obesity; appetite suppressants; food addiction; palatable food; animal models
Prader–Willi syndrome (PWS) is a genetic imprinting disorder characterized mainly by hyperphagia and early childhood obesity. Previous functional neuroimaging studies used visual stimuli to examine abnormal activities in the eating-related neural circuitry of patients with PWS. It was found that patients with PWS exhibited both excessive hunger and hyperphagia consistently, even in situations without any food stimulation. In the present study, we employed resting-state functional MRI techniques to investigate abnormal brain networks related to eating disorders in children with PWS. First, we applied amplitude of low-frequency fluctuation analysis to define the regions of interest that showed significant alterations in resting-state brain activity levels in patients compared with their sibling control group. We then applied a functional connectivity (FC) analysis to these regions of interest in order to characterize interactions among the brain regions. Our results demonstrated that patients with PWS showed decreased FC strength in the medial prefrontal cortex (MPFC)/inferior parietal lobe (IPL), MPFC/precuneus, IPL/precuneus and IPL/hippocampus in the default mode network; decreased FC strength in the pre-/postcentral gyri and dorsolateral prefrontal cortex (DLPFC)/orbitofrontal cortex (OFC) in the motor sensory network and prefrontal cortex network, respectively; and increased FC strength in the anterior cingulate cortex/insula, ventrolateral prefrontal cortex (VLPFC)/OFC and DLPFC/VLPFC in the core network and prefrontal cortex network, respectively. These findings indicate that there are FC alterations among the brain regions implicated in eating as well as rewarding, even during the resting state, which may provide further evidence supporting the use of PWS as a model to study obesity and to provide information on potential neural targets for the medical treatment of overeating.
Prader; Willi syndrome; eating disorder; obesity; amplitude of low-frequency fluctuation; resting-state networks; functional MRI
Background and Hypothesis
It is well known that after prolonged abstinence, individuals who imbibe or use their drug of choice experience a powerful euphoria that precipitates serious relapse. While a biological explanation for this conundrum has remained elusive, we hypothesize that this clinically observed “super sensitivity” might be tied to genetic dopaminergic polymorphisms. Another therapeutic conundrum relates to the paradoxical finding that the dopaminergic agonist bromocriptine induces stronger activation of brain reward circuitry in individuals who carry the DRD2 A1 allele compared to DRD2 A2 allele carriers. Based upon the fact that carriers of the A1 allele relative to the A2 allele of the DRD2 gene have significantly lower D2 receptor density, a reduced sensitivity to dopamine agonist activity would be expected in the former. Thus, it is perplexing that with low D2 density there is an increase in reward sensitivity with the dopamine agonist bromocriptine. Moreover, under chronic or long-term therapy, the potential proliferation of D2 receptors with bromocriptine has been shown in vitro. This seems to lead to a positive outcome and significantly better treatment compliance only in A1 carriers.
Proposal and Conclusion
We propose that low D2 receptor density and polymorphisms of the D2 gene are associated with risk for relapse of substance abuse including alcohol dependence, heroin craving, cocaine dependence, methamphetamine abuse, nicotine sensitization, and glucose craving. With this in mind, we suggest a putative physiological mechanism that may help to explain the enhanced sensitivity following intense acute dopaminergic D2 receptor activation: “denervation supersensitivity.” Thus, the administration of dopamine D2 agonists would target D2 sensitization and attenuate relapse, especially in D2 receptor A1 allele carriers. This hypothesized mechanism is supported by clinical trials utilizing the amino-acid neurotransmitter precursors, enkephalinase and catechol-O-methyl-transferase (COMT) enzyme inhibition, which have resulted in attenuated relapse rates in Reward Deficiency Syndrome (RDS) probands. Future warranted translational research with positive outcome showing prevented or lower relapse in RDS will ultimately support the proposed concept, which we term “Deprivation-Amplification Relapse Therapy (DART).”
In an attempt to resolve controversy regarding the causal contributions of mesolimbic dopamine (DA) systems to reward, we evaluate the three main competing explanatory categories: “liking,” “learning,” and “wanting” . That is, DA may mediate (a) the hedonic impact of reward (liking), (b) learned predictions about rewarding effects (learning), or (c) the pursuit of rewards by attributing incentive salience to reward-related stimuli (wanting). We evaluate these hypotheses, especially as they relate to the Reward Deficiency Syndrome (RDS), and we find that the incentive salience or “wanting” hypothesis of DA function is supported by a majority of the evidence. Neuroimaging studies have shown that drugs of abuse, palatable foods, and anticipated behaviors such as sex and gaming affect brain regions involving reward circuitry, and may not be unidirectional. Drugs of abuse enhance DA signaling and sensitize mesolimbic mechanisms that evolved to attribute incentive salience to rewards. Addictive drugs have in common that they are voluntarily self-administered, they enhance (directly or indirectly) dopaminergic synaptic function in the nucleus accumbens, and they stimulate the functioning of brain reward circuitry (producing the “high” that drug users seek). Although originally believed simply to encode the set point of hedonic tone, these circuits now are believed to be functionally more complex, also encoding attention, reward expectancy, disconfirmation of reward expectancy, and incentive motivation. Elevated stress levels, together with polymorphisms of dopaminergic genes and other neurotransmitter genetic variants, may have a cumulative effect on vulnerability to addiction. The RDS model of etiology holds very well for a variety of chemical and behavioral addictions.
Reward Deficiency Syndrome (RDS); neuroimaging; dopamine; “wanting” and “liking”
Traditional fecal indicator bacteria (FIB) measurement is too slow (>18 hr) for timely swimmer warnings.
Assess relationship of rapid indicator methods (qPCR) to illness at a marine-beach impacted by urban-runoff.
We measured baseline and two-week health in 9525 individuals visiting Doheny Beach 2007-08. Illness rates were compared (swimmers vs. non-swimmers). FIB measured by traditional (Enterococcus spp. by EPA Method 1600 or Enterolert™, fecal coliforms, total coliforms) and three rapid qPCR assays for Enterococcus spp. (Taqman, Scorpion-1, Scorpion-2) were compared to health. Primary bacterial source was a creek flowing untreated into ocean; the creek did not reach the ocean when a sand berm formed. This provided a natural experiment for examining FIB-health relationships under varying conditions.
We observed significant increases in diarrhea (OR1.90, 95% CI 1.29-2.80 for swallowing water) and other outcomes in swimmers compared to non-swimmers. Exposure (body immersion, head immersion, swallowed water) was associated with increasing risk of gastrointestinal illness (GI). Daily GI incidence patterns were different: swimmers (2-day peak ) and non-swimmers (no peak). With berm-open, we observed associations between GI and traditional and rapid methods for Enterococcus; fewer associations occurred when berm status was not considered.
We found increased risk of GI at this urban-runoff beach. When FIB source flowed freely (berm-open), several traditional and rapid indicators were related to illness. When FIB source was weak (berm-closed) fewer illness-associations were seen. These different relationships under different conditions at a single beach demonstrate the difficulties using these indicators to predict health risk.
Gastrointestinal illness; recreational water quality; diarrhea; indicator organisms; qPCR
Over the past three decades obesity has become a major public health crisis in the United States. The prevalence of obesity in the United States and in other parts of the World has led to the new word, globesity, now being used to describe the problem. As a result of this increased emphasis on understanding the causes and consequences of obesity, novel theories have stimulated new research aimed to prevent, intervene with, and ameliorate the effects and reduce the incidence and medical consequences of globesity. One theory that has gained popularity in recent years, which we described and analyzed in our previous paper Neurobiology of Food Addiction, is based on the idea that excessive intake of highly-palatable foods shares similarities with the effects on brain and behavior that are seen with some drugs of abuse. While this theory is not new, empirically-based translational research has only recently provided strong support for this hypothesis. In this article, we review the present state of the science in this area and describe a variety of newer clinical and preclinical works that shed light on innovative and interesting overlaps between excessive palatable food intake and drug use.
Addiction; Dopamine; Food intake; Obesity; Overeating
Attention-deficit/hyperactivity disorder (ADHD) affects nearly 10% of children in the United States, and the prevalence of this disorder has increased steadily over the past decades. The cause of ADHD is unknown, although recent studies suggest that it may be associated with a disruption in dopamine signaling whereby dopamine D2 receptors are reduced in reward-related brain regions. This same pattern of reduced dopamine-mediated signaling is observed in various reward-deficiency syndromes associated with food or drug addiction, as well as in obesity. While genetic mechanisms are likely contributory to cases of ADHD, the marked frequency of the disorder suggests that other factors are involved in the etiology. In this article, we revisit the hypothesis that excessive sugar intake may have an underlying role in ADHD. We review preclinical and clinical data suggesting overlaps among ADHD, sugar and drug addiction, and obesity. Further, we present the hypothesis that the chronic effects of excessive sugar intake may lead to alterations in mesolimbic dopamine signaling, which could contribute to the symptoms associated with ADHD. We recommend further studies to investigate the possible relationship between chronic sugar intake and ADHD.
ADHD; sucrose; fructose; high-fructose corn syrup; reward-deficiency syndrome; dopamine; D2 receptor; obesity
Now after many years of successful bariatric (weight-loss) surgeries directed at the obesity epidemic clinicians are reporting that some patients are replacing compulsive overeating with newly acquired compulsive disorders such as alcoholism, gambling, drugs, and other addictions like compulsive shopping and exercise. This review article explores evidence from psychiatric genetic animal and human studies that link compulsive overeating and other compulsive disorders to explain the phenomenon of addiction transfer. Possibly due to neurochemical similarities, overeating and obesity may act as protective factors reducing drug reward and addictive behaviors. In animal models of addiction withdrawal from sugar induces imbalances in the neurotransmitters, acetylcholine and dopamine, similar to opiate withdrawal. Many human neuroimaging studies have supported the concept of linking food craving to drug craving behavior. Previously our laboratory coined the term Reward Deficiency Syndrome (RDS) for common genetic determinants in predicting addictive disorders and reported that the predictive value for future RDS behaviors in subjects carrying the DRD2 Taq A1 allele was 74%. While poly genes play a role in RDS, we have also inferred that disruptions in dopamine function may predispose certain individuals to addictive behaviors and obesity. It is now known that family history of alcoholism is a significant obesity risk factor. Therefore, we hypothesize here that RDS is the root cause of substituting food addiction for other dependencies and potentially explains this recently described Phenomenon (addiction transfer) common after bariatric surgery.
Bariatric surgery; Addiction transfer; Cross tolerance; Reward Deficiency Syndrome; Dopamine; Reward genes
Tobacco smoke contains nicotine and many other compounds that act in concert on the brain reward system. Therefore, animal models are needed that allow the investigation of chronic exposure to the full spectrum of tobacco smoke constituents.
The aim of these studies was to investigate if exposure to tobacco smoke leads to nicotine dependence in rats.
The intracranial self-stimulation procedure was used to assess the negative affective aspects of nicotine withdrawal. Somatic signs were recorded from a checklist of nicotine abstinence signs. Nicotine self-administration sessions were conducted to investigate if tobacco smoke exposure affects the motivation to self-administer nicotine. Nicotinic receptor autoradiography was used to investigate if exposure to tobacco smoke affects central α7 nicotinic acetylcholine receptor (nAChR) and non-α7 nAChR levels (primarily α4β2 nAChRs).
The nAChR antagonist mecamylamine dose-dependently elevated the brain reward thresholds of the rats exposed to tobacco smoke and did not affect the brain reward thresholds of the untreated control rats. Furthermore, mecamylamine induced more somatic withdrawal signs in the smoke exposed rats than in the control rats. Nicotine self-administration was decreased 1 day after the last tobacco smoke exposure sessions and was returned to control levels 5 days later. Tobacco smoke exposure increased the α7 nAChR density in the CA2/3 area and the stratum oriens and increased the non-α7 nAChR density in the dentate gyrus.
Tobacco smoke exposure leads to nicotine dependence as indicated by precipitated affective and somatic withdrawal signs and induces an upregulation of nAChRs in the hippocampus.
Tobacco; nicotine; dependence; withdrawal; rats
Sexual addiction is estimated to afflict up to 3-6% of the population. However, many clinicians lack clear criteria for detecting potential cases.
The present studies were conducted to assess the effectiveness of a brief sexual addiction screening instrument (i.e., PATHOS Questionnaire) to correctly classify patients being treated for sex addiction and healthy volunteers.
In Study One, a six-item questionnaire which utilizes the mnemonic “PATHOS” was examined in regard to sensitivity and specificity using a sample combining patients being treated for sex addiction and healthy volunteers (970 men/80.2% patients; 938 women/63.8% patients). In Study Two, a cross-validation sample of 672 men (93%patients) and 241 women (35.3% patients) completed the PATHOS screener.
Results of ROC analyses in Study One demonstrated that the PATHOS captured 92.6% of the area under the curve, and achieved 88.3% sensitivity and 81.6% specificity for classifying the male sample (n = 963) as patients and healthy subjects using a cut-off score of 3. Similarly, the PATHOS captured 90.2% of the area under the curve and, with a cut-off of 3, achieved 80.9% sensitivity and 87.2% specificity for the female sample (n = 808). In Study Two, results of ROC analyses indicated that the PATHOS captured 85.1% of the area under the curve, with sensitivity of 70.7% and specificity of 86.9% for men (cut-off of 3). For women, the PATHOS captured 80.9% of the area under the curve and achieved 69.7% sensitivity and 85.1% specificity with the cut-off of 3.
These studies provide support for the use of the PATHOS as a screening instrument to detect potential sexual addiction cases in clinical settings.
Sexual Addiction; Sexual Compulsivity; Screening; Assessment; Psychometrics
Adverse, unfavourable life conditions, particularly during early life stages and infancy, can lead to epigenetic regulation of genes involved in stress-response, behavioral disinhibition, and cognitive-emotional systems. Over time, the ultimate final outcome can be expressed through behaviors bedeviled by problems with impulse control, such as eating disorders, alcoholism, and indiscriminate social behavior. While many reward gene polymorphisms are involved in impulsive behaviors, a polymorphism by itself may not translate to the development of a particular behavioral disorder unless it is impacted by epigenetic effects. Brain-derived neurotrophic factor (BDNF) affects the development and integrity of the noradrenergic, dopaminergic, serotonergic, glutamatergic, and cholinergic neurotransmitter systems, and plasma levels of the neurotrophin are associated with both cognitive and aggressive impulsiveness. Epigenetic mechanisms associated with a multitude of environmental factors, including premature birth, low birth weight, prenatal tobacco exposure, non-intact family, young maternal age at birth of the target child, paternal history of antisocial behavior, and maternal depression, alter the developmental trajectories for several neuropsychiatric disorders. These mechanisms affect brain development and integrity at several levels that determine structure and function in resolving the final behavioral expressions.
Epigenetics; Disinhibition; Eating disorder; Alcoholism; BDNF
Heat-shock is an acute insult to the mammalian proteome. The sudden elevation in temperature has far-reaching effects on protein metabolism, leads to a rapid inhibition of most protein synthesis, and the induction of protein chaperones. Using heat-shock in cells of neuronal (SH-SY5Y) and glial (CCF-STTG1) lineage, in conjunction with detergent extraction and sedimentation followed by LC-MS/MS proteomic approaches, we sought to identify human proteins that lose solubility upon heat-shock. The two cell lines showed largely overlapping profiles of proteins detected by LC-MS/MS. We identified 58 proteins in detergent insoluble fractions as losing solubility in after heat shock; 10 were common between the 2 cell lines. A subset of the proteins identified by LC-MS/MS was validated by immunoblotting of similarly prepared fractions. Ultimately, we were able to definitively identify 3 proteins as putatively metastable neural proteins; FEN1, CDK1, and TDP-43. We also determined that after heat-shock these cells accumulate insoluble polyubiquitin chains largely linked via lysine 48 (K-48) residues. Collectively, this study identifies human neural proteins that lose solubility upon heat-shock. These proteins may represent components of the human proteome that are vulnerable to misfolding in settings of proteostasis stress.
This study focuses on how acupoints ST 36 (Zu San Li) and SP 9 (Yin Ling Quan) and their sham acupoints act acutely on the limbic system via dopamine to affect satiety, glucose (GLU) blood levels, and core body temperature (CBT).
This controlled clinical trial compared real acupuncture (ACU) versus minimal sham acupuncture (min SHAM) effects on metabolic physiology using functional magnetic resonance imaging (fMRI).
The study took place at the West China Hospital in Chengdu, Sichuan Province, China.
The study subjects were 19 right-handed healthy, “overweight,” nondieting adult Chinese males ages 21–45 (10 for ACU treatment and 9 for min SHAM) who had abstained from eating 12 hours prior to the fMRI experiment.
Values for GLU and CBT indicated no significant differences (P>0.05) in both inter- and intragroup comparisons resulting from variable individual responses to treatment. Hunger survey feedback was significant (P<0.05) between the ACU and min SHAM groups. Soreness, or De Qi, was the only significant (P<0.05) intergroup sensation.
Acupuncture stimulation activated neurophysiological pathways involving dopamine, basal metabolic rate, heart rate, and satiety regulation. This project will be of great importance in helping scientists understand how acupuncture can be studied as a safe inexpensive treatment modality for weight control.
Acupuncture; Dopamine; Glucose; Core Body Temperature; Satiety; De Qi; Overweight; fMRI
Internationally, sporting events represent a specific context in which heavy episodic drinking is common. The current study assessed determinants of heavy episodic drinking among tailgaters (i.e., individuals engaging in pre-game social festivities) prior to American football games at two large universities. A total of 466 individuals at two universities completed a short interview and provided a breathalyzer sample to estimate breath alcohol content (BrAC) during the tailgating window (150 minutes prior to and 10 minutes after the start of the game). The plurality of participants, 48.5% at the Southeastern University (School1) and 58.8% at the Midwestern University (School2), engaged in heavy episodic drinking. Only 54 individuals (11.6%) from the combined sample at both universities abstained from alcohol (confirmed via BrAC). In total, 40.2% of participants at School1 and 31.9% at School2 produced breath samples over the legal limit for driving (i.e., BrAC = 0.08 or higher). In site-specific regression analyses, younger ages, males, and non-students at School1, and younger ages and non-game attendance at School2 were associated with self-reported heavy episodic drinking and higher levels of estimated BrAC (p<0.05). Given the widespread participation in heavy episodic drinking among both students and non-students in this sample, public health interventions should be implemented both on- and off-campus to promote safety and to discourage heavy episodic drinking at American football games and other high-profile sporting events.
Tailgating; Heavy Episodic Drinking; College Football; Alcohol; Sporting Events
Background and Hypothesis:
Although the biological underpinnings of immediate and protracted trauma-related responses are extremely complex, 40 years of research on humans and other mammals have demonstrated that trauma (particularly trauma early in the life cycle) has long-term effects on neurochemical responses to stressful events. These effects include the magnitude of the catecholamine response and the duration and extent of the cortisol response. In addition, a number of other biological systems are involved, including mesolimbic brain structures and various neurotransmitters. An understanding of the many genetic and environmental interactions contributing to stress-related responses will provide a diagnostic and treatment map, which will illuminate the vulnerability and resilience of individuals to Posttraumatic Stress Disorder (PTSD).
Proposal and Conclusions:
We propose that successful treatment of PTSD will involve preliminary genetic testing for specific polymorphisms. Early detection is especially important, because early treatment can improve outcome. When genetic testing reveals deficiencies, vulnerable individuals can be recommended for treatment with “body friendly” pharmacologic substances and/or nutrients. Results of our research suggest the following genes should be tested: serotoninergic, dopaminergic (DRD2, DAT, DBH), glucocorticoid, GABAergic (GABRB), apolipoprotein systems (APOE2), brain-derived neurotrophic factor, Monamine B, CNR1, Myo6, CRF-1 and CRF-2 receptors, and neuropeptide Y (NPY). Treatment in part should be developed that would up-regulate the expression of these genes to bring about a feeling of well being as well as a reduction in the frequency and intensity of the symptoms of PTSD.
Post-traumatic Stress Disorder (PTSD); genes and environment; neurotransmitters; Reward Deficiency Syndrome (RDS).
Environmental tobacco smoke (ETS) has been linked to deleterious health effects, particularly pulmonary and cardiac disease; yet, the general public considers ETS benign to brain function in adults. In contrast, epidemiological data have suggested that ETS impacts the brain and potentially modulates neurodegenerative disease. The present study begins to examine yet unknown biochemical effects of ETS on the adult mammalian brain. In the developed animal model, adult male rats were exposed to ETS 3 h a day for 3 weeks. Biochemical data showed altered glial fibrillary acid protein levels as a main treatment effect of ETS, suggestive of reactive astrogliosis. Yet, markers of oxidative and cell stress were unaffected by ETS exposure in the brain regions examined. Increased proteolytic degradation of αII-spectrin by caspase-3 and the dephosphorylation of serine116 on PEA-15 indicated greater apoptotic cell death modulated by the extrinsic pathway in the brains of ETS-exposed animals. Further, β-synuclein was upregulated by ETS, a neuroprotective protein previously reported to exhibit anti-apoptotic and anti-fibrillogenic properties. These findings demonstrate that ETS exposure alters the neuroproteome of the adult rat brain, and suggest modulation of inflammatory and cell death processes.
ETS; SHS; Neuroproteomics; Apoptosis; Gliosis; Synuclein
The use of methamphetamine (METH) is a growing public health problem because its abuse is associated with long-term biochemical and structural effects on the human brain. Neurodegeneration is often observed in humans as a result of mechanical injuries (e.g. traumatic brain injury, TBI) and ischemic damage (strokes). In this review, we discuss recent findings documenting the fact that the psychostimulant drug, METH, can cause neuronal damage in several brain regions. The accumulated evidence from our laboratories and those of other investigators indicates that acute administration of METH leads to activation of calpain and caspase proteolytic systems. These systems are also involved in causing neuronal damage secondary to traumatic and ischemic brain injuries. Protease activation is accompanied by proteolysis of endogenous neuronal structural proteins (αII-spectrin and MAP-tau protein) evidenced by the appearance of their breakdown products after these injuries. When taken together, these observations suggest that METH exposure, like TBI, can cause substantial damage to the brain by causing both apoptotic and necrotic cell death in the brains of METH addicts who use large doses of the drug during their lifetimes. Finally, because METH abuse is accompanied by functional and structural changes in the brain similar to those in TBI, METH addicts might experience greater benefit if their treatment involved greater emphasis on rehabilitation in conjunction with the use of potential neuroprotective pharmacological agents such as calpain and caspase inhibitors similar to those used in TBI.
neurotoxicity; methamphetamine; psychoproteomics; proteolysis; calpain; caspase; αII-spectrin; neuroproteomics; brain injury
Many substances that form methemoglobin (MHb) effectively counter cyanide (CN) toxicity. Although MHb formers are generally applied as treatments for CN poisoning, it has been proposed that a stable, long-acting MHb former could serve as a CN pretreatment. Using this rationale, the 8-aminoquinoline WR242511, a potent long-lasting MHb former in rodents and beagle dogs, was studied in the rhesus monkey for advanced development as a potential CN pretreatment.
In this study, WR242511 was administered intravenously (IV) in 2 female and 4 male rhesus monkeys in doses of 3.5 and/or 7.0 mg/kg; a single male also received WR242511 orally (PO) at 7.0 mg/kg. Health status and MHb levels were monitored following exposure.
The selected doses of WR242511, which produced significant methemoglobinemia in beagle dogs in earlier studies conducted elsewhere, produced very little MHb (mean < 2.0%) in the rhesus monkey. Furthermore, transient hemoglobinuria was noted approximately 60 minutes postinjection of WR242511 (3.5 or 7.0 mg/kg), and 2 lethalities occurred (one IV and one PO) following the 7.0 mg/kg dose. Myoglobinuria was also observed following the 7.0 mg/kg dose. Histopathology analyses in the 2 animals that died revealed liver and kidney toxicity, with greater severity in the orally-treated animal.
These data demonstrate direct and/or indirect drug-induced toxicity. It is concluded that WR242511 should not be pursued as a pretreatment for CN poisoning unless the anti-CN characteristics of this compound can be successfully dissociated from those producing undesirable toxicity.
8-aminoquinolines; WR242511; rhesus monkeys; toxicity; pretreatment
In previous studies, we found that approximately 25% of patients having carotid endarterectomy with general anesthesia (CEA general) develop cognitive dysfunction compared with a surgical control Group 1 day and 1 mo after surgery. In this study, we tested the hypothesis that patients having CEA with regional anesthesia (CEA regional) will develop significant cognitive dysfunction 1 day after surgery compared with a control group of patients receiving sedation 1 day after surgery. We did not study persistence of dysfunction.
To test this hypothesis, we enrolled 60 patients in a prospective study. CEA regional was performed with superficial and deep cervical plexus blocks in 41 patients. The control group consisted of 19 patients having coronary angiography or coronary artery stenting performed with sedation. A control group is necessary to account for the “practice effect” associated with repeated cognitive testing. The patients from the CEA regional group were enrolled at New York Medical Center and the control group at Columbia-Presbyterian Medical Center. The cognitive performance of all patients was evaluated using a previously validated battery of neuropsychometric tests. Differences in performance, 1 day after compared with before surgery, were evaluated by both event-rate and group-rate analyses.
On postoperative day 1, 24.4% of patients undergoing CEA regional had significant cognitive dysfunction, where “significant” was defined as a total deficit score ≥2 SD worse than the mean performance in the control group.
Patients undergoing CEA regional had an incidence of cognitive dysfunction which was not different than patients having CEA general as previously published and compared with a contemporaneously enrolled group.
Methamphetamine is a popular addictive drug whose use is associated with multiple neuropsychiatric adverse events and toxic to the dopaminergic and serotonergic systems of the brain. Methamphetamine-induced neuropathology is associated with increased expression of microglial cells that are thought to participate in either pro-toxic or protective mechanisms in the brain. Although reactive microgliosis has been observed in animal models of methamphetamine neurotoxicity, no study has reported on the status of microglial activation in human methamphetamine abusers. The present study reports on 12 abstinent methamphetamine abusers and 12 age-, gender-, education-matched control subjects who underwent positron emission tomography using a radiotracer for activated microglia, [11C](R)-(1-[2-chlorophenyl]-N-methyl-N-[1-methylpropyl]-3-isoquinoline carboxamide) ([11C](R)-PK11195). Compartment analysis was used to estimate quantitative levels of binding potentials of [11C](R)-PK11195 in brain regions with dopaminergic and/or serotonergic innervation. The mean levels of [11C](R)-PK11195 binding were higher in methamphetamine abusers than those in control subjects in all brain regions (> 250% higher, p < 0.01 for all). In addition, the binding levels in the midbrain, striatum, thalamus, and orbitofrontal and insular cortices (p < 0.05) correlated inversely with the duration of methamphetamine abstinence. These results suggest that chronic self-administration of methamphetamine can cause reactive microgliosis in the brains of human methamphetamine abusers, a level of activation that appears to subside over longer periods of abstinence.
methamphetamine; addiction; neurotoxicity; microglia; positron emission tomography; human