Correlation study between brain N-acetylaspartate and executive function in alcoholics

Perceived Effectiveness of Medications Among Mental Health Service Users With and Without Alcohol Dependence

Quantitative proton spectroscopic studies were performed on 39 volunteers and 16 patients with intracranial tumours. Estimates of T2 were obtained in white matter, grey matter, cerebellum, astrocytomas and meningiomas; T1 was determined in white matter only. White matter values of T2 for trimethylamines, creatine and N-acetyl aspartate (NAA) were 309 +/- 84, 195 +/- 41 and 369 +/- 124 ms, respectively (mean +/- SD, n = 20). Metabolite concentrations in white matter were 2.0 +/- 0.4 mumol/g wet weight for trimethylamines, 7.3 +/- 1.1 for creatine and 11.4 +/- 1.4 for NAA. The mean concentrations of creatine and NAA in grey matter and all of three metabolites in cerebellum were greater than those in white matter. Tumour spectra were characterized by increased trimethylamines, reduced creatine and NAA and occasionally the presence of lactate. Meningiomas were further characterized by the presence of alanine. The mean T2 and concentration of trimethylamines in tumours was significantly greater than in normal brain. Creatine and NAA concentrations were decreased in all tumours. The longer T2 of trimethylamines and presence of alanine in meningiomas indicate that important differences exist in membrane and glucose metabolism within these tumours when compared to either astrocytomas or normal brain tissue.

BackgroundMany cancer survivors experience cancer-related cognitive impairment (CRCI), often with significant negative consequences across various life domains. Emerging evidence suggests that allowing additional time to process information before acting may be a useful strategy for those with CRCI to mitigate some of its impacts. The Wisconsin Card Sorting Task (WCST), a measure of general cognition, has shown that for some cancer survivors, longer task completion time facilitates similar task performance outcomes to control populations concerning perseveration errors; a key performance metric of the WCST. However, assessing if this strategy may be useful, as well as determining for whom it may be useful, with regard to strengths and weaknesses among select cognitive domains, is challenging due to factors such as the problem of task impurity. Accordingly, this study provides an initial computational and experimental assessment of whether additional time to process information before acting is a useful strategy for those with CRCI.MethodsWe simulated individual cognitive differences observed in humans by varying contributions of executive functioning components (updating, shifting, inhibition) to yield 48 distinct computational models of the WCST. Our main manipulation was then to provide these models with more or less time (at three levels of 20, 40 and 60 cycles) before models executed an action to sort a given card. We compared the number of perseveration errors on the WCST produced by the computational models. Additionally, we determined models that simulated the performance of cancer survivors on the WCST by comparing the number of perseveration errors produced by the models to human data.ResultsAdditional processing time resulted in the models producing significantly fewer perseveration errors, supporting our hypothesis. In addition, 8 unique models simulated the performance of cancer survivors on the WCST. Additional time appeared to have a positive influence on performance primarily by mitigating the impacts of severe inhibition impairments. For more severe global executive function impairments, a substantial amount of additional time was required to mitigate the impacts of the impairments. For the most severe impairments, additional time was unable to adequately mitigate the impact on performance.ConclusionAdditional processing time may be a useful strategy to rectify perseveration errors among cancer survivors with CRCI. Our findings have implications for the development of practical strategies, such as workload and deadline management in occupational settings, which may mitigate the negative effects of CRCI.

Hookah use among college students: Prevalence, mental health and drug use

In most parts of the world, alcohol is consumed for social and recreational reasons. However, the initially controllable use can become compulsive and alcohol dependence develops. Late dependence is characterized by persistent neuroadaptations in various brain neurotransmitter systems, including the endogenous opioid and dopamine system, which are thought to underlie relapse. Many hypotheses on the state of brain neurotransmitter systems are based on positron emission tomography (PET) studies. However, the interpretation of those data is challenging as PET signals are sensitive not only to receptor but also ligand levels. For instance, increased μ-opioid receptor (MOR) PET binding potentials are interpreted as elevated receptor levels. Those are thought to be the target of the anti-relapse medication naltrexone, an opioid antagonist. However, naltrexone’s effect size is relatively small and only a subset of alcohol-dependent patients appears to benefit. Furthermore, only few studies on the opioid and dopamine system during protracted abstinence are available. This is surprising as this phase is characterized by high relapse propensity and, thus, is clinically highly relevant. Therefore, this thesis aims to demonstrate the state of the opioid and dopamine system during alcohol abstinence. A translational approach was applied by analyzing these systems in four separate studies (Study I-IV) in post-mortem brain tissue of human alcoholics and an animal model of alcohol dependence. In Study I, transcriptional and protein levels (receptor binding sites) of the MOR are found to be strongly reduced in the striatum of alcoholics. Additionally, a PET study associates decreased striatal MOR binding potential with higher relapse risk. Decreased MOR expression is mirrored by data from alcohol-dependent rats in Study II. Furthermore, the precursor of the MOR-ligand β-endorphin Pomc is significantly reduced. Signaling at the δ-opioid receptor (DOR) appears to be decreased in alcohol dependence while the κ-opioid receptor (KOR) system is upregulated. In Study III, chronic naltrexone treatment counteracts the changes in MOR/Pomc levels by significantly increasing expression and further enhanced KOR density. The DOR, in contrast, seems not to be a target of naltrexone under the applied experimental conditions. Because the endogenous opioid system is known to modulate dopamine release, the dopamine system was investigated in Study IV. Here, human post-mortem tissue reveals strongly decreased dopamine transporter and D1 receptor levels in alcoholics while D2 is unchanged. These findings are further supported by the alcohol-dependent animals where an oscillatory-like regulation of the dopamine system is observed during acute withdrawal and protracted abstinence. While previous studies report on a hypodopaminergic state during acute withdrawal, here, a hyperdopaminergic state is demonstrated during protracted abstinence by measurements of striatal dopamine release and a meta-analysis followed by functional validations. Based on these data, both hypo- and hyperdopaminergic states are suggested as phases with increased vulnerability for alcohol relapse. In summary, the results presented in this thesis provide consistent evidence for a severe dysregulation of the endogenous opioid and dopamine system during alcohol abstinence that demands reinterpretation of existing PET data. It is proposed for future studies to combine the analysis of human post-mortem tissue and established animal models with PET studies to achieve a more precise picture of the state of brain neurotransmitter systems in alcoholic patients. Moreover, decreased MOR and dopamine receptor/transporter levels may represent molecular markers of the disease course that can be used to develop personalized treatment approaches.

Alcoholism is a chronic and severe disease that impairs life-quality and causes problems in health, in psychological, and in social issues over time. In the past very few treatment services were available for alcoholism. Nowadays, since alcohol dependence is defined as a psychiatric disease treatment offers have augmented. Despite multiple treatment facilities abstinence rates or successful long term treatment outcomes are still modest. This raises the question if treatment methods can be improved by adapting or tailoring treatments more to patients’ individual need, like in personalized medicine, where patients’ individual characteristics provoke different treatment implications. Alcoholism is a disease heterogeneous in appearance and in its consequences. Thus reasons for alcohol drinking, the expected effects of alcohol and the course of drinking patterns are very different among alcohol dependents. Therefore it seems clear that there cannot be a standardized, uniform treatment for alcoholism which is adequate for everyone. Personalized treatments for alcoholism including different aspects with different implications for treatment are needed. Hence, the present cumulative dissertation consists of three publications from clinical research addressing different aspects in the treatment of alcoholism, which play an important role and have impact on treatment outcomes as well as on future research. In the first article the feasibility and effectiveness of a voluntary smoking cessation offer was investigated parallel to an alcohol detoxification treatment. Outcomes in smoking quit rates were modest, but a clear advantage in the reduction rate of cigarettes was found in the CBT condition. Furthermore, it was found that the sub-group of heavy smokers benefited the most of the CBT intervention. The second article investigated the impact of self-help group attendance, namely 12-step programs predominantly Alcoholics Anonymous on relapse rates. There was only a slightly better outcome for patients attending a 12-step group involvement regularly as an aftercare group exclusively in the first month after treatment discharge. In the third article self-perceived interpersonal problems were examined finding that alcohol-dependent patients exhibited a higher burden of interpersonal problems in general compared to healthy controls. Furthermore, alcohol-dependent women exhibited in total more and different dimensions of interpersonal problems compared to alcohol-dependent men. All these results from clinical research may help to adapt treatments in a way, so that patients benefit more. A higher attraction of the treatment may lead to a higher participation and probably to a higher compliance. Findings may help to improve quality of therapies, best in the sense of a personalized treatment, which in turn may improve outcomes.

Structural MRI findings of abnormalities in the prefrontal cortex in schizophrenia and affective disorder have been inconsistent likely due to small, heterogeneous samples, the evaluation of prefrontal gray and white matter combined, and the fact that prefrontal cortex is typically not delineated into separate gyri (e.g., Shenton et al., 2001; Strakowski et al., 2002). We previously reported smaller prefrontal gray matter in first-episode schizophrenia relative to first-episode affective psychosis and controls (Hirayasu et al., 2001). One unresolved question in the literature is whether or not further volume reduction will be observed over time, the focus of this report. Prefrontal gray and white matter volumes were measured (see Fig. 1) in patients at the time of first hospitalization for schizophrenia (n=12, 3 females) or affective psychosis (n=10, 1 female, 9 bipolar, 1 unipolar), and psychiatrically well subjects (n=15, 1 female). Subjects were rescanned approximately 1.5 years later. Seven schizophrenia, six affective, and four comparison subjects were previously described solely at first scan (Hirayasu et al., 2001). Samples did not differ in age (28.1±8.4; 22.9±2.8; 25.4±4.5; F(2,34)=2.2, p=0.12) or WAIS Information scores (11.8±3.4; 12.2±3.1, 11.8±2.0; F(2.32)=0.6, p=0.9), nor in parental socioeconomic status (F(2.34)=2.32, p=0.11) or handedness (F(2.33)=1.6, p=0.22). BPRS scores were higher in schizophrenics (41.2±13.2) than affectives (33.8±8.0) (F(1,20)=5.71, p=0.027). Similar neuroleptics were prescribed for the patient groups (schizophrenics: 7 typical, 4 atypical, 1 none; affectives: 6 typical, 3 atypical, 1 none). Fig. 1 Prefrontal ROI definitions and volumes. (a) Coronal slice, (b) axial slice showing prefrontal gray and white matter, and (c) three. Three-dimensional reconstruction of the extent of gray and white matter boundaries. MR images were acquired with a 1.5-T ... Relative volumes [i.e., absolute volumes divided by intracranial contents (ICC)] were used in the analyses. Repeated-measures ANOVA was performed with diagnosis as the between-subjects factor and time and side as the within-subjects factors for gray and white matter separately. Prefrontal gray matter at time 1 was significantly different among groups (F2,30=5.56, p=0.009), with schizophrenics smaller than controls and affectives, who did not differ from each other. There was no interaction for group by time by side for prefrontal gray matter (F2,34=0.65, p=0.53). All groups showed larger gray matter on the left (F2,30=8.72, p=0.006). White matter volumes did not differ among groups (p>0.87), and all groups showed more white matter on the right (F1,30=39.20, p<0.001) and a reduction over time (F1,30=10.902, p=0.002), there was a trend for this effect to be larger on the right (F1,30=3.14, p=0.086) (%change over time for right white matter: schizophrenics 2.8%; affectives 6.5%; controls 2.1%). Neither removing the unipolar depression subject nor removing the females altered the results. There was no significant correlation between ROI volume change and medication dosage at time 1 for either patient group (Time 2 data came from out patients based on self-report and was for this reason not used). These data suggest that prefrontal cortical gray matter is selectively smaller at first hospitalization for schizophrenia relative to affective psychosis and controls, but this volume difference did not change over the relatively short post-first hospitalization time examined. Small gray matter volumes may be due to reduced dendritic arborization or increased neural density in prefrontal cortex in schizophrenia (Benes et al., 1992; Selemon et al., 1998). White matter, which was not different among groups, showed a decline with time in all groups, possibly consistent with normal aging (Good et al., 2001, although Bartzokis et al., 2001). Potential reasons for our not observing selective gray matter reductions point to several limitations of this study including the gender distribution, as females may have greater dorsolateral and orbitofrontal lobe involvement and males greater dorsomedial changes in schizophrenia (Gur et al., 2000); the use of large ROI, as sub-regions within the prefrontal cortex may change in volume at different rates (Gur et al., 1998; DeLisi et al., 1997); and lack of exact medication dosages and compliance histories during the intrascan interval cannot be ruled out as possible confounds. Although the sample size was small, the effect size was also small (Fig. 1) suggesting that even enlarging the sample would not result in a significant change in volume over time for either gray or white matter.

Relationship between N-acetyl-aspartate in gray and white matter of abstinent methamphetamine abusers and their history of drug abuse: A proton magnetic resonance spectroscopy study

The dual theory establishes that the decision-making process relies on two different systems, the affective system and the executive function (EF), developed during adolescence. This study analyzes the relationship between the decision-making and EF processes in a group of early adolescents (mean age = 12.51 years, SD = 0.61), where more affective impulse processes are developed, and in young adults (mean age = 19.38 years, SD = 1.97), where cognitive control processes have already matured. For this purpose, 140 participants in Spain completed the Iowa Gambling Task (IGT) to measure their risky decisions and the Wisconsin Card Sorting Task (WCST) to measure their EF. Performance on the IGT improves over blocks; however, adolescents received lower mean scores than young adults. However, controlling for age, perseverative errors were negatively associated with the mean net score on the risky blocks of IGT; thus, those who committed more perseverative errors in the WCST were more likely to take cards from the disadvantageous decks on the last blocks of the IGT. The current study shows that adolescents and adults solve ambiguous decisions by trial and error; however, adolescents are more likely to make risky decisions without attending to the long-term consequences. Following the dual theory hypothesis, the maturation of EF with age partly accounts for this difference in risky decision-making between adolescents and adults.

To quantify regional variations in metabolite levels in the developing brain using quantitative proton MR spectroscopic imaging (MRSI). Fifteen healthy subjects three to 19 years old were examined by in vivo multislice proton MRSI. Concentrations of N-acetyl aspartate (NAA), total choline (Cho), total creatine (Cr), and peak area ratios were determined in selected frontal and parietal gray and white matter regions, basal ganglia, and thalamus. In cortical gray matter regions, the ratio of NAA/Cho increased to a maximum at 10 years and decreased thereafter (P = 0.010). In contrast, in white matter, average ratios NAA/Cho increased linearly with age (P = 0.045). In individual brain regions, age-related changes in NAA/Cho were found in the putamen (P = 0.044). No significant age-related changes in NAA, Cho, Cr, or other metabolite ratios could be determined. Consistent with recent studies using other structural and functional neuroimaging techniques, our data suggest that small but significant changes occur in regional cerebral metabolism during childhood and adolescence. Non-linear age related changes of NAA/Cho in frontal and parietal areas, resembling previously reported age related changes in rates of glucose utilization and cortical volumes, may be associated with dendritic and synaptic development and regression. Linear age-related changes of NAA/Cho in white matter are also in agreement with age-related increases in white matter volumes, and may reflect progressive increases in axonal diameter and myelination.

views and personal experiences of people who have especially contributed to the evolution of ideas in the Journal's field of interest.

Objective: The cholinergic system is important in the search for the pathophysiology of schizophrenia due to its role in cognitive function, interaction with the dopamine system in brain regions relevant to schizophrenia, side effects of antipsychotic medication and potential antipsychotic effect of muscarinic receptor antagonists. This study investigated the association of type I muscarinic receptor (CHRM1) genetic polymorphisms with the clinical characteristics of chronic schizophrenic inpatients. Methods: We determined the genotype of CHRM1 genetic polymorphisms in 243 schizophrenic patients hospitalized in chronic care wards. Psychotic symptoms were assessed using the Brief Psychiatric Rating Scale (BPRS), and cognitive function was assessed using the Folstein Mini-Mental Status Examination (MMSE) test. Sixty of the 243 subjects also completed the Wisconsin Card Sorting Test (WCST). Results: There was a significant difference in the number of correct responses and the percentage of perseverative errors in the WCST in the CHRM1 C267A genotype group of schizophrenia patients. There was no significant association between age at onset, chlorpromazine equivalents, BPRS scores, MMSE or schizophrenia per se in patients with the CHRM1 C267A genotype. The full exon of the CHRM1 gene was screened out with single-strand conformation polymorphism, and 2 single nucleotide polymorphisms (C267A and C1353T) were identified in our patients and control subjects. These 2 single nucleotide polymorphisms were linked together without exception. Conclusion: This study demonstrated that in schizophrenic patients, the heterozygote group of CHRM1 C267A polymorphism (267C/A) had more correct responses and less perseverative errors on the WCST performance than the 267C/C homozygote group, implicating that this polymorphism may be related to prefrontal cortical function. Our results also suggested that the C267A polymorphism plays no major role in the susceptibility to and clinical manifestations of schizophrenia.

Background: Although studies have indicated that the frontal lobe plays an important role in performance on the Wisconsin Card Sorting Test (WCST) and that basal ganglia play a specific role in frontal lobe function, the role of striatal dopamine (DA) activity in performance on the WCST remains unclear. Methods: We assessed the relation between the availability of striatal dopamine transporters (DATs) and performance on the WCST as a measure of executive function in healthy individuals. We approximated the availability of DATs in 53 healthy volunteers aged 19–61 years by use of single photon emission computed tomography with technetium-99m (99mTc)-TRODAT-1 as the ligand. The WCST was administered to all participants. Results: The availability of DAT was significantly negatively correlated with perseverative errors on the WCST, both before and after adjustment for body mass index ( rbefore = −0.39, p = 0.004; rafter = −0.39, p = 0.005). Limitations: This was an association study; thus, a causal relation between DAT availability and performance cannot be confirmed. Conclusion: Our results suggest that striatal DAT availability may play a role in executive function as measured by the WCST.

Background: Alcohol Use Disorder (AUD) is associated with significant cognitive impairments, particularly in executive functioning, yet evidence for cognitive rehabilitation therapy (CRT) in low-resource settings remains limited. This study evaluated the efficacy of CRT for mild executive dysfunction among male AUD patients in Zambia. Methods: A randomized controlled trial was conducted with 56 participants (aged 18-40 years) recruited from a residential rehabilitation center in Lusaka. Participants were randomized to either an 8-week CRT program (Brain Wave-R, n=28) or active control (painting sessions, n=28), both delivered alongside standard treatment. Executive function was assessed pre- and post-intervention using the Zambian Neurobehavioral Test Battery, including the Wisconsin Card Sorting Test (WCST), Colour Trails Test 2 (CTT), and Stroop Test. Results: The CRT group demonstrated significant improvements in response inhibition (Stroop Test: fewer errors, p=0.01; more words completed, p&lt;0.01) compared to controls. However, no significant between-group differences emerged for cognitive flexibility (WCST: correct responses p=0.87; categories completed p=0.06) or task-switching (CTT: errors p=0.12; time p=0.56). Secondary analyses revealed government-employed participants showed better outcomes on WCST (p=0.04) and CTT (p=0.03), while those with chronic medical conditions performed worse on WCST (p&lt;0.001). The control group showed unexpected but significant Stroop Test improvements (p&lt;0.001), suggesting non-specific benefits of structured activities. Conclusion: CRT shows selective efficacy for improving response inhibition in Zambian AUD patients, with employment status and health conditions moderating treatment effects. These findings support targeted implementation of CRT in low-resource settings, particularly for patients without significant comorbidities. Future research should investigate optimal intervention duration and strategies to enhance effects on complex executive functions.

Alcohol self-administration in the laboratory has been used to evaluate pharmacological treatments and neurobiological mechanisms that underlie alcohol use in alcohol-dependent individuals. This study evaluated whether attenuation of serotonin synthesis via depletion of its precursor tryptophan reduces the amount of alcohol consumed in a self-administration paradigm in non-treatment-seeking individuals with alcohol use disorders. Individuals with alcohol dependence (n = 8) and alcohol abuse (n = 4) who were not seeking treatment were recruited by advertisement and participated in two test days, 1 week apart. Each test session was preceded by administration of a concentrated amino acid drink that resulted in a rapid and significant decline in plasma free tryptophan (active depletion) or a similar drink containing tryptophan (placebo depletion). Tests were conducted in a randomized, double-blind fashion. The test session began with a cue exposure session where subjects were exposed to their favorite alcoholic beverage and asked to rate their craving for alcohol. After this, subjects were administered a priming drink designed to raise blood alcohol levels to 0.02 g%. Subjects then had the opportunity to drink up to eight additional drinks, each designed to raise blood alcohol levels by 0.02 g%, or to receive $3 for each drink not consumed over a 2-hr period. There were no significant differences in alcohol consumed or subjective intoxication with active tryptophan depletion compared with placebo. Self-reported craving correlated with the amount of alcohol consumed in the session. These data question the dependence of alcohol self-administration on the ongoing synthesis of serotonin.