Publications by authors named "Mark A Mandelkern"

81 Publications

Information Transfer and Multifractal Analysis of EEG in Mild Blast-Induced TBI.

Comput Math Methods Med 2021 6;2021:6638724. Epub 2021 Apr 6.

The Boeing Company, USA.

Mild, blast-induced traumatic brain injury (mbTBI) is a common combat brain injury characterized by typically normal neuroimaging findings, with unpredictable future cognitive recovery. Traditional methods of electroencephalography (EEG) analysis (e.g., spectral analysis) have not been successful in detecting the degree of cognitive and functional impairment in mbTBI. We therefore collected resting state EEG (5 minutes, 64 leads) from twelve patients with a history of mbTBI, along with repeat neuropsychological testing (D-KEFS Tower test) to compare two new methods for analyzing EEG (multifractal detrended fluctuation analysis (MF-DFA) and information transfer modeling (ITM)) with spectral analysis. For MF-DFA, we extracted relevant parameters from the resultant multifractal spectrum from all leads and compared with traditional power by frequency band for spectral analysis. For ITM, because the number of parameters from each lead far exceeded the number of subjects, we utilized a reduced set of 10 leads which were compared with spectral analysis. We utilized separate 30 second EEG segments for training and testing statistical models based upon regression tree analysis. ITM and MF-DFA models both generally had improved accuracy at correlating with relevant measures of cognitive performance as compared to spectral analytic models ITM and MF-DFA both merit additional research as analytic tools for EEG and cognition in TBI.
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http://dx.doi.org/10.1155/2021/6638724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051525PMC
September 2021

The relationship between duration of abstinence and gray-matter brain structure in chronic methamphetamine users.

Am J Drug Alcohol Abuse 2021 01 10;47(1):65-73. Epub 2021 Jan 10.

Department of Psychiatry and Biobehavioral Sciences, UCLA Semel Institute for Neuroscience, David Geffen School of Medicine, Los Angeles, CA, USA.

Brain structural findings in chronic methamphetamine users have been inconsistent. Identifying contributing influences (e.g., sex, abstinence duration) can help clarify the clinical course of recovery. We studied the effects of long-term methamphetamine abstinence on gray-matter volume. Our hypothesis was that smaller volume early in abstinence would precede long-term recovery. Individuals who used methamphetamine (≥100 g lifetime use, mandated to residential treatment for methamphetamine-positive urine; 40 men, 21 women), undergoing supervised abstinence (men: 12-400 days; women: 130-594 days), were compared to healthy controls (49 men, 36 women) using T1-weighted MRI. Volumes of orbitofrontal, anterior cingulate and parietal cortex, hippocampus, and striatum were measured using Freesurfer software. Associations of volumes with abstinence duration were tested in males and females separately because their abstinence times differed (121.5 ± 124.5 vs. 348.0 ± 128.6 days, < 0.001); only males were studied in early abstinence. The General Linear Model was used to test effects of abstinence duration and group (methamphetamine users vs. controls). In males, duration of abstinence was multivariate significant for gray-matter volumes ( = 0.017). Abstinence duration was associated with increases in volumes of the orbitofrontal and parietal cortices (ps = 0.031, 0.016) and hippocampi (ps = 0.044). Irrespective of abstinence, male methamphetamine users had smaller hippocampi than male controls ( = 0.008). Females showed no significant effects of group or abstinence. In males, abstinence from methamphetamine appears to result in volumetric increases in regions important for cognitive function, which may affect recovery during the course of treatment. Data from the period of early abstinence are required to evaluate volumetric changes in females.
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http://dx.doi.org/10.1080/00952990.2020.1778712DOI Listing
January 2021

Striatal dopamine D-type receptor availability and peripheral 17β-estradiol.

Mol Psychiatry 2021 Jun 8;26(6):2038-2047. Epub 2021 Jan 8.

Jane and Terry Semel Institute for Neuroscience and Human Behavior at UCLA, Los Angeles, CA, 90095, USA.

Research using rodent models has established a relationship between the steroid hormone estrogen and dopamine function, by revealing changes throughout the estrous cycle and by directly manipulating neuroendocrine signaling through ovariectomy and administration of estrogen. However, a direct link between estrogen levels and dopamine signaling had not been established in humans. The goal of this study, therefore, was to assess the relationship between circulating 17β-estradiol and dopamine signaling in the human brain by testing for a relationship between two proxies for these variables: peripheral 17β-estradiol and striatal dopamine D-type receptor availability, measured with [F]fallypride and positron emission tomography (PET). Sixteen (23-45 years of age) women were tested on 2 days of the menstrual cycle estimated prospectively to occur during (a) the early follicular phase, when estrogen levels are near their nadir, and (b) the periovulatory phase, when estrogen levels peak. PET scans with [F]fallypride were performed on these 2 days, and serum 17β-estradiol was measured using radioimmunoassay. Dopamine D-type receptor availability did not differ significantly in the whole striatum or the caudate, putamen, or accumbens subregions during the high-estrogen vs. the low-estrogen phases of the menstrual cycle. We conclude that circulating estrogen levels do not affect dopamine D-type receptor availability in the human striatum although other indices of dopaminergic function may be affected.
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http://dx.doi.org/10.1038/s41380-020-01000-1DOI Listing
June 2021

No significant elevation of translocator protein binding in the brains of recently abstinent methamphetamine users.

Drug Alcohol Depend 2020 Jun 11;213:108104. Epub 2020 Jun 11.

Department of Research, Veterans Administration Greater Los Angeles Healthcare System (VAGLAHS), Los Angeles, CA, 90073, USA; Department of Physics, University of California Irvine, Irvine, CA, 92697, USA.

Background: Radioligands for the translocator protein (TSPO) 18 kDa have been used with positron emission tomography (PET) to assess neuroinflammation and microglial activation in psychiatric disorders. One study using this approach showed substantial TSPO elevation throughout the brain in chronic methamphetamine users following long-term abstinence (0.5-4 years), but clients typically present for treatment earlier in abstinence.

Methods: We used PET with [C]DAA1106 to compare standardized uptake values (SUVs) as an index of TSPO binding in the brains of methamphetamine-dependent participants who were abstinent for < 6 months (n = 11) and healthy controls (n = 12). We also assayed other typical correlates of Methamphetamine Dependence (e.g., striatal D2-type dopamine receptor deficits, depressed mood, anxiety and impaired emotion regulation).

Results: Methamphetamine users exhibited depression (p < 0.0001), anxiety (p = 0.002), difficulties in emotional regulation (p = 0.01), and lower striatal dopamine D2-type receptor availability vs. controls (p = 0.02). SUVs for [C]DAA1106 were larger in all brain regions of methamphetamine-dependent participants vs. controls, but the effect size was small to medium and not statistically significant.

Conclusions: The discrepancy between the lack of significant difference in TSPO binding in early-abstinent methamphetamine users vs. controls in this study and a previous report of elevated binding in longer-abstinent methamphetamine users may reflect methodological differences or limitations of TSPO binding as an index of neuroinflammation. It also seems possible that gliosis increases over time during the first 6 months of abstinence; longitudinal studies could clarify this possibility.
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http://dx.doi.org/10.1016/j.drugalcdep.2020.108104DOI Listing
June 2020

EEG multifractal analysis correlates with cognitive testing scores and clinical staging in mild cognitive impairment.

J Clin Neurosci 2020 Jun 16;76:195-200. Epub 2020 Apr 16.

Greater Los Angeles VA Dept. of Nuclear Imaging, University of California, Irvine, United States; Dept. of Physics, University of California, Irvine, United States.

Alzheimer's disease and mild cognitive impairment are increasingly prevalent global health concerns in aging industrialized societies. There are only limited non-invasive biomarkers for the cognitive and functional impairment associated with dementia. Multifractal analysis of EEG has recently been proposed as having the potential to be an improved method of quantitative EEG analysis compared to existing techniques (e.g., spectral analysis). We utilized an existing database of a study of healthy elderly patients (N = 20) who were assessed with cognitive testing (Folstein Mini Mental Status Exam; MMSE) and resting state EEG (4 leads). Each subject's EEG was separated into two 30 s tracings for training and testing a statistical model against the MMSE scores. We compared multifractal detrended fluctuation analysis (MF-DFA) against Fourier Transform (FT) in the ability to produce an accurate classification and regression trees estimator for the testing EEG segments. The MF-DFA-based statistical model MMSE estimation strongly correlated with the actual MMSE when applied to the test EEG parameter dataset, whereas the corresponding FT-based model did not. Using a standardized cutoff value for MMSE-based clinical staging, the MF-DFA-based statistical model was both sensitive and specific for clinical staging of both mild Alzheimer's disease and mild cognitive impairment. MF-DFA shows promise as a method of quantitative EEG analysis to accurately estimate cognition in Alzheimer's disease.
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http://dx.doi.org/10.1016/j.jocn.2020.04.003DOI Listing
June 2020

Effects of Citalopram on Cue-Induced Alcohol Craving and Thalamic D2/3 Dopamine Receptor Availability.

Int J Neuropsychopharmacol 2019 04;22(4):286-291

Department of Psychiatry, Harbor-UCLA Medical Center, Los Angeles, California.

Background: Selective serotonin reuptake inhibitors are often used in alcohol use disorders. Clinical trials with selective serotonin reuptake inhibitors for alcohol use disorders, however, have yielded mixed results. The goal of this project was to assess whether a single i.v. dose of a selective serotonin reuptake inhibitor reduces craving for alcohol and/or simultaneously increases striatal dopamine concentration in individuals with alcohol dependence.

Methods: Alcohol-dependent (DSM-IV-TR criteria) volunteers and matched controls (n = 10/group) underwent a double-blind, placebo-controlled, within-subjects study. Participants received i.v. citalopram (40 mg) or saline (counter-balanced) followed by a cue-induced craving assessment and [18F]-fallypride positron emission tomography scanning.

Results: In the alcohol-dependent individuals, the citalopram (compared with saline) resulted in decreased cue-induced craving for alcohol. For the whole study group, cue-induced alcohol craving was inversely correlated with thalamic (but not striatal) dopamine D2/3 receptor availability.

Conclusions: Acute serotonin reuptake inhibition reduces cue-induced alcohol craving. Furthermore, thalamic dopamine abnormalities and the striatal hyperdopaminergic hypothesis of alcohol use disorder are supported.
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http://dx.doi.org/10.1093/ijnp/pyz010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441125PMC
April 2019

Effect of overnight smoking abstinence on a marker for microglial activation: a [C]DAA1106 positron emission tomography study.

Psychopharmacology (Berl) 2018 Dec 20;235(12):3525-3534. Epub 2018 Oct 20.

Nuclear Medicine Service, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA.

Rationale: Microglia are the main immune cells in the central nervous system and participate in neuroinflammation. When activated, microglia express increased levels of the translocator protein 18 kDa (TSPO), thereby making TSPO availability a marker for neuroinflammation. Using positron emission tomography (PET) scanning, our group recently demonstrated that smokers in the satiated state had 16.8% less binding of the radiotracer [C]DAA1106 (a radioligand for TSPO) in the brain than nonsmokers.

Objectives: We sought to determine the effect of overnight smoking abstinence on [C]DAA1106 binding in the brain.

Methods: Forty participants (22 smokers and 18 nonsmokers) completed the study (at one of two sites) and had usable data, which included images from a dynamic [C]DAA1106 PET scanning session (with smokers having been abstinent for 17.9 ± 2.3 h) and a blood sample for TSPO genotyping. Whole brain standardized uptake values (SUVs) were determined, and analysis of variance was performed, with group (overnight abstinent smoker vs. nonsmoker), site, and TSPO genotype as factors, thereby controlling for site and genotype.

Results: Overnight abstinent smokers had lower whole brain SUVs (by 15.5 and 17.0% for the two study sites) than nonsmokers (ANCOVA, P = 0.004). The groups did not significantly differ in injected radiotracer dose or body weight, which were used to calculate SUV.

Conclusions: These results in overnight abstinent smokers are similar to those in satiated smokers, indicating that chronic cigarette smoking leads to global impairment of microglial activation which persists into early abstinence. Other explanations for study results, such as smoking leading to reduced numbers of microglia or smokers having more rapid metabolism of the radiotracer than nonsmokers, are also possible.
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http://dx.doi.org/10.1007/s00213-018-5077-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497451PMC
December 2018

Low Striatal Dopamine D2-type Receptor Availability is Linked to Simulated Drug Choice in Methamphetamine Users.

Neuropsychopharmacology 2018 03 30;43(4):751-760. Epub 2017 Jun 30.

Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Individuals with drug use disorders seek drugs over other rewarding activities, and exhibit neurochemical deficits related to dopamine, which is involved in value-based learning and decision-making. Thus, a dopaminergic disturbance may underpin drug-biased choice in addiction. Classical drug-choice assessments, which offer drug-consumption opportunities, are inappropriate for addicted individuals seeking treatment or abstaining. Fifteen recently abstinent methamphetamine users and 15 healthy controls completed two laboratory paradigms of 'simulated' drug choice (choice for drug-related vs affectively pleasant, unpleasant, and neutral images), and underwent positron emission tomography measurements of dopamine D2-type receptor availability, indicated by binding potential (BP) for [F]fallypride. Thirteen of the methamphetamine users and 10 controls also underwent [C]NNC112 PET scans to measure dopamine D1-type receptor availability. Group analyses showed that, compared with controls, methamphetamine users chose to view more methamphetamine-related images on one task, with a similar trend on the second task. Regression analyses showed that, on both tasks, the more methamphetamine users chose to view methamphetamine images, specifically vs pleasant images (the most frequently chosen images across all participants), the lower was their D2-type BP in the lateral orbitofrontal cortex, an important region in value-based choice. No associations were observed with D2-type BP in striatal regions, or with D1-type BP in any region. These results identify a neurochemical correlate for a laboratory drug-seeking paradigm that can be administered to treatment-seeking and abstaining drug-addicted individuals. More broadly, these results refine the central hypothesis that dopamine-system deficits contribute to drug-biased decision-making in addiction, here showing a role for the orbitofrontal cortex.
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http://dx.doi.org/10.1038/npp.2017.138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809782PMC
March 2018

Effect of Cigarette Smoking on a Marker for Neuroinflammation: A [C]DAA1106 Positron Emission Tomography Study.

Neuropsychopharmacology 2017 Jul 6;42(8):1630-1639. Epub 2017 Mar 6.

Department of Radiology, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA.

In the brain, microglia continuously scan the surrounding extracellular space in order to respond to damage or infection by becoming activated and participating in neuroinflammation. When activated, microglia increase the expression of translocator protein (TSPO) 18 kDa, thereby making the TSPO expression a marker for neuroinflammation. We used the radiotracer [C]DAA1106 (a ligand for TSPO) and positron emission tomography (PET) to determine the effect of smoking on availability of this marker for neuroinflammation. Forty-five participants (30 smokers and 15 non-smokers) completed the study and had usable data. Participants underwent a dynamic PET scanning session with bolus injection of [C]DAA1106 (with smokers in the satiated state) and blood draws during PET scanning to determine TSPO affinity genotype and plasma nicotine levels. Whole-brain standardized uptake values (SUVs) were determined, and analysis of variance was performed, with group (smoker vs non-smoker) and genotype as factors, thereby controlling for genotype. Smokers and non-smokers differed in whole-brain SUVs (P=0.006) owing to smokers having 16.8% lower values than non-smokers. The groups did not differ in injected radiotracer dose or body weight, which were used to calculate SUV. An inverse association was found between whole-brain SUV and reported cigarettes per day (P<0.05), but no significant relationship was found for plasma nicotine. Thus, smokers have less [C]DAA1106 binding globally than non-smokers, indicating less microglial activation. Study findings are consistent with much prior research demonstrating that smokers have impaired inflammatory functioning compared with non-smokers and that constituents of tobacco smoke other than nicotine affect inflammatory processes.
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http://dx.doi.org/10.1038/npp.2017.48DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518907PMC
July 2017

Neuromodulation for Treatment-Refractory PTSD.

Fed Pract 2017 Mar;34(Suppl 2):20S-33S

is a neurosurgeon, is a neurologist, is a radiologist, and is a neurophysiologist in the research and development service; and are mental/behavioral health physicians, is a psychologist, and is a mental/behavioral health physician in the psychiatry and mental health service; all at the VA Greater Los Angeles Healthcare System in California. Dr. Langevin, Dr. Koek, Dr. Chen, Dr. Sultzer, Dr. Mandelkern, and Dr. Krahl are professors at David Geffen School of Medicine at the University of California Los Angeles.

Deep brain stimulation has been successful in treating Parkinson disease and essential tremor and is now reducing PTSD symptoms in the first patient enrolled in an early-phase safety trial.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375501PMC
March 2017

F-Fluorodeoxyglucose Positron Emission Tomography Cortical Metabolic Activity Associated with Distinct Agitation Behaviors in Alzheimer Disease.

Am J Geriatr Psychiatry 2017 Jun 31;25(6):569-579. Epub 2017 Jan 31.

Brain Behavior and Aging Research Center, VA Greater Los Angeles Healthcare System, Los Angeles, CA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA.

Objective: This study aimed to investigate the neurobiologic correlates of two distinct clusters of agitation symptoms to identify the unique biologic substrates underlying agitated behaviors.

Methods: Eighty-eight outpatients with mild to moderate Alzheimer disease (AD) were recruited from the VA Greater Los Angeles Healthcare System Geropsychiatry Outpatient Program. A cross-sectional investigation was conducted of the relationship between cerebral glucose metabolism measured via F-fluorodeoxyglucose positron emission tomography and agitated symptoms from the Neuropsychiatric Inventory (NPI) in patients with AD. Two empirically derived clusters of agitation symptoms were investigated: an Agitation factor comprising agitation/aggression and irritability/lability items of the NPI, and a Behavioral Dyscontrol factor comprising elation/euphoria, disinhibition, aberrant motor behavior, sleep, and appetite items of the NPI. Mean cerebral metabolism for patients who scored positively on each of the two factors was compared with mean cerebral metabolism for those who did not.

Results: Patients with AD who scored positively on the Agitation factor showed reduced glucose metabolism of the right temporal, right frontal, and bilateral cingulate cortex. In contrast, the Behavioral Dyscontrol factor did not show specific neurobiologic correlates.

Conclusion: Symptoms encompassed within the Agitation factor have distinct neurobiologic underpinnings. The precipitants, course, and outcomes related to these symptoms may be unique from other neuropsychiatric symptoms characteristic of AD. Special attention to treatment of agitated behaviors involving anger, aggressiveness, hostility, and irritability/emotional lability is warranted, because they appear to reflect a clinically relevant symptom cluster with unique underlying neurobiologic correlates.
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http://dx.doi.org/10.1016/j.jagp.2017.01.017DOI Listing
June 2017

Cholinergic Receptor Binding in Alzheimer Disease and Healthy Aging: Assessment In Vivo with Positron Emission Tomography Imaging.

Am J Geriatr Psychiatry 2017 Apr 4;25(4):342-353. Epub 2017 Jan 4.

Imaging Service, VA Greater Los Angeles Healthcare Center, Los Angeles, CA; Department of Physics, University of California-Irvine, Irvine, CA.

Objective: To compare regional nicotinic cholinergic receptor binding in older adults with Alzheimer disease (AD) and healthy older adults in vivo and to assess relationships between receptor binding and clinical symptoms.

Methods: Using cross-sectional positron emission tomography (PET) neuroimaging and structured clinical assessment, outpatients with mild to moderate AD (N = 24) and healthy older adults without cognitive complaints (C group; N = 22) were studied. PET imaging of α4β2* nicotinic cholinergic receptor binding using 2-[F]fluoro-3-(2(S)azetidinylmethoxy)pyridine (2FA) and clinical measures of global cognition, attention/processing speed, verbal memory, visuospatial memory, and neuropsychiatric symptoms were used.

Results: 2FA binding was lower in the AD group compared with the C group in the medial thalamus, medial temporal cortex, anterior cingulate, insula/opercula, inferior caudate, and brainstem (p < 0.05, corrected cluster), but binding was not associated with cognition. The C group had significant inverse correlations between 2FA binding in the thalamus (left: r = -0.55, p = 0.008; right: r = -0.50, p = 0.02; N = 22) and hippocampus (left: r = -0.65, p = 0.001; right: r = -0.55, p = 0.009; N = 22) and the Trails A score. The AD group had inverse correlation between 2FA binding in anterior cingulate (left: r = -0.50, p = 0.01; right: r = -0.50, p = 0.01; N = 24) and Neurobehavioral Rating Scale agitation/disinhibition factor score.

Conclusion: Cholinergic receptor binding is reduced in specific brain regions in mild to moderate AD and is related to neuropsychiatric symptoms. Among healthy older adults, lower receptor binding may be associated with slower processing speed. Cholinergic receptor binding in vivo may reveal links to other key brain changes associated with aging and AD and may provide a potential molecular treatment target.
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http://dx.doi.org/10.1016/j.jagp.2016.11.011DOI Listing
April 2017

Cigarette Use and Striatal Dopamine D2/3 Receptors: Possible Role in the Link between Smoking and Nicotine Dependence.

Int J Neuropsychopharmacol 2016 11 3;19(11). Epub 2016 Dec 3.

Department of Psychiatry and Biobehavioral Sciences (Drs Okita and London), Department of Molecular and Medical Pharmacology (Dr London), and Brain Research Institute (Dr London), University of California, Los Angeles, CA;

Background: Cigarette smoking induces dopamine release in the striatum, and smoking- or nicotine-induced ventral striatal dopamine release is correlated with nicotine dependence. Smokers also exhibit lower dopamine D2/3 receptor availability in the dorsal striatum than nonsmokers. Negative correlations of striatal dopamine D2/3 receptor availability with smoking exposure and nicotine dependence, therefore, might be expected but have not been tested.

Methods: Twenty smokers had positron emission tomography scans with [F]fallypride to measure dopamine D2/3 receptor availability in ventral and dorsal regions of the striatum and provided self-report measures of recent and lifetime smoking and of nicotine dependence.

Results: As reported before, lifetime smoking was correlated with nicotine dependence. New findings were that ventral striatal dopamine D2/3 receptor availability was negatively correlated with recent and lifetime smoking and also with nicotine dependence.

Conclusion: The results suggest an effect of smoking on ventral striatal D2/3 dopamine receptors that may contribute to nicotine dependence.
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http://dx.doi.org/10.1093/ijnp/pyw074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5137283PMC
November 2016

Deep Brain Stimulation of the Basolateral Amygdala: Targeting Technique and Electrodiagnostic Findings.

Brain Sci 2016 Aug 10;6(3). Epub 2016 Aug 10.

Research and Development Service, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA.

The amygdala plays a critical role in emotion regulation. It could prove to be an effective neuromodulation target in the treatment of psychiatric conditions characterized by failure of extinction. We aim to describe our targeting technique, and intra-operative and post-operative electrodiagnostic findings associated with the placement of deep brain stimulation (DBS) electrodes in the amygdala. We used a transfrontal approach to implant DBS electrodes in the basolateral nucleus of the amygdala (BLn) of a patient suffering from severe post-traumatic stress disorder. We used microelectrode recording (MER) and awake intra-operative neurostimulation to assist with the placement. Post-operatively, the patient underwent monthly surveillance electroencephalograms (EEG). MER predicted the trajectory of the electrode through the amygdala. The right BLn showed a higher spike frequency than the left BLn. Intra-operative neurostimulation of the BLn elicited pleasant memories. The monthly EEG showed the presence of more sleep patterns over time with DBS. BLn DBS electrodes can be placed using a transfrontal approach. MER can predict the trajectory of the electrode in the amygdala and it may reflect the BLn neuronal activity underlying post-traumatic stress disorder PTSD. The EEG findings may underscore the reduction in anxiety.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5039457PMC
http://dx.doi.org/10.3390/brainsci6030028DOI Listing
August 2016

Nicotinic acetylcholine receptor availability in cigarette smokers: effect of heavy caffeine or marijuana use.

Psychopharmacology (Berl) 2016 Sep 1;233(17):3249-57. Epub 2016 Jul 1.

Departments of Psychiatry and Research, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA.

Rationale: Upregulation of α4β2* nicotinic acetylcholine receptors (nAChRs) is one of the most well-established effects of chronic cigarette smoking on the brain. Prior research by our group gave a preliminary indication that cigarette smokers with concomitant use of caffeine or marijuana have altered nAChR availability.

Objective: We sought to determine if smokers with heavy caffeine or marijuana use have different levels of α4β2* nAChRs than smokers without these drug usages.

Methods: One hundred and one positron emission tomography (PET) scans, using the radiotracer 2-FA (a ligand for β2*-containing nAChRs), were obtained from four groups of males: non-smokers without heavy caffeine or marijuana use, smokers without heavy caffeine or marijuana use, smokers with heavy caffeine use (mean four coffee cups per day), and smokers with heavy marijuana use (mean 22 days of use per month). Total distribution volume (Vt/fp) was determined for the brainstem, prefrontal cortex, and thalamus, as a measure of nAChR availability.

Results: A significant between-group effect was found, resulting from the heavy caffeine and marijuana groups having the highest Vt/fp values (especially for the brainstem and prefrontal cortex), followed by smokers without such use, followed by non-smokers. Direct between-group comparisons revealed significant differences for Vt/fp values between the smoker groups with and without heavy caffeine or marijuana use.

Conclusions: Smokers with heavy caffeine or marijuana use have higher α4β2* nAChR availability than smokers without these drug usages. These findings are likely due to increased nicotine exposure but could also be due to an interaction on a cellular/molecular level.
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http://dx.doi.org/10.1007/s00213-016-4367-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4982797PMC
September 2016

Sex Differences in Midbrain Dopamine D2-Type Receptor Availability and Association with Nicotine Dependence.

Neuropsychopharmacology 2016 11 22;41(12):2913-2919. Epub 2016 Jun 22.

Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA, USA.

Women differ from men in smoking-related behaviors, among them a greater difficulty in quitting smoking. Unlike female smokers, male smokers have lower striatal dopamine D2-type receptor availability (binding potential, BPND) than nonsmokers and exhibit greater smoking-induced striatal dopamine release. Because dopamine D2-type autoreceptors in the midbrain influence striatal dopamine release, a function that has been linked to addiction, we tested for sex differences in midbrain dopamine D2-type receptor BPND and in relationships between midbrain BPND, nicotine dependence and striatal dopamine D2-type receptor BPND. Positron emission tomography was used with [F]fallypride to measure BPND in a midbrain region, encompassing the substantia nigra and ventral tegmental area, in 18 daily smokers (7 women, 11 men) and 19 nonsmokers (10 women, 9 men). A significant sex-by-group interaction reflected greater midbrain BPND in female but not male smokers than in corresponding nonsmokers (F=5.089, p=0.03). Midbrain BPND was positively correlated with BPND in the caudate nucleus and putamen in nonsmokers and female smokers but not in male smokers and with nicotine dependence in female but not in male smokers. Striatal BPND was correlated negatively with nicotine dependence and smoking exposure. These findings extend observations on dopamine D2-type receptors in smokers and suggest a sex difference in how midbrain dopamine D2-type autoreceptors influence nicotine dependence.
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http://dx.doi.org/10.1038/npp.2016.105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5061883PMC
November 2016

Emotion dysregulation and amygdala dopamine D2-type receptor availability in methamphetamine users.

Drug Alcohol Depend 2016 Apr 12;161:163-70. Epub 2016 Feb 12.

Department of Psychiatry and Biobehavioral Sciences, Los Angeles, CA 90024, USA; Department of Molecular and Medical Pharmacology, Los Angeles, CA 90024, USA; Brain Research Institute, University of California Los Angeles, Los Angeles, CA 90024, USA; Department of Research, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA. Electronic address:

Background: Individuals who use methamphetamine chronically exhibit emotional and dopaminergic neurochemical deficits. Although the amygdala has an important role in emotion processing and receives dopaminergic innervation, little is known about how dopamine transmission in this region contributes to emotion regulation. This investigation aimed to evaluate emotion regulation in subjects who met DSM-IV criteria for methamphetamine dependence, and to test for a relationship between self-reports of difficulty in emotion regulation and D2-type dopamine receptor availability in the amygdala.

Method: Ninety-four methamphetamine-using and 102 healthy-control subjects completed the Difficulties in Emotion Regulation Scale (DERS); 33 of those who used methamphetamine completed the Addiction Severity Index (ASI). A subset of 27 methamphetamine-group and 20 control-group subjects completed positron emission tomography with [(18)F]fallypride to assay amygdala D2-type dopamine receptor availability, measured as binding potential (BPND).

Results: The methamphetamine group scored higher than the control group on the DERS total score (p<0.001), with DERS total score positively correlated with the Drug Composite Score on the ASI (p=0.02) in the methamphetamine group. The DERS total score was positively correlated with amygdala BPND in both groups and the combined group of participants (combined: r=0.331, p=0.02), and the groups did not differ in this relationship.

Conclusion: These findings highlight problems with emotion regulation linked to methamphetamine use, possibly contributing to personal and interpersonal behavioral problems. They also suggest that D2-type dopamine receptors in the amygdala contribute to emotion regulation in both healthy and methamphetamine-using subjects.
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http://dx.doi.org/10.1016/j.drugalcdep.2016.01.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4792713PMC
April 2016

Placebo analgesia: Self-report measures and preliminary evidence of cortical dopamine release associated with placebo response.

Neuroimage Clin 2016 14;10:107-14. Epub 2015 Nov 14.

Department of Physiology, UCLA, Los Angeles, CA, United States; VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

Placebo analgesia is measured by self-report, yet current, expected, and recalled efficacy may be differentially related to brain function. Here we used a human thermal pain model to compare self-reports of expected, concurrent, and recalled efficacy of a topical placebo analgesic, and tested associations of the three measures of efficacy with changes in dopamine D2/D3 receptor availability in brain using [(18)F]fallypride with positron emission tomography (PET). Participants (15 healthy women) were assessed on three test days. The first test day included a laboratory visit, during which the temperature needed to evoke consistent pain was determined, placebo analgesia was induced via verbal and experience-based expectation, and the placebo response was measured. On two subsequent test days, PET scans were performed in Control and Placebo conditions, respectively, in counterbalanced order. During Visit 1, concurrent and recalled placebo efficacy were unrelated; during the Placebo PET visit, expected and recalled efficacy were highly correlated (ρ = 0.68, p = 0.005), but concurrent efficacy was unrelated to expected or recalled efficacy. Region of interest analysis revealed dopamine D2/D3 receptor availability was lower in left ventrolateral prefrontal cortex in the Placebo condition (p < 0.001, uncorrected), and greater change in this measure was associated with higher levels of recalled analgesic efficacy (ρ = 0.58, p = 0.02). These preliminary findings underscore the need to consider how self-reported symptom improvement is assessed in clinical trials of analgesics and suggest that dopaminergic activity in the ventrolateral prefrontal cortex may promote recalled efficacy of placebo.
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http://dx.doi.org/10.1016/j.nicl.2015.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683423PMC
October 2016

Discrete Scale Invariance of Human Large EEG Voltage Deflections is More Prominent in Waking than Sleep Stage 2.

Front Hum Neurosci 2015 2;9:638. Epub 2015 Dec 2.

Greater Los Angeles Veterans Administration Healthcare System, Departments of Psychiatry, (TZ) and Imaging (MM), University of California Los Angeles, CA, USA ; Department of Physics, University of California Irvine, CA, USA.

Electroencephalography (EEG) is typically viewed through the lens of spectral analysis. Recently, multiple lines of evidence have demonstrated that the underlying neuronal dynamics are characterized by scale-free avalanches. These results suggest that techniques from statistical physics may be used to analyze EEG signals. We utilized a publicly available database of fourteen subjects with waking and sleep stage 2 EEG tracings per subject, and observe that power-law dynamics of critical-state neuronal avalanches are not sufficient to fully describe essential features of EEG signals. We hypothesized that this could reflect the phenomenon of discrete scale invariance (DSI) in EEG large voltage deflections (LVDs) as being more prominent in waking consciousness. We isolated LVDs, and analyzed logarithmically transformed LVD size probability density functions (PDF) to assess for DSI. We find evidence of increased DSI in waking, as opposed to sleep stage 2 consciousness. We also show that the signatures of DSI are specific for EEG LVDs, and not a general feature of fractal simulations with similar statistical properties to EEG. Removing only LVDs from waking EEG produces a reduction in power in the alpha and beta frequency bands. These findings may represent a new insight into the understanding of the cortical dynamics underlying consciousness.
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http://dx.doi.org/10.3389/fnhum.2015.00638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667071PMC
December 2015

Striatal Dopamine D2/D3 Receptor Availability Is Associated with Executive Function in Healthy Controls but Not Methamphetamine Users.

PLoS One 2015 14;10(12):e0143510. Epub 2015 Dec 14.

Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, California, United States of America.

Background: Dopamine D2/D3 receptor availability in the striatum has been linked with executive function in healthy individuals, and is below control levels among drug addicts, possibly contributing to diminished executive function in the latter group. This study tested for an association of striatal D2/D3 receptor availability with a measure of executive function among research participants who met DSM-IV criteria for methamphetamine dependence.

Methods: Methamphetamine users and non-user controls (n = 18 per group) completed the Wisconsin Card Sorting Test and positron emission tomography with [18F]fallypride.

Results: The methamphetamine users displayed significantly lower striatal D2/D3 receptor availability on average than controls after controlling for age and education (p = 0.008), but they did not register greater proportions of either perseverative or non-perseverative errors when controlling for education (both ps ≥ 0.622). The proportion of non-perseverative, but not perseverative, errors was negatively correlated with striatal D2/D3 receptor availability among controls (r = -0.588, p = 0.010), but not methamphetamine users (r = 0.281, p = 0.258), and the group-wise interaction was significant (p = 0.030).

Conclusions: These results suggest that cognitive flexibility, as measured by perseverative errors on the Wisconsin Card Sorting Test, is not determined by signaling through striatal D2/D3 receptors in healthy controls, and that in stimulant abusers, who have lower D2/D3 receptor availability, compensation can effectively maintain other executive functions, which are associated with D2/D3 receptor signaling in controls.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0143510PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4699455PMC
August 2016

Relationship of Alexithymia Ratings to Dopamine D2-type Receptors in Anterior Cingulate and Insula of Healthy Control Subjects but Not Methamphetamine-Dependent Individuals.

Int J Neuropsychopharmacol 2016 05 29;19(5). Epub 2016 Apr 29.

Department of Psychiatry and Biobehavioral Sciences (Drs Okita, Ghahremani, and London), Department of Molecular and Medical Pharmacology (Drs Robertson and London), and Brain Research Institute (Dr London), University of California Los Angeles, Los Angeles, CA; Addiction Imaging Research Group, Centre for Addiction and Mental Health, Toronto, Ontario, Canada (Dr Payer); Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada (Dr Payer); Department of Research, VA Greater Los Angeles Healthcare System, Los Angeles, CA (Drs Okita, Robertson, Mandelkern, and London); Department of Physics, University of California Irvine, Irvine, CA (Dr Mandelkern).

Background: Individuals with substance-use disorders exhibit emotional problems, including deficits in emotion recognition and processing, and this class of disorders also has been linked to deficits in dopaminergic markers in the brain. Because associations between these phenomena have not been explored, we compared a group of recently abstinent methamphetamine-dependent individuals (n=23) with a healthy-control group (n=17) on dopamine D2-type receptor availability, measured using positron emission tomography with [(18)F]fallypride.

Methods: The anterior cingulate and anterior insular cortices were selected as the brain regions of interest, because they receive dopaminergic innervation and are thought to be involved in emotion awareness and processing. The Toronto Alexithymia Scale, which includes items that assess difficulty in identifying and describing feelings as well as externally oriented thinking, was administered, and the scores were tested for association with D2-type receptor availability.

Results: Relative to controls, methamphetamine-dependent individuals showed higher alexithymia scores, reporting difficulty in identifying feelings. The groups did not differ in D2-type receptor availability in the anterior cingulate or anterior insular cortices, but a significant interaction between group and D2-type receptor availability in both regions, on self-report score, reflected significant positive correlations in the control group (higher receptor availability linked to higher alexithymia) but nonsignificant, negative correlations (lower receptor availability linked to higher alexithymia) in methamphetamine-dependent subjects.

Conclusions: The results suggest that neurotransmission through D2-type receptors in the anterior cingulate and anterior insular cortices influences capacity of emotion processing in healthy people but that this association is absent in individuals with methamphetamine dependence.
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http://dx.doi.org/10.1093/ijnp/pyv129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4886668PMC
May 2016

Effect of Exercise Training on Striatal Dopamine D2/D3 Receptors in Methamphetamine Users during Behavioral Treatment.

Neuropsychopharmacology 2016 May 27;41(6):1629-36. Epub 2015 Oct 27.

Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

Methamphetamine use disorder is associated with striatal dopaminergic deficits that have been linked to poor treatment outcomes, identifying these deficits as an important therapeutic target. Exercise attenuates methamphetamine-induced neurochemical damage in the rat brain, and a preliminary observation suggests that exercise increases striatal D2/D3 receptor availability (measured as nondisplaceable binding potential (BPND)) in patients with Parkinson's disease. The goal of this study was to evaluate whether adding an exercise training program to an inpatient behavioral intervention for methamphetamine use disorder reverses deficits in striatal D2/D3 receptors. Participants were adult men and women who met DSM-IV criteria for methamphetamine dependence and were enrolled in a residential facility, where they maintained abstinence from illicit drugs of abuse and received behavioral therapy for their addiction. They were randomized to a group that received 1 h supervised exercise training (n=10) or one that received equal-time health education training (n=9), 3 days/week for 8 weeks. They came to an academic research center for positron emission tomography (PET) using [(18)F]fallypride to determine the effects of the 8-week interventions on striatal D2/D3 receptor BPND. At baseline, striatal D2/D3 BPND did not differ between groups. However, after 8 weeks, participants in the exercise group displayed a significant increase in striatal D2/D3 BPND, whereas those in the education group did not. There were no changes in D2/D3 BPND in extrastriatal regions in either group. These findings suggest that structured exercise training can ameliorate striatal D2/D3 receptor deficits in methamphetamine users, and warrants further evaluation as an adjunctive treatment for stimulant dependence.
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http://dx.doi.org/10.1038/npp.2015.331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832026PMC
May 2016

Deep Brain Stimulation of the Basolateral Amygdala for Treatment-Refractory Posttraumatic Stress Disorder.

Biol Psychiatry 2016 05 11;79(10):e82-e84. Epub 2015 Sep 11.

Research and Development Service, Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California; David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California.

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http://dx.doi.org/10.1016/j.biopsych.2015.09.003DOI Listing
May 2016

Striatal D1- and D2-type dopamine receptors are linked to motor response inhibition in human subjects.

J Neurosci 2015 Apr;35(15):5990-7

Departments of Molecular and Medical Pharmacology, and Department of Psychiatry and Biobehavioral Sciences, The Semel Institute for Neuroscience and Human Behavior at UCLA, and Brain Research Institute, University of California, Los Angeles, Los Angeles, California 90024, Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, California 90073, and

Motor response inhibition is mediated by neural circuits involving dopaminergic transmission; however, the relative contributions of dopaminergic signaling via D1- and D2-type receptors are unclear. Although evidence supports dissociable contributions of D1- and D2-type receptors to response inhibition in rats and associations of D2-type receptors to response inhibition in humans, the relationship between D1-type receptors and response inhibition has not been evaluated in humans. Here, we tested whether individual differences in striatal D1- and D2-type receptors are related to response inhibition in human subjects, possibly in opposing ways. Thirty-one volunteers participated. Response inhibition was indexed by stop-signal reaction time on the stop-signal task and commission errors on the continuous performance task, and tested for association with striatal D1- and D2-type receptor availability [binding potential referred to nondisplaceable uptake (BPND)], measured using positron emission tomography with [(11)C]NNC-112 and [(18)F]fallypride, respectively. Stop-signal reaction time was negatively correlated with D1- and D2-type BPND in whole striatum, with significant relationships involving the dorsal striatum, but not the ventral striatum, and no significant correlations involving the continuous performance task. The results indicate that dopamine D1- and D2-type receptors are associated with response inhibition, and identify the dorsal striatum as an important locus of dopaminergic control in stopping. Moreover, the similar contribution of both receptor subtypes suggests the importance of a relative balance between phasic and tonic dopaminergic activity subserved by D1- and D2-type receptors, respectively, in support of response inhibition. The results also suggest that the stop-signal task and the continuous performance task use different neurochemical mechanisms subserving motor response inhibition.
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http://dx.doi.org/10.1523/JNEUROSCI.4850-14.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4397600PMC
April 2015

Low Dopamine D2/D3 Receptor Availability is Associated with Steep Discounting of Delayed Rewards in Methamphetamine Dependence.

Int J Neuropsychopharmacol 2015 Jan 20;18(7):pyu119. Epub 2015 Jan 20.

Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles (Drs Ballard, Ishibashi, Dean, and London); Department of Molecular and Medical Pharmacology, University of California Los Angeles (Robertson and Dr London); Brain Research Institute, University of California Los Angeles (Dr London); Veterans Affairs Greater Los Angeles Healthcare System, CA (Drs Ballard, Mandelkern, Ishibashi, and London and Robertson); Department of Physics, University of California Irvine, CA (Dr Mandelkern); Department of Psychology, University of Southern California, Los Angeles, CA (Dr Monterosso and Hsu).

Background: Individuals with substance use disorders typically exhibit a predilection toward instant gratification with apparent disregard for the future consequences of their actions. Indirect evidence suggests that low dopamine D2-type receptor availability in the striatum contributes to the propensity of these individuals to sacrifice long-term goals for short-term gain; however, this possibility has not been tested directly. We investigated whether striatal D2/D3 receptor availability is negatively correlated with the preference for smaller, more immediate rewards over larger, delayed alternatives among research participants who met DSM-IV criteria for methamphetamine (MA) dependence.

Methods: Fifty-four adults (n = 27 each: MA-dependent, non-user controls) completed the Kirby Monetary Choice Questionnaire, and underwent positron emission tomography scanning with [(18)F]fallypride.

Results: MA users displayed steeper temporal discounting (p = 0.030) and lower striatal D2/D3 receptor availability (p < 0.0005) than controls. Discount rate was negatively correlated with striatal D2/D3 receptor availability, with the relationship reaching statistical significance in the combined sample (r = -0.291, p = 0.016) and among MA users alone (r = -0.342, p = 0.041), but not among controls alone (r = -0.179, p = 0.185); the slopes did not differ significantly between MA users and controls (p = 0.5).

Conclusions: These results provide the first direct evidence of a link between deficient D2/D3 receptor availability and steep temporal discounting. This finding fits with reports that low striatal D2/D3 receptor availability is associated with a higher risk of relapse among stimulant users, and may help to explain why some individuals choose to continue using drugs despite knowledge of their eventual negative consequences. Future research directions and therapeutic implications are discussed.
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http://dx.doi.org/10.1093/ijnp/pyu119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4540098PMC
January 2015

A naturalistic study of the association between antidepressant treatment and outcome of smoking cessation treatment.

J Clin Psychiatry 2014 Dec;75(12):e1433-8

Department of Psychiatry, VA Greater Los Angeles Healthcare System, 11301 Wilshire Blvd, B210/2nd Floor, Los Angeles CA 90073

Objective: Psychiatric, medical, and substance use comorbidities are highly prevalent among smokers, and many of these comorbidities have been found to be associated with reduced rate of success in clinical trials for smoking cessation. While much has been established about the best available treatments from these clinical trials, little is known about the effect of concomitant psychiatric medications on quit rates in smoking cessation programs. On the basis of results in populations with tobacco dependence and other substance use disorders, we hypothesized that smokers taking antidepressants would have a lower rate of quitting in an outpatient smoking cessation program.

Method: We performed a naturalistic chart review of veterans (N = 144) enrolled in the Veterans Affairs Greater Los Angeles Mental Health Clinic Smoking Cessation Program from March 2011 through July 2013, who met DSM-IV-TR criteria for nicotine dependence. The primary outcome was smoking cessation with treatment, as evidenced by a patient report of at least 1 week of abstinence and an exhaled carbon monoxide level of ≤ 6 ppm (if available) at the end of acute treatment, with comparators including concomitant psychotropic medication treatment, psychiatric and medical comorbidities, and the presence of a substance use disorder history. We utilized stepwise binary logistic regression as the main statistical technique.

Results: We found that current antidepressant treatment (P = .003) and history of substance use disorder (P = .01) (particularly cocaine [P = .02]) were associated with a lower rate of quitting smoking. Furthermore, the association between antidepressant treatment and reduced rate of smoking cessation was primarily seen in patients with a history of substance use disorder (P = .003).

Conclusions: While preliminary, these results suggest an important clinical interaction meriting future study. If these findings are confirmed, clinicians may want to consider the risk of reduced ability to quit smoking in patients with a history of substance use disorder who are taking antidepressants.
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http://dx.doi.org/10.4088/JCP.14m09012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666295PMC
December 2014

Radiation dosimetry and biodistribution of the translocator protein radiotracer [(11)C]DAA1106 determined with PET/CT in healthy human volunteers.

Nucl Med Biol 2014 Nov-Dec;41(10):871-5. Epub 2014 Aug 1.

Department of Imaging, VAGLAHS, 11301 Wilshire Blvd., Los Angeles, CA 90073; Department of Physics, University of California at Irvine, 4129 Frederick Reines Hall, Irvine, CA 92697.

Introduction: When microglia become activated (an integral part of neuroinflammation), cellular morphology changes and expression of translocator protein (TSPO) 18 kDa is increased. Over the past several years, [(11)C]DAA1106 has emerged as a reliable radiotracer for labeling TSPO with high affinity during positron emission tomography (PET) scanning. While [(11)C]DAA1106 PET scanning has been used in several research studies, a radiation dosimetry study of this radiotracer in humans has not yet been published.

Methods: Twelve healthy participants underwent full body dynamic [(11)C]DAA1106 PET scanning, with 8 sequential whole body scans (approximately 12 bed positions each), following a single injection. Regions of interest were drawn manually, and time activity curves (TACs) were obtained for 15 organs. OLINDA/EXM 1.1 was used to compute radiation absorbed doses to the target organs, as well as effective dose (ED) and effective dose equivalent (EDE).

Results: The ED and EDE were 4.06 ± 0.58 μSv/MBq and 5.89 ± 0.83 μSv/MBq, respectively. The highest absorbed doses were to the heart wall, kidney, liver, pancreas, and spleen. TACs revealed that peak dose rates are during the first scan (at 6 min) for all organs other than the urinary bladder wall, which had its peak dose rate during the fourth scan (at 30 min).

Conclusions: The recently developed radiotracer [(11)C]DAA1106 has its EDE and target-organ absorbed dose such that, for a single administration, its radiation dosimetry is well within the U.S. FDA guidelines for basic research studies in adults. This dose level implies that the dosimetry for multiple [(11)C]DAA1106 scans within a given year also falls within FDA guidelines, and this favorable property makes this radiotracer suitable for examining microglial activation repeatedly over time, which may in the future be useful for longitudinal tracking of disease progression and monitoring of therapy response in conditions marked by neuroinflammation (e.g., head trauma and multiple sclerosis).
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http://dx.doi.org/10.1016/j.nucmedbio.2014.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4192057PMC
June 2015

Brain nicotinic acetylcholine receptor availability and response to smoking cessation treatment: a randomized trial.

JAMA Psychiatry 2014 Jul;71(7):797-805

Department of Research, VA Greater Los Angeles Healthcare System, Los Angeles, California5Department of Physics, University of California, Irvine.

Importance: Cigarette smoking leads to upregulation of nicotinic acetylcholine receptors (nAChRs) in the human brain, including the common α4β2* nAChR subtype. While subjective aspects of tobacco dependence have been extensively examined as predictors of quitting smoking with treatment, no studies to our knowledge have yet reported the relationship between the extent of pretreatment upregulation of nAChRs and smoking cessation.

Objective: To determine whether the degree of nAChR upregulation in smokers predicts quitting with a standard course of treatment.

Design, Setting, And Participants: Eighty-one tobacco-dependent cigarette smokers (volunteer sample) underwent positron emission tomographic (PET) scanning of the brain with the radiotracer 2-FA followed by 10 weeks of double-blind, placebo-controlled treatment with nicotine patch (random assignment). Pretreatment specific binding volume of distribution (VS/fP) on PET images (a value that is proportional to α4β2* nAChR availability) was determined for 8 brain regions of interest, and participant-reported ratings of nicotine dependence, craving, and self-efficacy were collected. Relationships between these pretreatment measures, treatment type, and outcome were then determined. The study took place at academic PET and clinical research centers.

Main Outcomes And Measures: Posttreatment quit status after treatment, defined as a participant report of 7 or more days of continuous abstinence and an exhaled carbon monoxide level of 3 ppm or less.

Results: Smokers with lower pretreatment VS/fP values (a potential marker of less severe nAChR upregulation) across all brain regions studied were more likely to quit smoking (multivariate analysis of covariance, F8,69 = 4.5; P < .001), regardless of treatment group assignment. Furthermore, pretreatment average VS/fP values provided additional predictive power for likelihood of quitting beyond the self-report measures (stepwise binary logistic regression, likelihood ratio χ21 = 19.8; P < .001).

Conclusions And Relevance: Smokers with less upregulation of available α4β2* nAChRs have a greater likelihood of quitting with treatment than smokers with more upregulation. In addition, the biological marker studied here provided additional predictive power beyond subjectively rated measures known to be associated with smoking cessation outcome. While the costly, time-consuming PET procedure used here is not likely to be used clinically, simpler methods for examining α4β2* nAChR upregulation could be tested and applied in the future to help determine which smokers need more intensive and/or lengthier treatment.

Trial Registration: clinicaltrials.gov Identifier: NCT01526005.
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http://dx.doi.org/10.1001/jamapsychiatry.2014.138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4634637PMC
July 2014

The simplified reference tissue model with 18F-fallypride positron emission tomography: choice of reference region.

Mol Imaging 2013 Nov-Dec;12(8)

The development of high-affinity radiotracers for positron emission tomography (PET) has allowed for quantification of dopamine receptors in extrastriatal and striatal regions of the brain. As these new radiotracers have distinctly different kinetic properties than their predecessors, it is important to examine the suitability of kinetic models to represent their uptake, distribution, and in vivo washout. Using the simplified reference tissue model, we investigated the influence of reference region choice on the striatal binding potential of 18F-fallypride, a high-affinity dopamine D2/D3 receptor ligand. We compared the use of the visual cortex and a white matter region (superior longitudinal fasciculus) to the cerebellum, a commonly used reference tissue, in a PET-fallypride study of healthy and methamphetamine-dependent subjects. Compared to the cerebellum, use of the visual cortex produced significantly greater sample variance in binding potential relative to nondisplaceable uptake (BP(ND)). Use of the white matter region was associated with BP(ND) values and sample variance similar to those obtained with the cerebellum and a larger effect size for the group differences in striatal BP(ND) between healthy and methamphetamine-dependent subjects. Our results do not support the use of the visual cortex as a reference region in 18F-fallypride studies and suggest that white matter may be a reasonable alternative to the cerebellum as it displays similar statistical and kinetic properties.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4103900PMC
http://dx.doi.org/10.2310/7290.2013.00065DOI Listing
September 2014
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