy controls. Depressed bipolar patients had significantly higher PME values in comparison to euthymic bipolar patients. No significant difference could be detected between the PDE values of bipolars and controls. This meta-analysis found support for trait- and possibly state-dependent abnormalities of membrane phospholipid metabolism, which may reflect a dysregulation in brain-signal transduction systems of relevance in bipolar illness.

Adult↗

PubMed2001

Cocaine-induced cerebral vasoconstriction differs as a function of sex and menstrual cycle phase.

BACKGROUND: Chronic cocaine abusing women experience fewer cerebral perfusion defects and less neuronal injury than men with comparable drug use histories. This study assessed whether a basis for this discrepancy is a sex difference in cocaine's acute cerebrovascular effects. METHODS: The subjects in this study were 13 healthy and neurologically normal women, reporting occasional cocaine (mean 13, range 1-40 lifetime cocaine exposures). All subjects were administered cocaine (0.4 mg/kg) intravenously, during both the follicular (days 3-8) and luteal (days 18-24) menstrual cycle phases. Dynamic susceptibility contrast magnetic resonance imaging assessments of relative global cerebral blood volume (CBV) changes were conducted on both study days, 10 min after cocaine administration. RESULTS: Cocaine did not alter CBV in follicular phase women, but reduced luteal phase CBV by 10%, indicative of vasoconstriction (analysis of variance [ANOVA], F = 5.1, p <.05). Postcocaine CBV was lower in men administered the drug via an identical protocol relative to follicular phase women (ANOVA, F = 5.4, p <.04). Postcocaine CBV was also lower in the male referent group relative to luteal phase women, but this difference did not achieve statistical significance. No measurable sex or menstrual cycle phase differences in cocaine's cardiovascular effects were noted. CONCLUSIONS: These findings suggest both menstrual cycle phase and sex differences in cocaine's acute cerebrovascular effects, which may contribute to sex differences in the severity of brain dysfunction found in chronic cocaine abusers. These findings imply that gonadal steroids or the factors they modulate merit study as possible therapeutic agents for reducing cocaine-induced cerebrovascular disorders.

Adult↗

PubMed2001

Effects of short-term citicoline treatment on acute cocaine intoxication and cardiovascular effects.

RATIONALE: The majority of pharmacotherapies proposed for cocaine dependence have been marginally effective and frequently have undesirable side effects. We recently demonstrated that short-term treatment with citicoline decreased self-reported desire to use cocaine in crack cocaine users. OBJECTIVE: The present study was conducted to assess the safety of citicoline in combination with cocaine by investigating whether cocaine-induced cardiovascular and behavioral effects and cocaine plasma levels are altered by citicoline pretreatment. METHODS: Eight healthy male and female volunteers who used cocaine on an occasional basis participated in this randomized, placebo-controlled, three-visit study. During all three visits, subjects received an acute intranasal dose of cocaine (0.9 mg/kg) and were continuously monitored for the ensuing 3.5 h. The first visit involved no pretreatment, and visits 2 and 3 were preceded by a 4-day pretreatment period of either citicoline (1 g/day) or placebo. RESULTS: Citicoline pretreatment did not alter the cardiovascular, physiologic, or subjective effects of acute cocaine. CONCLUSIONS: Although citicoline did not block the acute subjective effects of cocaine in a laboratory environment, the combined use of citicoline and a moderate dose of intranasal cocaine presented no added risk of cardiovascular effects. Further study is necessary to determine whether this medication (which is currently used to treat strokes) will be a useful adjunct to treat cocaine dependence.

Adult↗

PubMed2001

Influence of baseline hematocrit and hemodilution on BOLD fMRI activation.

Current understanding of blood oxygenation level dependent (BOLD) fMRI physiology predicts a close relationship between BOLD signal and blood hematocrit level. However, neither this relationship nor its effect on BOLD percent activation (BPA) has been empirically examined in man. To that end, BPA in primary visual cortex in response to photic stimulation was determined in a group of 24 normal subjects. A positive linear relationship between BPA and hematocrit was seen, particularly in men. To evaluate the effect of change in hematocrit on BPA, 9 men were studied before and following isotonic saline hemodilution, resulting in an average 6% reduction in hematocrit and an 8-31% reduction in BPA. No significant change in the number of activated pixels was seen. A model of predicted BPA as a function of hematocrit and vessel size was developed, and results from this model closely mirrored the empiric data. These results suggest that hematocrit significantly influences the magnitude of BPA and that such baseline factors should be accounted for when comparing BOLD data across groups of subjects, particularly in the many instances in which hematocrit may vary systematically. Such instances include several disease states as well as studies involving sex differences, drug administration, stress and other factors. Finally, the robust agreement between predicted and empiric data serves to validate a semiquantitative approach to the analysis of BOLD fMRI data.

Brain↗

PubMed2001

Multinuclear magnetic resonance spectroscopy studies of brain purines in major depression.

OBJECTIVE: Studies of depressed adults have shown abnormalities in cerebral energy metabolism, as noted by low brain levels of nucleoside triphosphate (NTP), which primarily represents adenosine triphosphate (ATP). This study was undertaken to determine whether proton magnetic resonance spectroscopy (1H MRS) measures of the low-field purine resonance, which arises primarily from adenosine phosphates, can be used to assess abnormalities in cerebral purine metabolism in depressed adults. METHOD: Data from 1H MRS and phosphorus-31 (31P) MRS were acquired for depressed and nondepressed comparison subjects. Intensities of the purine resonance, by 1H MRS (7.5-8.5 ppm), and of NTP, by 31P MRS, were determined. RESULTS: Purine resonance intensities did not differ on average between depressed patients and comparison subjects. However, purine levels were approximately 30% lower in female depressed subjects who subsequently responded to fluoxetine treatment than in those who did not respond. Beta-NTP was lower by 21% in responders than in nonresponders and was correlated with purine levels for the depressed subjects. CONCLUSIONS: Brain purine levels are low in female depressed patients who respond to treatment with fluoxetine, suggesting that response to treatment might be predicted by using 1H MRS. These observations also suggest that agents that increase brain adenosine levels may have antidepressant efficacy.

Adenosine Triphosphate↗

PubMed2000

Sex differences in response to red and blue light in human primary visual cortex: a bold fMRI study.

Studies using a variety of investigative methods, including functional brain imaging and electroencephalography (EEG), have suggested that changes in central nervous system (CNS) dopamine function result in altered visual system processing. The discovery of abnormal retinal blue cone, but not red cone, electroretinogram in association with cocaine withdrawal and Parkinson's disease suggests that visual system response to blue light might be a marker for CNS dopamine tone. As there are numerous sex-related differences in central nervous system dopamine function, we predicted that blue and red light stimulation would produce sex-specific patterns of response in primary visual cortex when studied using the blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) technique. We analyzed the BOLD response to red and blue light in male and female human volunteers (N=20). Red and blue light responses in primary visual cortex (V1) to stepped intensities of red and blue light were compared by sex for threshold to detectable BOLD signal increase and for stimulus intensity vs. BOLD signal response. Near threshold, males and females showed similar BOLD signal change to red light, but males showed a threefold greater increase (0.52%) to blue light stimulation when compared to females (0.14%). Log-linear regression modeling revealed that the slope coefficients for the red light stimulus intensity vs. signal change curve were not significantly different for males and females (z=0.995, P=0.320), whereas the slope coefficients for the blue light stimulus intensity vs. signal change curve were significantly larger in males (z=2.251, P=0.024). These findings support a sex and color-dependent differential pattern of primary visual cortical response to photic stimulation and suggest a method for assessing the influence of specific dopamine agonist/antagonist medications on visual function.

Adult↗

PubMed2000

Assessment of GABA concentration in human brain using two-dimensional proton magnetic resonance spectroscopy.

A quantitative method to assess in vivo brain gamma-aminobutyric acid (GABA) levels is proposed using a J-resolved, two-dimensional (2D) magnetic resonance spectroscopy (MRS) technique. Localized, J-resolved 2D MR spectra were obtained from a 12-cm(3) voxel in the occipital lobe of 36 healthy volunteers (18 male and 18 female, age: 25.1+/-4.8 years). Based on phantom measurements, a GABA resonance peak located at 2.94 ppm, 7.45 Hz, in J-resolved 2D MRS overlaps the least with other resonance peaks which arise from N-acetylaspartate, choline, creatine, glutamate and glutamine. Measurements of this resonance peak yield in vivo GABA concentrations of 1.01+/-0.36 micromol/cm(3) for male and 1.16+/-0.43 micromol/cm(3) for female volunteers, without correction for T1 and T2 relaxation effects. These results are in good agreement with previously reported data and suggest that, with further development, 2D MRS may provide a practical means to estimate the concentration of this important neurotransmitter.

Creatine↗

PubMed2000

Increased orbitofrontal cortex levels of choline in depressed adolescents as detected by in vivo proton magnetic resonance spectroscopy.

BACKGROUND: The frontal lobe has been implicated in the pathology of depression in adults. Through the use of magnetic resonance spectroscopy, altered brain choline levels have also been linked to the pathophysiology of affective disorders. METHODS: To identify possible alterations in orbitofrontal cortex levels of cytosolic choline in adolescents with and without depression, 22 depressed and 43 control adolescents were recruited. Of those recruited, usable proton magnetic resonance spectra were acquired from a voxel in the left anterior medial frontal lobe of 17 depressed (mean age 15.8+/-1.6) and 28 healthy adolescents (mean age 14.5+/-1.7). RESULTS: Orbitofrontal cytosolic choline/creatine (Cho/Cr) ratios (p =.032) and cytosolic choline/N-acetyl aspartate (Cho/NAA) ratios (p =.043) were significantly higher in the depressed subjects than in the control subjects. There were no significant differences between depressed and control subjects in gray or white matter content within the voxel. CONCLUSIONS: These findings suggest that brain cytosolic choline may be increased in depressed adolescents in comparison with control subjects and independent of a corresponding structural change. These results are consistent with similar, previously reported findings in adults and suggest that depression in adolescents is associated with alterations in orbitofrontal metabolism.

Adolescent↗

PubMed2000

Proton magnetic resonance spectroscopy of human basal ganglia: response to cocaine administration.

BACKGROUND: Proton magnetic resonance spectroscopy was used to determine the effects of intravenous cocaine or placebo administration on human basal ganglia water and metabolite resonances. METHODS: Long echo time, proton magnetic resonance spectra of water and intracellular metabolites were continuously acquired from an 8-cm(3) voxel centered on the left caudate and putamen nuclei before, during, and after the intravenous administration of cocaine or a placebo in a double-blind manner. RESULTS: Cocaine, at both 0.2 and 0.4 mg/kg, did not alter the peak area for water. Cocaine at 0.2 mg/kg induced small and reversible increases in choline-containing compounds and N-acetylaspartate peak areas. Cocaine at 0.4 mg/kg induced larger and more sustained increases in choline-containing compounds and N-acetylaspartate peak areas. No changes in either water or metabolite resonances were noted following placebo administration. CONCLUSIONS: These increases in choline-containing compounds and N-acetylaspartate peak areas may reflect increases in metabolite T2 relaxation times secondary to osmotic stress and/or increased phospholipid signaling within the basal ganglia following cocaine administration. This is the first report of acute, drug-induced changes in the intensity of human brain proton magnetic resonance spectroscopy resonance areas.

Adult↗

PubMed2000

Neuroimaging in bipolar disorder: what have we learned?

New technologies are offering increasingly powerful means to obtain structural, chemical, and functional images of the brain during life, often without the use of ionizing radiation. Bipolar disorder, with its clear physiologic features, would appear to be a prime candidate for the application of current brain imaging; however, only a modest number of studies have been reported to date, and most studies have small sample sizes and heterogeneous subject groups. Nonetheless, there are a few consistent findings among these studies, including the following: 1) Structural imaging studies suggest an increased number of white matter hyperintensities in patients with bipolar disorder. These may be lesions unique to bipolar disorder and its treatment, or related to cardiovascular risk factors, which are more common in bipolar patients. Decreased cerebellar size and anomalies of cerebellar blood volume have also been reported. Increased sulcal prominence and enlargement of the lateral and third ventricles are less consistently observed findings. 2) Spectroscopic imaging suggests abnormalities of metabolism of choline-containing compounds in symptomatically ill bipolar patients and, possibly, treatment-induced changes in choline- and myoinositol-containing compounds. Each of these groups of metabolites serves as a component of membrane phospholipids and cellular second-messenger cycles. 3) Metabolic and blood flow studies provide evidence for decreased activity of the prefrontal cortex (PFC) in bipolar patients during depression. It is not clear if these changes are restricted to particular subregions of the PFC, nor if they are reversed with mania. No single pathophysiologic mechanism yet explains these findings, although all might be due to regional alterations in cellular activity and metabolism or changes in cell membrane composition and turnover. The development of imaging technologies has far outpaced their use in bipolar disorder. The promise of future studies is great, with more powerful magnetic resonance scanners, additional ligands for positron emission tomography and single photon emission computed tomography imaging, and improved image generation and processing already available.

Bipolar Disorder↗