Hongxian Chen

Reduced Dorsal Prefrontal Gray Matter After Chronic Ketamine Use

BACKGROUND Use of ketamine as a recreational drug is spreading rapidly among young people all over the world. Epidemiological studies have linked chronic ketamine use with a number of problems, including cognitive impairments, bladder dysfunction, and ketamine-related death. However, little is known about the long-term effects of ketamine use on brain structure and function. METHODS We used voxel based morphometry in conjunction with statistical parametric mapping on the structural magnetic resonance images of ketamine-dependent (n = 41) and drug-naive control individuals (n = 44) to assess differences in gray matter volume between the two groups. RESULTS We observed significant decreases in gray matter volume in bilateral frontal cortex (left superior frontal gyrus and right middle frontal gyrus) of ketamine users in comparison with control subjects (p < .05 corrected for multiple comparisons at cluster-level). Duration of ketamine use was negatively correlated with gray matter volume in bilateral frontal cortex, whereas the estimated total lifetime ketamine consumption was negatively correlated with gray matter volume in left superior frontal gyrus. CONCLUSIONS We have demonstrated a reduction in frontal gray matter volume in patients after chronic ketamine use. The link between frontal gray matter attenuation and the duration of ketamine use and cumulative doses of ketamine perhaps suggests a dose-dependent effect of long-term use of the drug. Our results have important connotations for the clinical picture that is likely to emerge with the growing recreational use of ketamine and is also relevant to the status of the drug as a model for schizophrenia.

Bilateral Fronto-Parietal Integrity in Young Chronic Cigarette Smokers: A Diffusion Tensor Imaging Study

Background Cigarette smoking continues to be the leading cause of preventable morbidity and mortality in China and other countries. Previous studies have demonstrated gray matter loss in chronic smokers. However, only a few studies assessed the changes of white matter integrity in this group. Based on those previous reports of alterations in white matter integrity in smokers, the aim of this study was to examine the alteration of white matter integrity in a large, well-matched sample of chronic smokers and non-smokers. Methodology/Principal Findings Using in vivo diffusion tensor imaging (DTI) to measure the differences of whole-brain white matter integrity between 44 chronic smoking subjects (mean age, 28.0±5.6 years) and 44 healthy age- and sex-matched comparison non-smoking volunteers (mean age, 26.3±5.8 years). DTI was performed on a 3-Tesla Siemens scanner (Allegra; Siemens Medical System). The data revealed that smokers had higher fractional anisotropy (FA) than healthy non-smokers in almost symmetrically bilateral fronto-parietal tracts consisting of a major white matter pathway, the superior longitudinal fasciculus (SLF). Conclusion/Significance We found the almost symmetrically bilateral fronto-parietal whiter matter changes in a relatively large sample of chronic smokers. These findings support the hypothesis that chronic cigarette smoking involves alterations of bilateral fronto-parietal connectivity.

Alterations in regional homogeneity of resting-state brain activity in ketamine addicts.

Ketamine is a non-competitive anatognist of the N-methyl-D-aspartate (NMDA) receptor commonly used as an anesthetic and analgesic. In sub-anesthetic doses, it can induce temporary psychotic symptoms and has served as a pharmacological model for schizophrenia. While its acute effects on brain and behavior have been studied, the effects of long-term exposure to ketamine on brain activity have been largely unexplored. In this study, we aimed to examine such effects on spontaneous brain dynamics measure using resting-state functional magnetic resonance imaging (fMRI). Forty-one patients with ketamine dependence and forty-four healthy control subjects were imaged with BOLD fMRI using a 3.0-Tesla Siemens scanner at the Magnetic Resonance Center of Hunan Provincial Peoples Hospital, analyzed with the regional homogeneity (ReHo) method. Compared with healthy controls, decreased ReHo was found in ketamine users in the right anterior cingulate cortex and increased ReHo was found in left precentral frontal gyrus (p<0.05, cluster-level corrected). We also observed negative correlations between increased ReHo in precentral frontal gyrus and estimated total lifetime ketamine consumption and ketamine craving levels. To our knowledge, this is the first study the long-term effects of ketamine exposure on brain functional activity. Our findings indicate that ketamine dependence is associated with alterations in the functional connectivity of medial and lateral prefrontal cortices.

Morphine withdrawal decreases responding reinforced by sucrose self-administration in progressive ratio.

Previous studies have shown that withdrawal from psychostimulant drugs such as d‐amphetamine or methamphetamine decreases motivation to work for a natural reinforcement, which is thought to be associated with the withdrawal‐induced depressive state and hypofunction of the mesolimbic dopamine system. However, to our knowledge, studies exploring the effect of morphine withdrawal on motivation for a natural reinforcement are lacking. The purpose of the present study was to examine whether motivation to work for a natural reinforcement changes during morphine withdrawal. Three groups of male Sprague–Dawley rats were trained to respond on a nose poke for a 4% sucrose solution under a progressive ratio schedule and were subsequently administered a 10‐day regimen of injection of high or low dose of morphine or saline. Their duration of break point and withdrawal symptoms were assessed. The finding showed that break points were significantly reduced on day 1 and persisted to at least day 10 of withdrawal without change in locomotor activity. There were hardly any differences bear mentioning when comparing the magnitude of the decrease between the high‐ and the low‐dose group, whereas the withdrawal scales were significant greater in the high‐dose group than in the low‐dose group. The results suggest that the morphine withdrawal resulted in decreased motivation to obtain the natural reinforcement. The progressive ratio procedure may be a useful technique for evaluation of changes in motivation for natural reinforcing stimuli following withdrawal from opiates.

Altered spontaneous activity in young chronic cigarette smokers revealed by regional homogeneity

BackgroundFew studies have been previously published about the resting state brain activity in young chronic smokers, although many previous fMRI studies have shown that the task-related activity pattern is altered in chronic smokers.MethodsIn the present study, forty-five healthy smokers (age: 27.9 ± 5.6 year) and forty-four healthy non-smoking control subjects (age: 26.3 ± 5.8 year) have been imaged with functional magnetic resonance imaging (fMRI) and analyzed with the regional homogeneity (ReHo) approach.ResultsCompared with healthy controls, decreased ReHo was found in smokers in the right inferior frontal cortex and increased ReHo was found in the left superior parietal lobe (P < 0.01, 35 Voxels,Alphasim corrected).ConclusionsOur data suggested that, during resting state, neural function is less synchronized in the right inferior frontal cortex and more synchronized in the left superior parietal lobe in chronic smokers compared to non-smokers. The decreased synchronization in the right inferior frontal cortex may reflect lacking of control over reward-related behavior, and the increased synchronization may reflect smoking urges.

Development, extinction and reinstatement of morphine withdrawal-induced conditioned place aversion in rats.

The motivational component of drug withdrawal may contribute to drug seeking and relapse through the negative reinforcement‐based process. Here, we used conditioned place aversion (CPA) induced by naloxone‐precipitated morphine withdrawal to measure the aversive effects. Using an unbiased conditioning paradigm, we treated rats with morphine hydrochloride [(10 mg/kg intraperitoneally (i.p.)] twice per day (at 08:00 and 20:00) for 6.5 days (from day 1 to day 7 morning), while gave them naloxone (0.3 mg/kg i.p.) on day 6, a precipitated withdrawal paired with a compartment that caused CPA to the side. Then, the rats exhibited CPA were received 12 extinction trials from days 7 to 13, by daily exposed to the two compartments for free exploration. On day 13, the rats with extinguished CPA were treated with a priming injection of morphine (10 mg/kg i.p.) followed by naloxone (0.3 mg/kg i.p.) that reliably reinstated CPA. These results demonstrated that repeatedly morphine‐treated rats showed the formation, extinction and reinstatement of CPA. The present CPA model induced by these procedures may be useful for studying the biological mechanisms underlying the aversive motivational component of opiate withdrawal.

The dopamine D2 partial agonist and antagonist terguride decreases heroin self-administration on fixed- and progressive-ratio schedules

Dopamine partial agonists have been suggested to be potential therapeutic candidates for pharmacological intervention in drug addiction. These drugs bind to dopamine receptors with high affinity and low intrinsic activity and are hypothesized to behave as functional antagonists in conditions of high dopaminergic tone. The aim of the present study was to characterize the effects of terguride, a partial dopamine agonist at the dopamine D(2) receptor, on intravenous heroin self-administration on fixed- and progressive-ratio schedules of reinforcement. The effects of terguride on oral sweet solution (4% sucrose) self-administration on a fixed-ratio schedule were also tested. Terguride dose-dependently decreased heroin self-administration on the fixed-ratio schedule and decreased the maximum number of responses for heroin self-administration on a progressive-ratio schedule. In contrast, terguride did not significantly affect oral sucrose self-administration. These data suggest that terguride may represent a novel pharmacological strategy for the treatment of opiate addiction.

Docosahexaenoic acid intake ameliorates ketamine-induced impairment of spatial cognition and learning ability in ICR mice.

Several studies have reported the ketamine-induced cognitive impairment. Docosahexaenoic acid (DHA) supplementation improves cognitive function in human infants and protects against learning impairment in patients with Alzheimers disease (AD). In this study, we investigated the effect of DHA on ketamine-induced impairment of spatial cognition and learning ability in Institute of Cancer Research (ICR) mice. Morris water maze (MWM) was used to assess spatial learning and memory. Gamma-aminobutyric acid (GABA) levels in the hippocampus and prefrontal cortex were measured using high-performance liquid chromatography (HPLC). The results showed that intraperitoneal injection of ketamine (30mg/kg, twice per day) for 4 weeks led to the decline of spatial cognitive ability in mice, and 420mg/(kgd) DHA supplementation for 6 weeks improved ketamine-induced spatial cognitive impairment to a certain extent. The up-regulation of GABA levels in the hippocampus and prefrontal cortex was related to the improvement in spatial learning. Our results suggested that DHA supplementation would be a promising intervention to improve ketamine-induced spatial memory and cognitive dysfunction, and this effect of DHA might be correlated with the up-regulation of GABA levels.

Decreased Thalamocortical Connectivity in Chronic Ketamine Users.

Disintegration in thalamocortical integration suggests its role in the mechanistic ‘switch’ from recreational to dysregulated drug seeking/addiction. In this study, we aimed to address whether thalamic nuclear groups show altered functional connectivity within the cerebral cortex in chronic ketamine users. One hundred and thirty subjects (41 ketamine users and 89 control subjects) underwent rsfMRI (resting-state functional Magnetic Resonance Imaging). Based on partial correlation functional connectivity analysis we partitioned the thalamus into six nuclear groups that correspond well with human histology. Then, in the area of each nuclear group, the functional connectivity differences between the chronic ketamine user group and normal control group were investigated. We found that the ketamine user group showed significantly less connectivity between the thalamic nuclear groups and the cortical regions-of-interest, including the prefrontal cortex, the motor cortex /supplementary motor area, and the posterior parietal cortex. However, no increased thalamic connectivity was observed for these regions as compared with controls. This study provides the first evidence of abnormal thalamocortical connectivity of resting state brain activity in chronic ketamine users. Further understanding of pathophysiological mechanisms of the thalamus in addiction (ketamine addiction) may facilitate the evaluation of much-needed novel pharmacological agents for improved therapy of this complex disease.

Craving Responses to Methamphetamine and Sexual Visual Cues in Individuals With Methamphetamine Use Disorder After Long-Term Drug Rehabilitation

Studies utilizing functional magnetic resonance imaging (fMRI) cue-reactivity paradigms have demonstrated that short-term abstinent or current methamphetamine (MA) users have increased brain activity in the ventral striatum, caudate nucleus and medial frontal cortex, when exposed to MA-related visual cues. However, patterns of brain activity following cue-reactivity in subjects with long-term MA abstinence, especially long-term compulsory drug rehabilitation, have not been well studied. To enrich knowledge in this field, functional brain imaging was conducted during a cue-reactivity paradigm task in 28 individuals with MA use disorder following long-term compulsory drug rehabilitation, and 27 healthy control subjects. The results showed that, when compared with controls, individuals with MA use disorder displayed elevated activity in the bilateral medial prefrontal cortex (mPFC) and right lateral posterior cingulate cortex in response to MA-related images. Additionally, the anterior cingulate region of mPFC activation during the MA-related cue-reactivity paradigm was positively correlated with craving alterations and previous frequency of drug use. No significant differences in brain activity in response to pornographic images were found between the two groups. Compared to MA cues, individuals with MA use disorder had increased activation in the occipital lobe when exposed to pornographic cues. In conclusion, the present study indicates that, even after long-term drug rehabilitation, individuals with MA use disorder have unique brain activity when exposed to MA-related cues. Additionally, our results illustrate that the libido brain response might be restored, and that sexual demand might be more robust than drug demand, in individuals with MA use disorder following long-term drug rehabilitation.