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Biomedical subjects

Alan J Fischman

Publications and source records attributed to Alan J Fischman.

At least 55 records · Page 3Linked to original sources
PubMed2004

Regional cerebral blood flow in the amygdala and medial prefrontal cortex during traumatic imagery in male and female Vietnam veterans with PTSD.

CONTEXT: Theoretical neuroanatomic models of posttraumatic stress disorder (PTSD) and the results of previous neuroimaging studies of PTSD highlight the potential importance of the amygdala and medial prefrontal regions in this disorder. However, the functional relationship between these brain regions in PTSD has not been directly examined. OBJECTIVE: To examine the relationship between the amygdala and medial prefrontal regions during symptom provocation in male combat veterans (MCVs) and female nurse veterans (FNVs) with PTSD. DESIGN: Case-control study. SETTING: Academic medical center. PARTICIPANTS: Volunteer sample of 17 (7 men and 10 women) Vietnam veterans with PTSD (PTSD group) and 19 (9 men and 10 women) Vietnam veterans without PTSD (control group). MAIN OUTCOME MEASURES: We used positron emission tomography and the script-driven imagery paradigm to study regional cerebral blood flow (rCBF) during the recollection of personal traumatic and neutral events. Psychophysiologic and emotional self-report data also were obtained to confirm the intended effects of script-driven imagery. RESULTS: The PTSD group exhibited rCBF decreases in medial frontal gyrus in the traumatic vs neutral comparison. When this comparison was conducted separately by subgroup, MCVs and FNVs with PTSD exhibited these medial frontal gyrus decreases. Only MCVs exhibited rCBF increases in the left amygdala. However, for both subgroups with PTSD, rCBF changes in medial frontal gyrus were inversely correlated with rCBF changes in the left amygdala and the right amygdala/periamygdaloid cortex. Furthermore, in the traumatic condition, for both subgroups with PTSD, symptom severity was positively related to rCBF in the right amygdala and negatively related to rCBF in medial frontal gyrus. CONCLUSIONS: These results suggest a reciprocal relationship between medial prefrontal cortex and amygdala function in PTSD and opposing associations between activity in these regions and symptom severity consistent with current functional neuroanatomic models of this disorder.

Amygdala↗
PubMed2004

Ventromedial prefrontal cortex and amygdala dysfunction during an anger induction positron emission tomography study in patients with major depressive disorder with anger attacks.

CONTEXT: Although a variety of functional neuroimaging studies have used emotion induction paradigms to investigate the neural basis of anger in control subjects, no functional neuroimaging studies using anger induction have been conducted in patient populations. OBJECTIVE: To study the neural basis of anger in unmedicated patients with major depressive disorder with anger attacks (MDD + A), unmedicated patients with MDD without anger attacks (MDD - A), and controls. DESIGN: We used positron emission tomography, psychophysiologic measures, and autobiographical narrative scripts in the context of an anger induction paradigm. SETTING: Academic medical center. PARTICIPANTS: Thirty individuals, evenly divided among the 3 study groups. INTERVENTIONS: In separate conditions, participants were exposed to anger and neutral autobiographical scripts during the positron emission tomography study. Subjective self-report and psychophysiologic data were also collected. MAIN OUTCOME MEASURES: Voxelwise methods were used for analyses of regional cerebral blood flow changes for the anger vs neutral contrast within and between groups. RESULTS: Controls showed significantly (P<.001) greater regional cerebral blood flow increases in the left ventromedial prefrontal cortex during anger induction than patients with MDD + A, whereas these differences were not present in other between-group analyses. Also, in controls, an inverse relationship was demonstrated between regional cerebral blood flow changes during anger induction in the left ventromedial prefrontal cortex and left amygdala, whereas in patients with MDD + A there was a positive correlation between these brain regions during anger induction. There was no significant relationship between these brain regions during anger induction in patients with MDD - A. CONCLUSION: These results suggest a pathophysiology of MDD + A that is distinct from that of MDD - A and that may be responsible for the unique clinical presentation of patients with MDD + A.

Adult↗
PubMed2004

Hippocampal function in posttraumatic stress disorder.

Recent studies have reported memory deficits and reduced hippocampal volumes in posttraumatic stress disorder (PTSD). The goal of the current research was to use functional neuroimaging and a validated explicit memory paradigm to examine hippocampal function in PTSD. We used positron emission tomography (PET) and a word-stem completion task to study regional cerebral blood flow (rCBF) in the hippocampus in 16 firefighters: 8 with PTSD (PTSD group) and 8 without PTSD (Control group). During PET scanning, participants viewed three-letter word stems on a computer screen and completed each stem with a word they had previously encoded either deeply (High Recall condition) or shallowly (Low Recall condition). Relative to the Control group, the PTSD group exhibited significantly smaller rCBF increases in the left hippocampus in the High vs Low Recall comparison. However, this finding reflected relatively elevated rCBF in the Low Recall condition in the PTSD group. Collapsing across High and Low Recall conditions, (1) the PTSD group had higher rCBF in bilateral hippocampus and left amygdala than the Control group, and (2) within the PTSD group, symptom severity was positively associated with rCBF in hippocampus and parahippocampal gyrus. The groups did not significantly differ with regard to accuracy scores on the word-stem completion task. The PTSD group had significantly smaller right (and a trend for smaller left) hippocampal volumes than the Control group. The results suggest an abnormal rCBF response in the hippocampus during explicit recollection of nonemotional material in firefighters with PTSD, and that this abnormal response appears to be driven by relatively elevated hippocampal rCBF in the comparison condition.

Adult↗
PubMed2004

Preparation and pharmacokinetics of 11C labeled stavudine (d4T).

Stavudine, a potent antiviral agent for treating human immunodeficiency virus (HIV) infections, was radiolabeled with (11)C by methylation of a specifically designed precursor, 5'-O-(2-tetrahydropyranyl)-5-bromo-2',3'-didehydro-3'-deoxythymidine, with (11)C H(3)I. The radiolabeled drug was isolated by reverse phase HPLC. A total time of approximately 45 minutes was required for synthesis, purification and isolation of (11)C stavudine with chemical and radiochemical purities of greater than 98%. (11)C stavudine was combined with unlabeled drug (2.0 mg/kg) and used to study its pharmacokinetics in rats by measurement of radioactivity in excised tissues. In this species, there was rapid accumulation of drug in all tissue. In all tissues, with the exceptions of testis and brain, highest concentrations of drug were detected at 5 minutes after injection and decreased monotonically thereafter. The peak concentration (microg/g) of stavudine in blood was 1.78 +/- 0.16 and similar levels were achieved in most other tissues; heart 1.66 +/- 0.11, lung 1.60 +/- 0.15, liver 2.13 +/- 0.17, spleen 1.61 +/- 0.15, adrenal 1.47 +/- 0.20, stomach 1.40 +/- 0.11, GI tract 1.44 +/- 0.14, skeletal muscle 1.38 +/- 0.15 and bone 1.30 +/- 0.16. Much higher peak concentrations were achieved in kidney; 7.23 +/- 0.57 microg/g. Concentrations in testis were lower and remained relatively constant over 1 hour; peak 0.62 +/- 0.14 microg/g at 15 min Brain concentrations were low but increased monotonically over time; peak 0.26 +/- 0.02 microg/g at 60 min. Future PET studies with this radiopharmaceutical will allow in vivo measurements of the pharmacokinetics of stavudine in both animal models and human subjects.

Animals↗
PubMed2004

Fluorodeoxyglucose positron emission tomography and CT after talc pleurodesis.

BACKGROUND: Talc pleurodesis is widely performed for the management of persistent pneumothorax or pleural effusion, particularly malignant effusions. However, there are very few data characterizing fluorodeoxyglucose (FDG)-positron emission tomography (PET) and CT findings after treatment. METHODS: We retrospectively evaluated the FDG-PET and CT studies of nine patients who underwent talc pleurodesis for the treatment of malignant pleural effusions or persistent air leak. RESULTS: FDG-PET studies were performed on average 22 months after talc pleurodesis, and the mean CT follow-up period was 25 months. There was moderate-to-intense plaque-like or focal nodular-increased FDG uptake in the pleura on PET with mean standardized uptake value of 5.4 (SEM, 1.2; range, 2.0 to 16.3). The FDG uptake was either diffuse (two patients) or focal (seven patients), and most commonly occurred in the posterior costophrenic angles (five patients), followed by the apical regions (three patients), anterior costophrenic angle (one patient), and the anterior chest wall (one patient). On CT, high-density areas of pleural thickening or nodularity (mean, 230 Hounsfield units [HU]; SEM, 23 HU; range, 140 to 380 HU) corresponded to regions of increased FDG uptake. These pleural foci had an average thickness of 1.2 cm and measured up to 8.2 cm (mean, 7.1 cm) in length. Rounded pleural nodules were as large as 3.1 cm (mean, 1.5 cm). CONCLUSIONS: Talc pleurodesis produces increased FDG uptake on PET and high-density areas of pleural thickening on CT that remain unchanged on serial imaging. When PET detects increased uptake in the pleural space, correlation with CT is recommended to detect the presence of pleural thickening of increased attenuation that suggests talc deposits rather than tumor.

Adult↗
PubMed2004

Does whole-body 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography have an advantage over thoracic positron emission tomography for staging patients with lung cancer?

BACKGROUND: Whole-body (WB) positron emission tomography (PET) with 2-[(18)F]-fluoro-2-deoxy-D-glucose (FDG) is more accurate than other imaging studies for detecting lung cancer and extrathoracic metastatic disease. Thoracic PET (from the skull base through the kidneys) may be equally as useful as WB PET (skull base to mid-thigh). With the recent introduction of hybrid CT-PET systems, use of thoracic PET would minimize radiation dose. METHODS: A retrospective review of a series of WB PET scans performed in our department was performed to identify patients evaluated for a solitary pulmonary nodule or newly diagnosed lung cancer who had distant extracranial and extrathoracic metastases detected by PET. All patients with true extrathoracic metastases were documented by ancillary radiologic and clinical data. Patients were staged according to the American Joint Committee on Cancer TNM system based on findings within the confines of a thoracic PET and WB PET. Comparison was made between staging based on thoracic and WB PET to determine if there was a significant difference. RESULTS: Of 1,026 studies, distant extracranial metastases were described in 35 patients with lung cancer. Findings were determined to be false-positive in nine patients. Of the 26 patients with true metastases on WB PET, 25 patients had metastatic lesions within the confines of thoracic PET. Relative to WB PET, the sensitivity of thoracic PET is 96.2% (95% confidence interval, 1 to 99.3%) for detection of distant metastases. Only one patient had an isolated metastasis that was detected only by WB PET. This patient would have been staged IIIB by thoracic PET as opposed to stage IV by WB PET. CONCLUSIONS: Thoracic PET, when compared to WB PET, is 96.2% sensitive for detecting extrathoracic metastases in patients with newly diagnosed non-small cell lung cancer.

Adult↗
PubMed2004

Insulin resistance in thermally-injured rats is associated with post-receptor alterations in skeletal muscle, liver and adipose tissue.

Several of the possible molecular mechanisms that contribute to the insulin resistance associated with burn injury were examined in a rat model of thermal injury. Rats were subjected to full thickness scald injury (25% total body surface area, 10 sec burn) and resuscitated with saline. After 1, 2 and 3 weeks, urinary C-peptide excretion was measured in burned and sham-treated control animals. At 3 weeks after injury, glucose production by the liver and utilization by skeletal muscle was measured under insulin clamp conditions, insulin receptor binding was measured in skeletal muscle, liver and adipose tissue membranes and IRS-1 expression was measured by Western blot methods. Urinary C-peptide excretion was significantly elevated at 1, 2 and 3 weeks after injury. At 3 weeks after injury, several key metabolic processes were blunted, including the ability of insulin infusion to stimulate glucose uptake by skeletal muscle, the potency of insulin infusion for inhibiting hepatic glucose production, and the ability of a bolus injection of insulin to simulate phosphorylation of IRS-1 in liver, skeletal muscle or adipose tissue. In contrast, there were no apparent alterations in the binding of insulin to membranes from liver, skeletal muscle or adipose tissue. These findings support the concept that the burn injury stimulates insulin production 3 weeks after burn injury, and produces insulin resistance in skeletal muscle, adipose tissue and liver by processes that are associated with post-receptor alterations in the absence of changes in insulin receptor binding.

Adipose Tissue↗
PubMed2003

Non-amine-based dopamine transporter (reuptake) inhibitors retain properties of amine-based progenitors.

Without exception, therapeutic and addictive drugs that produce their primary effects by blocking monoamine transporters in brain contain an amine nitrogen in their structure. This fundamental canon of drug design was based on a prevailing premise that an amine nitrogen is required to mimic the structures of monoamine neurotransmitters and other natural products. Non-amines, a novel class of compounds that contain no amine nitrogen, block monoamine transporters in the nM range and display markedly high selectivity for monoamine transporters, but not for receptors. Non-amines retain the spectrum of biochemical and pharmacological properties characteristic of amine-bearing counterparts. These novel drugs compel a revision of current concepts of drug-monoamine transporter complex formation and open avenues for discovery of a new generation of therapeutic drugs.

Animals↗
PubMed2003

Striatal dopamine release during unrewarded motor task in human volunteers.

SUMMARY: Striatal dopamine is associated with the processing of rewarded motor tasks. Its involvement in mediating unrewarded tasks is, however, unclear. We used a recently developed PET technique to dynamically measure the rate of displacement of a dopamine receptor ligand raclopride in healthy volunteers performing a finger opposition task. Rapid displacement of the ligand from the posterior putamen and the caudate immediately after the task initiation suggested striatal dopamine release during task performance. Since dopamine release was observed in the striatal areas that are implicated in unrewarded tasks by neuroimaging studies, the results demonstrate that the PET method can be used to extend the findings of conventional neuroimaging techniques, that do not provide information about signal transduction.

Adult↗
PubMed2003

Impaired hippocampal recruitment during normal modulation of memory performance in schizophrenia.

BACKGROUND: Patients with schizophrenia demonstrate poor verbal memory, ascribed to impaired prefrontal and hippocampal function. Healthy adults can increase recall accuracy following encoding interventions, such as item repetition and the formation of semantic associations. We examined the effects of these interventions on both memory performance and retrieval-related hippocampal activity in healthy adults and patients with schizophrenia. METHODS: Twelve patients with schizophrenia and twelve healthy control subjects participated. During study, subjects counted either the number of meanings or T-junctions in words seen only once or repeated four times. At test, O15-positron emission tomography scans were acquired while subjects completed word-stems with previously studied items. RESULTS: Control subjects recalled more words overall, but both groups demonstrated similar performance benefits following deeper encoding. Both item repetition and the use of a semantic encoding task were associated with memory retrieval-related hippocampal recruitment in control but not schizophrenic participants. Patients with schizophrenia demonstrated greater activation of prefrontal cortical areas during word retrieval. CONCLUSIONS: Despite a lack of hippocampal recruitment, patients with schizophrenia showed intact modulation of memory performance following both encoding interventions. Impaired hippocampal recruitment, in concert with greater prefrontal activation, may reflect a specific deficit in conscious recollection in schizophrenia.

Hippocampus↗
PubMed2003

A novel method for noninvasive detection of neuromodulatory changes in specific neurotransmitter systems.

Over the last decade, it has become possible to study theories of cognition using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). These methods yield statistical parametric maps of changes in cerebral blood flow (CBF) elicited by cognitive tasks. A limitation of these studies is that they provide no information about the underlying neurochemistry. However, it is possible to extend the concept of activation studies to include measurements targeting neurotransmitters and specific receptor populations. Cognitive activation increases neuronal firing rate, increasing the endogenous neurotransmitter level. The increased neurotransmitter level can be used to alter the kinetics of specifically bound radioligands. We describe a new approach to the design and analysis of neuromodulation experiments. This approach uses PET, a single-scan session design, and a linear extension of the simplified reference region model (LSSRM) that accounts for changes in ligand binding induced by cognitive tasks or drug challenge. In the LSSRM, an "activation" parameter is included that represents the presence or absence of change in apparent dissociation rate. Activation of the neurotransmitter is detected statistically when the activation parameter is shown to violate the null hypothesis. Simulation was used to explore the properties of the LSSRM with regard to model identifiability, effect of statistical noise, and confounding effects of CBF-related changes. Simulation predicted that it is possible to detect and map neuromodulatory changes in single-subject designs. A human study was conducted to confirm the predictions of simulation using (11)C-raclopride and a motor planning task. Parametric images of transport, binding potential, areas of significant dopamine release, and statistical parameters were computed. Examination of the kinetics of activation demonstrated that maximum dopamine release occurred immediately following task initiation and then decreased with a half-time of about 3 min. This method can be extended to explore neurotransmitter involvement in other behavioral and cognitive domains.

Adult↗
PubMed2003

Myocardial flow regulation in people with mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes/myoclonic epilepsy and ragged red fibers and other mitochondrial syndromes.

OBJECTIVE: This study tests the hypothesis that elevated levels of rest myocardial blood flow (MBF), indicative of inefficient aerobic metabolism, will be present in some patients with mitochondrial disorders but structurally normal hearts. BACKGROUND: Regulation of MBF is a complex process closely linked to myocardial energy production. Aerobic metabolism in turn depends on normal mitochondrial function and so investigation of patients with mitochondrial disorders may provide important information regarding heritable mechanisms involved in regulation of myocardial flow. METHODS: Rest and adenosine-stimulated MBF was measured by the positron emission tomography (PET) 13NH(3) technique in nine patients with mitochondrial disorders and compared with 15 age-matched control participants. RESULTS: Basal heart rate (beats/min) and rate pressure product (mm Hg/min) were elevated in patients (76+/-13 and 9302+/-1910, mean+/-SD, respectively) compared with control participants (63+/-9 and 7411+/-1531, P<0.01 and P<0.05, respectively). However, rest and adenosine-stimulated MBF (ml/min per g) did not differ significantly between groups (patients, 1.13+/-0.52 and 4.17+/-0.84, respectively; control participants, 0.85+/-0.30 and 3.56+/-0.63, respectively). Normalization of rest MBF to rate pressure product, however, demonstrated three patients whose values exceeded that of all control participants (chi2=5.71, P<0.05, Fisher's exact test). CONCLUSIONS: Elevated basal MBF, in some patients with mitochondrial disorders but structurally normal hearts, suggests the level of basal flow is responsive to efficiency of aerobic metabolism, which closely reflects mitochondrial function. Mitochondrial heteroplasmy with relative sparing of myocardial mitochondria may account for normal basal flow in others with these disorders.

Acidosis, Lactic↗
PubMed2003

Cerebral metabolic correlates as potential predictors of response to anterior cingulotomy for treatment of major depression.

OBJECT: Neurosurgical procedures are a viable intervention for severe, treatment-refractory major depression, although they have been associated with only modest rates of efficacy. The purpose of this study was to identify possible neuroimaging predictors of treatment response to anterior cingulotomy in patients with major depression. METHODS: Thirteen patients underwent stereotactic anterior cingulotomy for treatment-refractory major depression. Symptom severity was measured using the Beck Depression Inventory (BDI) both before and approximately 12 months after surgery. The authors performed [18F]fluorodeoxyglucose-positron emission tomography (PET) studies in all patients preoperatively. Statistical parametric mapping methods were used to test for loci of significant correlation between preoperative regional cerebral metabolism and postoperative reduction in BDI scores. The mean (+/- standard deviation) change in the BDI score from the preoperative period (43.7 +/- 7.8) to the postoperative period (30.5 +/- 21.3) was 33.1 +/- 45.4%. Two loci--the left subgenual prefrontal cortex and left thalamus--were identified as sites at which preoperative metabolism was significantly correlated with subsequent improvement in depressive symptom severity following cingulotomy. Specifically, higher preoperative rates of metabolism at these loci were associated with better postoperative results. CONCLUSIONS: Possible PET scanning predictors of treatment response were identified in patients with major depression who had undergone anterior cingulotomy. Further research will be necessary to determine the reproducibility of this finding. If confirmed, the availability of an index for noninvasively predicting a patient's response to cingulotomy for the treatment of major depression would be of great clinical value.

Adult↗
PubMed2003

Central role of interleukin-6 in burn induced stimulation of hepatic amino acid transport.

Burn injury produces a marked and prolonged hypermetabolic state, which is characterized by accelerated hepatic amino acid metabolism and negative nitrogen balance. The effect of burn injury on hepatocyte transport of glutamine, a key substrate in gluconeogenesis and ureagenesis, was examined following the administration of a full thickness 20% total body surface scald injury. The burn injury was induced in wild-type mice, as well as two types of knockout mice: a CD-14 knockout and an interleukin-6 (IL-6) knockout. In both the wild-type and CD-14 knockout mice a latent and profound 2-fold increase in hepatocyte glutamine transport was seen. In contrast, hepatocytes isolated from IL-6 knockout mice failed to show an induction of glutamine transport after burn injury. Hepatocytes isolated from burned wild-type and CD-14 knockout mice produced significantly higher levels of IL-6 as compared to hepatocytes isolated from sham burned mice. Histologic analysis of skin isolated from wild-type mice showed a robust inflammatory response whereas skin from IL-6 deficient mice showed minimal inflammation and decreased granulation tissue. The results of this study suggest that IL-6 may play a key role in the stimulation of hepatic glutamine transport following burn injury.

Amino Acids↗
PubMed2003

Quantification of regional ventilation-perfusion ratios with PET.

UNLABELLED: The topographic matching of alveolar ventilation (V(A)) and perfusion (Q) is the main determinant of gas exchange efficiency of the lung. However, no pulmonary functional imaging technique has been shown to predict whole-lung gas exchange in health and disease. This study aims to present a PET-based method to estimate regional alveolar ventilation-to-perfusion ratios (V(A)/Q) predictive of arterial blood gases. METHODS: The method is based on the regional tracer kinetics of (13)N-nitrogen ((13)NN) after an intravenous bolus injection during a breath-hold period and subsequent washout from the lungs with resumption of breathing. The method takes into account the presence of inter- and intraregional nonuniformities at length scales smaller than the imaging spatial resolution. An algorithm used regional tracer washout to classify regional V(A)Q/ uniformity. Intraregional V(A)/Q mismatch in nonuniform regions was described with a 2-compartment model. Regional V(A)/Q estimates were combined into a whole-lung distribution of V(A)/Q ratios and were used to compute global arterial blood gases. The method was applied to 3-dimensional PET data from anesthetized and mechanically ventilated sheep before and after methacholine bronchoconstriction (n = 3) and pulmonary embolism (n = 3) and after saline lung lavage (n = 3). RESULTS: PET images revealed regional changes in ventilation and perfusion consistent with the different disease models. Quantification of the images using PET-derived V(A)Q/ distributions showed unimodal and narrow distributions in control conditions that became wider and unimodal after pulmonary embolism and saline lung lavage and bimodal after bronchoconstriction. Images of regional gas exchange allowed for visualization of regional gas exchange. Arterial blood gases estimated from the PET-based V(A)/Q distributions closely agreed with measured values (partial pressure of oxygen, arterial [PaO(2)]: r(2) = 0.97, P < 0.001; partial pressure of carbon dioxide, arterial [PaCO(2)]: r(2) = 0.96, P < 0.001). CONCLUSION: Tracer kinetics analysis of PET images after an intravenous injection of (13)NN provides a quantitative assessment of regional V(A)/Q heterogeneity including that corresponding to length scales smaller than the spatial resolution of the imaging method. Quantification of V(A)/Q mismatch obtained with the presented technique is directly related to severity of gas exchange impairment as determined by arterial blood gases.

Algorithms↗