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Biomedical subjects

Mark A Mandelkern

Publications and source records attributed to Mark A Mandelkern.

At least 19 recordsLinked to original sources
PubMed2007

Neural substrates of resisting craving during cigarette cue exposure.

BACKGROUND: In cigarette smokers, the most commonly reported areas of brain activation during visual cigarette cue exposure are the prefrontal, anterior cingulate, and visual cortices. We sought to determine changes in brain activity in response to cigarette cues when smokers actively resist craving. METHODS: Forty-two tobacco-dependent smokers underwent functional magnetic resonance imaging, during which they were presented with videotaped cues. Three cue presentation conditions were tested: cigarette cues with subjects allowing themselves to crave (cigarette cue crave), cigarette cues with the instruction to resist craving (cigarette cue resist), and matched neutral cues. RESULTS: Activation was found in the cigarette cue resist (compared with the cigarette cue crave) condition in the left dorsal anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), and precuneus. Lower magnetic resonance signal for the cigarette cue resist condition was found in the cuneus bilaterally, left lateral occipital gyrus, and right postcentral gyrus. These relative activations and deactivations were more robust when the cigarette cue resist condition was compared with the neutral cue condition. CONCLUSIONS: Suppressing craving during cigarette cue exposure involves activation of limbic (and related) brain regions and deactivation of primary sensory and motor cortices.

Adult↗
PubMed2006

A detector head design for small-animal PET with silicon photomultipliers (SiPM).

Small-animal PET systems are now striving for sub-millimetre resolution. Current systems based upon PSPMTs and finely pixellated scintillators can be pushed to higher resolution, but at the expense of other performance parameters and a rapidly escalating cost. Moreover, depth of interaction (DOI) information is usually difficult to assess in such systems, even though this information is highly desirable to reduce the parallax error, which is often the dominant error for such high-resolution systems. In this study we propose a high-resolution detector head for a small-animal PET imaging system with intrinsic DOI information. Instead of a pixellated scintillator, our design is based upon the classic Anger camera principle, i.e. the head is constructed of modular layers each consisting of a continuous slab of scintillator, viewed by a new type of compact silicon photodetector. The photodetector is the recently developed silicon photomultiplier (SiPM) that as well as being very compact has many other attractive properties: high gain at low bias voltage, excellent single-photoelectron resolution and fast timing. A detector head of about 4 x 4 cm2 in area is proposed, constructed from three modular layers of the type described above. We perform a simulation study, using the Monte Carlo simulation package Geant4. The simulation results are used to optimize the geometry of the detector head and characterize its performance. Additionally, hit estimation algorithms are studied to determine the interaction position of annihilation photons correctly over the whole detector surface. The resulting detector has a nearly uniform efficiency for 511 keV photons of approximately 70% and an intrinsic spatial resolution of less than approximately 0.4 mm full width at half maximum (fwhm).

Animals↗
PubMed2006

Gene variants of brain dopamine pathways and smoking-induced dopamine release in the ventral caudate/nucleus accumbens.

CONTEXT: Preclinical studies demonstrate that nicotine administration leads to dopamine release in the ventral striatum. However, human studies reveal considerable interindividual variability in the extent of smoking-induced dopamine release. OBJECTIVE: To determine whether common gene variants of the brain dopamine pathway explain this observed phenotypic variability in humans. DESIGN: Blood samples were drawn to determine gene variants of dopamine system components, and positron emission tomography scanning with the radiotracer raclopride labeled with radioactive carbon (11C) was performed to measure smoking-induced dopamine release. SETTING: Academic brain imaging center. PARTICIPANTS: Forty-five tobacco-dependent smokers. INTERVENTIONS: Subjects either smoked a cigarette (n = 35) or did not smoke (n = 10) during positron emission tomography scanning. MAIN OUTCOME MEASURES: Gene variants of dopamine system components (the dopamine transporter variable nucleotide tandem repeat, D2 receptor Taq A1/A2, D4 receptor variable nucleotide tandem repeat, and catechol-O-methyltransferase Val158Met polymorphisms) and change in [11C]raclopride binding potential in the ventral caudate/nucleus accumbens on positron emission tomography scans. RESULTS: For subjects who smoked during scanning, those with at least one 9 allele of the dopamine transporter variable nucleotide tandem repeat, fewer than 7 repeats of the D4 variable nucleotide tandem repeat, and the Val/Val catechol-O-methyltransferase genotype had greater decreases in binding potential (an indirect measure of dopamine release) with smoking than those with the alternate genotypes. An overall decrease in ventral caudate/nucleus accumbens binding potential in those who smoked compared with those who did not smoke was also found but was smaller in magnitude than previously reported. CONCLUSIONS: Smokers with genes associated with low resting dopamine tone have greater smoking-induced (phasic) dopamine release than those with alternate genotypes. These findings suggest that dopamine system genotype variabilities explain a significant proportion of the interindividual variability in smoking-induced dopamine release and indicate that smoking-induced dopamine release has a genetic predisposition.

Adult↗
PubMed2006

Cigarette smoking saturates brain alpha 4 beta 2 nicotinic acetylcholine receptors.

CONTEXT: 2-[18F]fluoro-3-(2(S)-azetidinylmethoxy) pyridine (2-F-A-85380, abbreviated as 2-FA) is a recently developed radioligand that allows for visualization of brain alpha 4 beta 2* nicotinic acetylcholine receptors (nAChRs) with positron emission tomography (PET) scanning in humans. OBJECTIVE: To determine the effect of cigarette smoking on alpha 4 beta 2* nAChR occupancy in tobacco-dependent smokers. DESIGN: Fourteen 2-FA PET scanning sessions were performed. During the PET scanning sessions, subjects smoked 1 of 5 amounts (none, 1 puff, 3 puffs, 1 full cigarette, or to satiety [2(1/2) to 3 cigarettes]). SETTING: Academic brain imaging center. PARTICIPANTS: Eleven tobacco-dependent smokers (paid volunteers). Main Outcome Measure Dose-dependent effect of smoking on occupancy of alpha 4 beta 2* nAChRs, as measured with 2-FA and PET in nAChR-rich brain regions. RESULTS: Smoking 0.13 (1 to 2 puffs) of a cigarette resulted in 50% occupancy of alpha 4 beta 2* nAChRs for 3.1 hours after smoking. Smoking a full cigarette (or more) resulted in more than 88% receptor occupancy and was accompanied by a reduction in cigarette craving. A venous plasma nicotine concentration of 0.87 ng/mL (roughly 1/25th of the level achieved in typical daily smokers) was associated with 50% occupancy of alpha 4 beta 2* nAChRs. CONCLUSIONS: Cigarette smoking in amounts used by typical daily smokers leads to nearly complete occupancy of alpha 4 beta 2* nAChRs, indicating that tobacco-dependent smokers maintain alpha 4 beta 2* nAChR saturation throughout the day. Because prolonged binding of nicotine to alpha 4 beta 2* nAChRs is associated with desensitization of these receptors, the extent of receptor occupancy found herein suggests that smoking may lead to withdrawal alleviation by maintaining nAChRs in the desensitized state.

Adult↗
PubMed2006

Longitudinal change in perceptual and brain activation response to visceral stimuli in irritable bowel syndrome patients.

BACKGROUND & AIMS: Symptom-related fears and associated hypervigilance toward visceral stimuli may play a role in central pain amplification and irritable bowel syndrome (IBS) pathophysiology. Repeated stimulus exposure leads to decreased salience of threat and reduction of hypervigilance. We sought to evaluate hypervigilance in IBS visceral hypersensitivity and associated brain activity. METHODS: Twenty IBS patients (14 female; moderate to severe symptoms) and 14 healthy controls participated in symptom and rectal distention assessments 6 times over 12 months. In a subset of 12 IBS patients, H2 15O-positron emission tomography images were obtained during baseline, rectal distentions, and anticipation of an aversive distention during the first and last session. Statistical parametric mapping (SPM99) was used to identify areas and networks activated during each session as well as those with differential activation across the 2 sessions. RESULTS: Perceptual ratings of the rectal inflations normalized over 12 months, whereas IBS symptom severity did not. There were no sex-related differences in these response patterns. Stable activation of the central pain matrix was observed over 12 months, and activity in limbic, paralimbic, and pontine regions decreased. During the anticipation condition, there were significant decreases in amygdala, dorsal anterior cingulate cortex, and dorsal brainstem activation at 12 months. Covariance analysis supported the hypothesis of changes in an arousal network including limbic, pontine, and cortical areas underlying the decreased perception seen over the multiple stimulations. CONCLUSIONS: In IBS patients, repeated exposure to experimental aversive visceral stimuli results in the habituation of visceral perception and central arousal, despite stable activation of networks processing visceral pain and its anticipation.

Abdominal Pain↗
PubMed2006

Anxiety and regional cortical glucose metabolism in patients with Alzheimer's disease.

In this study, the authors investigated the relationship between anxiety and regional cortical metabolism in Alzheimer's disease. Using the Neuropsychiatric Inventory (NPI), the authors evaluated anxiety in 41 patients with Alzheimer's disease. Regional cortical glucose metabolism was measured using [(18)F] fluorodeoxyglucose positron emission tomography in the resting state. Relationships were assessed using voxel-based (SPM2) and anatomic region-based analyses. Higher NPI anxiety score (frequency x severity) was associated with lower metabolism in bilateral entorhinal cortex, anterior parahippocampal gyrus, and left superior temporal gyrus and insula. Functional activity changes in distinct regions of the cortex contribute to the expression of anxiety in Alzheimer's disease.

Aged↗
PubMed2005

Cerebral metabolic dysfunction and impaired vigilance in recently abstinent methamphetamine abusers.

BACKGROUND: Methamphetamine (MA) abusers have cognitive deficits, abnormal metabolic activity and structural deficits in limbic and paralimbic cortices, and reduced hippocampal volume. The links between cognitive impairment and these cerebral abnormalities are not established. METHODS: We assessed cerebral glucose metabolism with [F-18]fluorodeoxyglucose positron emission tomography in 17 abstinent (4 to 7 days) methamphetamine users and 16 control subjects performing an auditory vigilance task and obtained structural magnetic resonance brain scans. Regional brain radioactivity served as a marker for relative glucose metabolism. Error rates on the task were related to regional radioactivity and hippocampal morphology. RESULTS: Methamphetamine users had higher error rates than control subjects on the vigilance task. The groups showed different relationships between error rates and relative activity in the anterior and middle cingulate gyrus and the insula. Whereas the MA user group showed negative correlations involving these regions, the control group showed positive correlations involving the cingulate cortex. Across groups, hippocampal metabolic and structural measures were negatively correlated with error rates. CONCLUSIONS: Dysfunction in the cingulate and insular cortices of recently abstinent MA abusers contribute to impaired vigilance and other cognitive functions requiring sustained attention. Hippocampal integrity predicts task performance in methamphetamine users as well as control subjects.

Adult↗
PubMed2005

Whole-body radiation dosimetry of 2-[18F]Fluoro-A-85380 in human PET imaging studies.

2-[18F]Fluoro-A-85380 (2-[18F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine, 2-[18F]FA) is a recently developed PET radioligand for noninvasive imaging of nicotinic acetylcholine receptors. Previous radiation absorbed dose estimates for 2-[18F]FA were limited to evaluation of activity in only several critical organs. Here, we performed 2-[18F]FA radiation dosimetry studies on two healthy human volunteers to obtain data for all important body organs. Intravenous injection of 2.9 MBq/kg of 2-[18F]FA was followed by dynamic PET imaging. Regions of interest were placed over images of each organ to generate time-activity curves, from which we computed residence times. Radiation absorbed doses were calculated from the residence times using the MIRDOSE 3.0 program (version 3.0, ORISE, Oak Ridge, TN). The urinary bladder wall receives the highest radiation absorbed dose (0.153 mGy/MBq, 0.566 rad/mCi, for a 2.4-h voiding interval), followed by the liver (0.0496 mGy/MBq, 0.184 rad/mCi) and the kidneys (0.0470 mGy/MBq, 0.174 rad/mCi). The mean effective dose equivalent is estimated to be 0.0278 mSv/MBq (0.103 rem/mCi), indicating that radiation dosimetry associated with 2-[18F]FA is within acceptable limits.

Adult↗
PubMed2005

Differences in brain responses to visceral pain between patients with irritable bowel syndrome and ulcerative colitis.

Patients with mild chronic inflammation of the rectum or ileum have reduced perceptual responses to rectosigmoid distension compared to patients with irritable bowel syndrome (IBS). The current study sought to identify differences in regional cerebral blood flow (rCBF) during rectal distension, which might correspond to these perceptual differences. In 8 male ulcerative colitis (UC) patients with quiescent disease, 7 male IBS patients and 7 healthy male controls, rCBF was assessed using 15O-water positron emission tomography at baseline and during actual and anticipated but undelivered rectal distensions. No group differences were seen in anterior insula and dorsal anterior cingulate cortex (dACC), two regions consistently activated by painful intestinal stimuli. However, IBS patients showed greater activation of the amygdala, rostroventral ACC, and dorsomedial frontal cortical regions. In contrast, no significant differences were observed between UC and controls. When these two non-IBS groups were combined, functional connectivity analyses showed that right lateral frontal cortex (RLFC) activation positively correlated with activation of the dorsal pons/periaqueductal gray, a key region involved in endogenous pain inhibition. According to the connectivity analysis, this effect was mediated by inhibition of medial frontal cortex by the RLFC. Chronic colonic inflammation is not necessarily associated with increased visceral afferent input to the brain during rectal distension. In the sample studied, the primary difference between functional and quiescent inflammatory disease of the colon was in terms of greater activation of limbic/paralimbic circuits in IBS, and inhibition of these circuits in UC and controls by the RLFC.

Adult↗
PubMed2005

Frontal lobe hypometabolism and impaired insight in Alzheimer disease.

OBJECTIVE: The authors examined the relationship between impaired insight regarding cognitive and functional deficits and frontal cortex hypometabolism in 41 patients with Alzheimer disease (AD). METHODS: Regional cerebral glucose metabolism was determined with (18F)fluorodeoxyglucose and positron emission tomography. Level of insight was measured with the clinician-rated Neurobehavioral Rating Scale, and severity of global cognitive impairment was determined with the Mini-Mental State Exam. RESULTS: Inaccurate insight was correlated with glucose metabolic rate in the right lateral frontal cortex (Brodmann areas 6 and 45, and the lateral aspect of Brodmann areas 8 and 9) after controlling for global cognitive dysfunction. CONCLUSIONS: The findings from this study help to further elucidate the neurobiological mechanisms underlying impaired insight in AD, indicating a link between this important clinical phenomenon and dysmetabolism in a focal region of the right prefrontal cortex.

Activities of Daily Living↗
PubMed2004

Attenuation of cue-induced cigarette craving and anterior cingulate cortex activation in bupropion-treated smokers: a preliminary study.

In untreated smokers, exposure to cigarette-related cues increases both the intensity of cigarette craving and relative glucose metabolism of the perigenual/ventral anterior cingulate cortex (ACC). Given that treatment with bupropion HCl reduces overall cigarette craving levels in nicotine dependent subjects, we performed a preliminary study of smokers to determine if bupropion HCl treatment attenuates cue-induced cigarette craving and associated brain metabolic activation. Thirty-seven, otherwise healthy smokers (20 untreated and 17 who had received open-label treatment with bupropion HCl) underwent two (18)F-fluorodeoxyglucose positron emission tomography scanning sessions in randomized order--one when presented with neutral cues and the other when presented with cigarette-related cues. Bupropion-treated smokers had smaller cigarette cue-induced increases in craving scores on the Urge to Smoke (UTS) Scale and less activation of perigenual/ventral ACC metabolism from the neutral to the cigarette cue scan than untreated smokers. Thus, in addition to its known effects on spontaneous cigarette craving and withdrawal symptoms, bupropion HCl diminishes cue-induced cigarette craving and appears to attenuate cigarette cue-induced ACC activation. These results are consistent with the known effects of bupropion HCl, including its enhancement of catecholaminergic neurotransmission.

Adult↗
PubMed2004

Differences between smokers and nonsmokers in regional gray matter volumes and densities.

BACKGROUND: Magnetic resonance imaging (MRI) studies have demonstrated large-scale brain abnormalities in cigarette smokers, such as ventricular enlargement and atrophy. Converging lines of evidence point to functional differences between smokers and nonsmokers in specific brain regions, namely the lateral prefrontal cortex (PFC), anterior cingulate cortex (ACC), ventral striatum, and thalamus. Using MRI, we examined these regions for differences in gray matter between smokers and nonsmokers. METHODS: Thirty-six otherwise healthy adults (19 smokers and 17 nonsmoking control subjects) underwent three-dimensional Fourier-transform spoiled-gradient-recalled acquisition MRI of the brain. Both hand-drawn regions of interest and the computer program voxel-based morphometry were used to assess group differences in regional gray matter volumes and densities, respectively. RESULTS: Smokers had smaller gray matter volumes and lower gray matter densities than nonsmokers in the PFC bilaterally, along with smaller volumes in the left dorsal ACC and lower gray matter densities in the right cerebellum. Smokers also had negative associations between pack-year smoking history and PFC gray matter densities. CONCLUSIONS: Smokers and nonsmokers differed in regional gray matter in brain areas previously linked with nicotine dependence. These findings might reflect effects of chronic smoking, predisposing traits that lead to smoking, or some combination of these factors.

Adult↗
PubMed2004

Mood disturbances and regional cerebral metabolic abnormalities in recently abstinent methamphetamine abusers.

BACKGROUND: Mood disturbances in methamphetamine (MA) abusers likely influence drug use, but the neurobiological bases for these problems are poorly understood. OBJECTIVE: To assess regional brain function and its possible relationships with negative affect in newly abstinent MA abusers. DESIGN: Two groups were compared by measures of mood and cerebral glucose metabolism ([18F]fluorodeoxyglucose positron emission tomography) during performance of a vigilance task. SETTING: Participants were recruited from the general community to a research center. PARTICIPANTS: Seventeen abstaining (4-7 days) MA abusers (6 women) were compared with 18 control subjects (8 women). MAIN OUTCOME MEASURES: Self-reports of depressive symptoms and anxiety were measured, as were global and relative glucose metabolism in the orbitofrontal, cingulate, lateral prefrontal, and insular cortices and the amygdala, striatum, and cerebellum. RESULTS: Abusers of MA provided higher self-ratings of depression and anxiety than control subjects and differed significantly in relative regional glucose metabolism: lower in the anterior cingulate and insula and higher in the lateral orbitofrontal area, middle and posterior cingulate, amygdala, ventral striatum, and cerebellum. In MA abusers, self-reports of depressive symptoms covaried positively with relative glucose metabolism in limbic regions (eg, perigenual anterior cingulate gyrus and amygdala) and ratings of state and trait anxiety covaried negatively with relative activity in the anterior cingulate cortex and left insula. Trait anxiety also covaried negatively with relative activity in the orbitofrontal cortex and positively with amygdala activity. CONCLUSIONS: Abusers of MA have abnormalities in brain regions implicated in mood disorders. Relationships between relative glucose metabolism in limbic and paralimbic regions and self-reports of depression and anxiety in MA abusers suggest that these regions are involved in affective dysregulation and may be an important target of intervention for MA dependence.

Adult↗
PubMed2004

Asymmetry in alpha power predicts accuracy of hemispheric lexical decision.

OBJECTIVE: Previous work has shown that individual differences in resting alpha asymmetry are associated with efficacy on a variety of cognitive tasks. Still unresolved is how ongoing alpha asymmetry relates to behavioral asymmetry, explored here using lateralized lexical decision. METHODS: Alpha power immediately preceding lexical decision trials was measured to assess cognitive engagement during word recognition. This was compared with behavioral performance for the task, measured by accuracy and latency of the lexical decision response. RESULTS: Greater relative left hemisphere alpha power (i.e. higher asymmetry) immediately before presentation of a word led to reduced likelihood for its successful identification. Greater alpha asymmetry was also associated with reduced performance for identifying stimuli lateralized to the right visual field. CONCLUSIONS: Word recognition is facilitated by decreased asymmetry in cognitive engagement in the two cerebral hemispheres, particularly when the stimuli are lateralized to the left hemisphere (right visual field). SIGNIFICANCE: Results address the role of cognitive engagement in the two cerebral hemispheres, and its relationship with lexical access.

Alpha Rhythm↗
PubMed2004

Statistical parametric mapping applied to an autoradiographic study of cerebral activation during treadmill walking in rats.

Autoradiographs are conventionally analyzed by a region-of-interest (ROI) analysis. However, definition of ROIs on an image set is labor intensive, is subject to potential inter-rater bias, and is not well suited for anatomically variable structures that may not consistently correspond to specific ROIs. Most importantly, the ROI method is poorly suited for whole-brain analysis, where one wishes to detect all activations resulting from an experimental paradigm. A system developed for analysis of imaging data in humans, Statistical Parametric Mapping (SPM), avoids some of these limitations but has not previously been adapted as a tool for the analysis of autoradiographs. Here, we describe the application of SPM to an autoradiographic data set mapping cerebral activation in rats during treadmill walking. We studied freely moving, non-tethered rats that received injections of the cerebral blood flow tracer [14C]-iodoantipyrine, while they were performing a treadmill task (n = 7) or during a quiescent control condition (n = 6). Results obtained with SPM were compared to those previously reported using a standard ROI-based method of analysis [J. Cereb. Blood Flow Metab. 23(2003) 925]. The SPM method confirmed most areas detected as significant using the ROI approach. However, in the subcortex, SPM detected additional significant regions that, because of their irregular structures, fell short of statistical significance when analyzed by ROI. The SPM approach offers the ability to perform a semi-automated whole-brain analysis, and coupled with autoradiography, provides an effective means to globally localize functional activity in small animals.

Animals↗
PubMed2004

Smoking-induced ventral striatum dopamine release.

OBJECTIVE: Substantial evidence from animal models demonstrates that dopamine release in the ventral striatum underlies the reinforcing properties of nicotine. The authors used [(11)C]raclopride bolus-plus-continuous-infusion positron emission tomography (PET) to determine smoking-induced ventral striatum dopamine release in humans. METHOD: Twenty nicotine-dependent smokers (who smoked > or =15 cigarettes/day) underwent a [(11)C]raclopride bolus-plus-continuous-infusion PET session. During the session, subjects had a 10-minute break outside the PET apparatus during which 10 subjects smoked a cigarette and 10 did not smoke (as a control condition). RESULTS: The group that smoked had greater reductions in [(11)C]raclopride binding potential in ventral striatum regions of interest than the group that did not smoke, particularly in the left ventral caudate/nucleus accumbens and left ventral putamen (range for smoking group=-25.9% to -36.6% reduction). Significant correlations were found between change from before to after the smoking break in craving ratings and change from before to after the break in binding potential for these two regions. CONCLUSIONS: Nicotine-dependent subjects who smoked during a break in PET scanning had greater reductions in [(11)C]raclopride binding potential (an indirect measure of dopamine release) than nicotine-dependent subjects who did not smoke. The magnitude of binding potential changes was comparable to that found in studies that used similar methods to examine the effects of other addictive drugs.

Adult↗
PubMed2003

Complementary hemispheric specialization for word and accent detection.

When we hear a familiar word pronounced in a foreign accent, which parts of the brain identify the word and which identify the accent? Here we present converging evidence from PET blood flow, event-related scalp potentials, and behavioral responses during dichotic listening, showing homologous and complementary hemispheric specialization for word and accent detection. Accuracy of detecting target words was greater when stimuli were presented to the right ear, indicating left hemisphere specialization, with no ear advantage for detecting target accents. Detection of words also produced increased blood flow in a left frontal area associated with motor and phonetic processing, and a left temporal area associated with semantic memory. Homologous areas of the right hemisphere, together with right prefrontal and precuneus regions, showed increased blood flow during detection of accents. Separate analyses for each detection task indicated that voxels whose activity maximally correlated with accuracy were in the left hemisphere for word detection, but in the right hemisphere for accent detection. Voxels whose activity maximally correlated with inaccuracy were in the opposite hemisphere for both tasks, strengthening the interpretation that between-task differences in brain activation are related to lateralized specializations for task performance. ERP waveforms and reaction times suggested that greater left hemisphere activation during word detection preceded greater right hemisphere activation during accent detection. The results are interpreted as supporting left hemisphere specialization for extraction of the linguistic, phonetic, and semantic information contained in speech, and right hemisphere specialization for pragmatics, the social context of linguistic communication.

Adult↗