Andrew B. Newberg

A Randomized Add-on Trial of an N-methyl-d-aspartate Antagonist in Treatment-Resistant Bipolar Depression

CONTEXT Existing therapies for bipolar depression have a considerable lag of onset of action. Pharmacological strategies that produce rapid antidepressant effects-for instance, within a few hours or days-would have an enormous impact on patient care and public health. OBJECTIVE To determine whether an N-methyl-D-aspartate-receptor antagonist produces rapid antidepressant effects in subjects with bipolar depression. DESIGN A randomized, placebo-controlled, double-blind, crossover, add-on study conducted from October 2006 to June 2009. SETTING Mood Disorders Research Unit at the National Institute of Mental Health, Bethesda, Maryland. Patients Eighteen subjects with DSM-IV bipolar depression (treatment-resistant). INTERVENTIONS Subjects maintained at therapeutic levels of lithium or valproate received an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days 2 weeks apart. The Montgomery-Asberg Depression Rating Scale was used to rate subjects at baseline and at 40, 80, 110, and 230 minutes and on days 1, 2, 3, 7, 10, and 14 postinfusion. MAIN OUTCOME MEASURES Change in Montgomery-Asberg Depression Rating Scale primary efficacy measure scores. RESULTS Within 40 minutes, depressive symptoms significantly improved in subjects receiving ketamine compared with placebo (d = 0.52, 95% confidence interval [CI], 0.28-0.76); this improvement remained significant through day 3. The drug difference effect size was largest at day 2 (d = 0.80, 95% CI, 0.55-1.04). Seventy-one percent of subjects responded to ketamine and 6% responded to placebo at some point during the trial. One subject receiving ketamine and 1 receiving placebo developed manic symptoms. Ketamine was generally well tolerated; the most common adverse effect was dissociative symptoms, only at the 40-minute point. CONCLUSION In patients with treatment-resistant bipolar depression, robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist.

The measurement of regional cerebral blood flow during the complex cognitive task of meditation: a preliminary SPECT study

This study measured changes in regional cerebral blood flow (rCBF) during the complex cognitive task of meditation using single photon emission computed tomography. Eight experienced Tibetan Buddhist meditators were injected at baseline with 7 mCi HMPAO and scanned 20 min later for 45 min. The subjects then meditated for 1 h at which time they were injected with 25 mCi HMPAO and scanned 20 min later for 30 min. Values were obtained for regions of interest in major brain structures and normalized to whole brain activity. The percentage change between meditation and baseline was compared. Correlations between structures were also determined. Significantly increased rCBF (P<0.05) was observed in the cingulate gyrus, inferior and orbital frontal cortex, dorsolateral prefrontal cortex (DLPFC), and thalamus. The change in rCBF in the left DLPFC correlated negatively (P<0.05) with that in the left superior parietal lobe. Increased frontal rCBF may reflect focused concentration and thalamic increases overall increased cortical activity during meditation. The correlation between the DLPFC and the superior parietal lobe may reflect an altered sense of space experienced during meditation. These results suggest a complex rCBF pattern during the task of meditation.

F-18 FDG uptake in the large arteries : A new observation

Purpose The cellular components of the atherosclerotic plaque, such as macrophages, exhibits high glucose metabolic activity. The aim of this study was to show the frequency of vascular uptake and possibly to explain the significance of this finding on fluorodeoxyglucose (FDG) positron emission tomographic (PET) scans. Methods We evaluated the presence of FDG vascular uptake in 132 consecutive patients undergoing whole-body PET scans and 5 patients who had only lower extremity scans. The presence of vascular FDG uptake was assessed in the abdominal aorta, iliac, and proximal femoral arteries on the 132 whole-body scans, whereas only the femoral and the popliteal arteries were examined on the leg scans. The patients’ ages ranged from 20 to 80 years, and they were divided into three age groups: 35 patients were younger than 40 years (group 1; mean age, 32.4 years), 48 patients were 41 to 60 years (group 2; mean age, 50.3 years), and 54 patients were older than 60 years (group 3; mean age, 70.3 years). Results Fifty percent (69 of 137) of the total population showed vascular FDG uptake in at least one vessel. Thirty-four percent (12 of 35) of group 1, 50% (24 of 48) of group 2, and 61% (33 of 54) of group 3 showed vascular wall uptake (P = 0.017 between groups 1 and 3). In addition, the correlation between the mean age of the age groups and the prevalence of FDG vascular uptake is strong (r = 0.99). Conclusions Vascular FDG uptake is present in 50% of the patients examined for this study, with an increased prevalence in older patients. This vascular uptake might be explained by smooth muscle metabolism in the media, subendothelial smooth muscle proliferation from senescence, and the presence of macrophages within the atherosclerotic plaque. The relative contribution of these sources needs further investigation.

Neuroimaging in Traumatic Brain Imaging

SummaryTraumatic brain injury (TBI) is a common and potentially devastating clinical problem. Because prompt proper management of TBI sequelae can significantly alter the clinical course especially within 48 h of the injury, neuroimaging techniques have become an important part of the diagnostic work up of such patients. In the acute setting, these imaging studies can determine the presence and extent of injury and guide surgical planning and minimally invasive interventions. Neuroimaging also can be important in the chronic therapy of TBI, identifying chronic sequelae, determining prognosis, and guiding rehabilitation.

Voxel-level comparison of arterial spin-labeled perfusion MRI and FDG-PET in Alzheimer disease.

Objective: We compared the ability of arterial spin labeling (ASL), an MRI method that measures cerebral blood flow (CBF), to that of FDG-PET in distinguishing patients with Alzheimer disease (AD) from healthy, age-matched controls. Methods: Fifteen patients with AD (mean age 72 ± 6 years, Mini-Mental State Examination score [MMSE] 20 ± 6) and 19 age-matched controls (mean age 68 ± 6 years, MMSE 29 ± 1) underwent structural MRI. Participants were injected with 5 mCi of FDG during pseudocontinuous ASL scan, which was followed by PET scanning. Statistical parametric mapping and regions of interest (ROI) analysis were used to compare the ability of the 2 modalities in distinguishing patients from controls. Similarity between the 2 modalities was further assessed with linear correlation maps of CBF and metabolism to neuropsychological test scores. Results: Good agreement between hypoperfusion and hypometabolism patterns was observed, with overlap primarily in bilateral angular gyri and posterior cingulate. ROI results showed similar scales of functional deficit between patients and controls in both modalities. Both ASL and FDG-PET were able to distinguish neural networks associated with different neuropsychological tests with good overlap between modalities. Conclusions: Our voxel-wise results indicated that ASL-MRI provides largely overlapping information with FDG-PET. ROI analysis demonstrated that both modalities detected similar degrees of functional deficits in affected areas. Given its ease of acquisition and noninvasiveness, ASL-MRI may be an appealing alternative for AD studies.

Cerebral Blood Flow during Meditative Prayer: Preliminary Findings and Methodological Issues:

Meditative practices typically require several coordinated cognitive activities. This study measured changes in cerebral blood flow during “verbal” based meditation by Franciscan nuns involving the internal repetition of a particular phrase. These results are compared with those we previously described in eight Buddhist meditators who use a type of “visualization” technique. Three experienced practitioners of verbal meditation were injected via IV at rest with 260MBq of Tc-99m HMPAO and scanned 30 min. later on a triple head SPECT camera for 45 min. Following the baseline scan, subjects meditated for approximately 40 min. at which time they were injected with 925MBq of HMPAO while they continued to meditate for 10 min. more (total of 50 min. of meditation). The injection during meditation was designed not to disturb practice. Subjects were scanned 20 min. later for 30 min. Counts were obtained for regions of interest for major brain structures and normalized to whole-brain blood flow Compared to baseline, mean verbal meditation scans showed increased blood flow in the prefrontal cortex (7.1%), inferior parietal lobes (6.8%), and inferior frontal lobes (9.0%). There was a strong inverse correlation between the blood flow change in the prefrontal cortex and in the ipsilateral superior parietal lobe (p<.01). This study on a limited number of subjects demonstrated the feasibility of studying different types of meditation with neuroimaging techniques, suggested that several coordinated cognitive processes occur during meditation, and also raised important methodological issues.

[99mTc]TRODAT-1 SPECT imaging correlates with odor identification in early Parkinson disease.

Background: In vivo imaging of the dopamine transporter with [99mTc]TRODAT-1 (TRODAT) and olfactory testing have both been proposed as potential biomarkers in Parkinson disease (PD). Objective: To evaluate the relationship between TRODAT SPECT imaging, odor identification skills, and motor function in patients with early PD. Methods: Twenty-four patients with a clinical diagnosis of early-stage PD (mean Hoehn & Yahr stage = 1.4) underwent TRODAT imaging, Unified PD Rating Scale (UPDRS) ratings of motor function, and administration of the University of Pennsylvania Smell Identification Test (UPSIT). Brain images were obtained using a standardized processing protocol and specific uptake ratios for striatal regions of interest were calculated. Partial correlations between the imaging indices, disease duration, UPSIT scores, and UPDRS motor scores were then calculated. Results: UPSIT scores were correlated with TRODAT uptake in the striatum as a whole (r = 0.66, p = 0.001). The putamen showed the strongest correlation with the UPSIT (r = 0.74; p < 0.001). The correlation between dopamine transporter density in the caudate and UPSIT was moderate (r = 0.36, p = 0.11), but was not significant. Conclusions: Olfactory function is highly correlated with dopamine transporter imaging abnormalities in early Parkinson disease (PD). Further studies are warranted to determine whether changes over time in these two measures are also correlated in early PD.

Phase I evaluation of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer.

Background Preclinical data support further investigation of ascorbic acid in pancreatic cancer. There are currently insufficient safety data in human subjects, particularly when ascorbic acid is combined with chemotherapy. Methods and Findings 14 subjects with metastatic stage IV pancreatic cancer were recruited to receive an eight week cycle of intravenous ascorbic acid (three infusions per week), using a dose escalation design, along with standard treatment of gemcitabine and erlotinib. Of 14 recruited subjects enrolled, nine completed the study (three in each dosage tier). There were fifteen non-serious adverse events and eight serious adverse events, all likely related to progression of disease or treatment with gemcitabine or erlotinib. Applying RECIST 1.0 criteria, seven of the nine subjects had stable disease while the other two had progressive disease. Conclusions These initial safety data do not reveal increased toxicity with the addition of ascorbic acid to gemcitabine and erlotinib in pancreatic cancer patients. This, combined with the observed response to treatment, suggests the need for a phase II study of longer duration. Trial Registration Clinicaltrials.gov NCT00954525

FDG-PET imaging can diagnose periprosthetic infection of the hip.

AbstractA battery of diagnostic tests is often required to differentiate aseptic loosening from periprosthetic infection since the gold standard remains elusive. We designed a prospective study to determine the accuracy of fluorodeoxyglucose positron emission tomography (FDG-PET) imaging in diagnosing periprosthetic infection in a large multicenter setting. One hundred and thirteen patients with 127 painful hip prostheses were evaluated by FDG-PET. Images were considered positive for infection if PET demonstrated increased FDG activity at the bone-prosthesis interface of the femoral component. A combination of preoperative tests, intraoperative findings, histopathology, and clinical followup constituted the gold standard for diagnosing infection. Among the 35 positive PET scans, 28 hips were confirmed infected according to our criteria for diagnosing periprosthetic infection. Of the 92 hip prostheses with negative FDG-PET findings, 87 were considered aseptic. The sensitivity, specificity, positive and negative predictive values for FDG-PET were 0.85 (28 of 33), 0.93 (87 of 94), 0.80 (28 of 35), and 0.95 (87 of 92), respectively. The overall accuracy of this novel noninvasive imaging modality reached 0.91 (115 of 127). Based on our results, FDG-PET appears a promising and accurate diagnostic tool for distinguishing septic from aseptic painful hip prostheses. Level of Evidence: Level II, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence.

Human Mu Opioid Receptor (OPRM1 A118G) polymorphism is associated with brain mu-opioid receptor binding potential in smokers

Evidence points to the endogenous opioid system, and the mu-opioid receptor (MOR) in particular, in mediating the rewarding effects of drugs of abuse, including nicotine. A single nucleotide polymorphism (SNP) in the human MOR gene (OPRM1 A118G) has been shown to alter receptor protein level in preclinical models and smoking behavior in humans. To clarify the underlying mechanisms for these associations, we conducted an in vivo investigation of the effects of OPRM1 A118G genotype on MOR binding potential (BPND or receptor availability). Twenty-two smokers prescreened for genotype (12 A/A, 10 */G) completed two [11C]carfentanil positron emission tomography (PET) imaging sessions following overnight abstinence and exposure to a nicotine-containing cigarette and a denicotinized cigarette. Independent of session, smokers homozygous for the wild-type OPRM1 A allele exhibited significantly higher levels of MOR BPND than smokers carrying the G allele in bilateral amygdala, left thalamus, and left anterior cingulate cortex. Among G allele carriers, the extent of subjective reward difference (denicotinized versus nicotine cigarette) was associated significantly with MOR BPND difference in right amygdala, caudate, anterior cingulate cortex, and thalamus. Future translational investigations can elucidate the role of MORs in nicotine addiction, which may lead to development of novel therapeutics.