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Gray matter (GM) volume reductions as a function of cocaine addiction (CUD < CON, 82 individuals; CUD indicates cocaine use disorders, and CON, controls). Each brain region (DLPFC, dorsolateral prefrontal cortex; Hipp, hippocampus; OFC, orbitofrontal cortex; Temp, temporal; numbers in parentheses are Brodmann areas) is presented with a graph using the voxels of interest to show that the main effects of addiction are contributed by both genotype groups (except for the OFC). The y-axis units display the percentage of GM volume in the cluster around the peak coordinates listed in Table 2. Error bars represent standard error of the mean. The GM volume map in each of the graphs shows the clusters of significance between the diagnostic groups (P < .05, false discovery rate corrected, 100 voxels minimum). The parahippocampus is not shown because its values were identical to the hippocampus volumes of interest, as they came from the same cluster. MAOA*H and MAOA*L indicate high- and low-repeat monoamine oxidase A genotype, respectively.
Gene × disease interaction in the orbitofrontal cortex (OFC; numbers in parentheses are Brodmann areas). The gray matter (GM) volume measures in CUD-L < CON-L (red) and CUD-H < CON-H (blue) are overlaid on the SPM5 canonical template (Wellcome Department of Cognitive Neurology, London, England; http://www.fil.ion.ucl.ac.uk/spm) (CUD indicates cocaine use disorders, and CON, controls; H and L refer to high- and low-repeat monoamine oxidase A gene, MAOA, genotype, respectively). The respective interaction graphs show regional GM volume differences between the groups, in which the individuals in the CUD-L group have less GM than those in the CUD-H group and both CON groups. Error bars represent standard error of the mean. The y-axis units display the percentage of GM volume cluster around the peak coordinates in Table 2 (P < .05, false discovery rate corrected, 100 voxels minimum).
Lifetime effects of drug use on gray matter (GM) volume. The image shows correlation of GM volume with lifetime use of each drug (cocaine, red; alcohol, yellow; smoking, green) overlaid on the SPM5 canonical template (Wellcome Department of Cognitive Neurology, London, England; http://www.fil.ion.ucl.ac.uk/spm). The respective scatterplots are also overlaid with the correlations of GM volume (y-axis) and lifetime years of cocaine use in the cocaine use disorders group (red) and lifetime years of alcohol use (yellow) and smoking (green) in all participants (open circles represent controls), with the respective slope (P < .001, uncorrected, 100 voxels minimum). Hipp indicates hippocampus, and OFC, orbitofrontal cortex; number in parentheses is Brodmann area.
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Alia-Klein N, Parvaz MA, Woicik PA, et al. Gene × Disease Interaction on Orbitofrontal Gray Matter in Cocaine Addiction. Arch Gen Psychiatry. 2011;68(3):283–294. doi:10.1001/archgenpsychiatry.2011.10
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Long-term cocaine use has been associated with structural deficits in brain regions having dopamine-receptive neurons. However, the concomitant use of other drugs and common genetic variability in monoamine regulation present additional structural variability.
To examine variations in gray matter volume (GMV) as a function of lifetime drug use and the genotype of the monoamine oxidase A gene, MAOA, in men with cocaine use disorders (CUD) and healthy male controls.
Cross-sectional comparison.
Clinical Research Center at Brookhaven National Laboratory.
Forty individuals with CUD and 42 controls who underwent magnetic resonance imaging to assess GMV and were genotyped for the MAOA polymorphism (categorized as high- and low-repeat alleles).
Main Outcome Measures
The impact of cocaine addiction on GMV, tested by (1) comparing the CUD group with controls, (2) testing diagnosis × MAOA interactions, and (3) correlating GMV with lifetime cocaine, alcohol, and cigarette smoking, and testing their unique contribution to GMV beyond other factors.
(1) Individuals with CUD had reductions in GMV in the orbitofrontal, dorsolateral prefrontal, and temporal cortex and the hippocampus compared with controls. (2) The orbitofrontal cortex reductions were uniquely driven by CUD with low- MAOA genotype and by lifetime cocaine use. (3) The GMV in the dorsolateral prefrontal cortex and hippocampus was driven by lifetime alcohol use beyond the genotype and other pertinent variables.
Long-term cocaine users with the low-repeat MAOA allele have enhanced sensitivity to gray matter loss, specifically in the orbitofrontal cortex, indicating that this genotype may exacerbate the deleterious effects of cocaine in the brain. In addition, long-term alcohol use is a major contributor to gray matter loss in the dorsolateral prefrontal cortex and hippocampus, and is likely to further impair executive function and learning in cocaine addiction.
Drug addiction is a chronic disease associated with deficits in brain dopamine1 (DA) and brain function in regions underlying the impaired response inhibition and salience attribution syndrome (see Goldstein and Volkow2 for review). These regions encompass the reward and the inhibitory circuitry that contain DA-receptive neurons, where ventral prefrontal regions such as the orbitofrontal cortex (OFC) have received much emphasis.2,3 Multiple neuroimaging studies in the past decade demonstrated a reliable pattern of functional deficits during cognitive/emotional challenges that involve reward contingencies (salience attribution) and inhibitory control (response inhibition) in cocaine use disorders (CUD).4,5 For example, positron emission tomography and functional magnetic resonance (MR) imaging studies have demonstrated that DA-related functional deficits in the OFC may underlie disproportionate salience attribution to cocaine and compulsive drug intake.3,5-7
Although relatively few, studies have tested structural alterations in the same circuitry where functional activations are compromised and have documented such deficits.8 Individuals with cocaine addiction have shown decreased gray matter volume (GMV) or thinner cortex in the dorsolateral prefrontal cortex (DLPFC), OFC, and anterior cingulate cortex9-12; other regions included the insula, temporal cortex, and amygdala compared with healthy controls (CON).11-14 Because DA projections influence cerebral morphologic characteristics during development and throughout adulthood, it is expected that long-term exposure to substances that trigger supraphysiologic DA levels in the synapse, such as cocaine, might cause persistent cellular changes resulting in reduced neural volume compared with nonexposed individuals.8 Moreover, positron emission tomography studies have shown that the reduction in brain metabolism in DLPFC, OFC, and anterior cingulate cortex in cocaine abusers is associated with loss of postsynaptic DA markers.15
Addiction to crack cocaine involves long-term concurrent use of other substances that are known to influence brain morphologic characteristics.16-19 More than 60% of individuals with CUD also had a comorbid alcohol use disorder and more than 80% smoked cigarettes, further compounding GM loss throughout the brain.16-20 These high comorbidity rates make the assessment of long-term drug use other than cocaine imperative for the generalizability of the results to community samples of individuals with CUD. Therefore, the present study used MR imaging and whole-brain voxel-based morphometry (VBM) analysis to test changes in cerebral GMV as a function of CUD and in correlation with the chronicity of lifetime drug use. This analysis, however, does not indicate whether the predicted structural alterations result uniquely from years of chronic drug use. It is possible that individuals with CUD had reduced DA and reduced neural volume in the relevant brain circuits before disease onset, which could have predisposed them to drug use and addiction. The potential contribution of genetic differences to GMV may be present before disease onset and may interact with long-term drug use, rendering some individuals with CUD more sensitive to GM loss than others.
Genetic variations that interact with and affect brain development may contribute to behaviors that increase addiction liability.21 The product of the monoamine oxidase A gene, MAOA, is an enzyme that regulates the metabolism of monoamine neurotransmitters, thereby modulating brain function and structure.22,23 During prenatal development, the MAOA enzyme is crucial for catabolic degradation of DA and norepinephrine,23 inducing changes with long-term consequences during childhood.24 The MAOA genotype (defined as OMIM +309850), a variable number tandem repeat (uVNTR) region, is divergent in primates, suggesting that it plays a pivotal role in differential MAOA expression in both humans and monkeys.25 The MAOA genotype is relevant to GMV in healthy CON.26,27 In a large VBM study, healthy carriers of the low-repeat allele of MAOA (MAOA*L) had reduced GMV in the cingulate cortex and bilateral amygdala and increased GMV in the OFC compared with high-repeat allele (MAOA*H) carriers.28 Furthermore, in the presence of extreme environmental challenge (childhood abuse), MAOA*L genotype increases the risk of antisocial behaviors in adulthood, pointing to a gene × environment interaction.29 Studies have also suggested association of MAOA*L with the risk of alcohol addiction.30,31 We reasoned that, for individuals with CUD, the disease onset and its progression could be viewed as an environmental challege,32 possibly influencing GMV in affected members of the MAOA*L genotype (CUD-L group).
Therefore, in this study we predicted a main effect of addiction by which individuals with CUD would have reductions in GMV compared with CON. Next, we hypothesized a gene × disease interaction driven mostly by GMV loss in the CUD-L group. We hypothesized that a model containing both genetic and long-term drug use variables would better explain the predicted morphologic deficits in CUD.
Eighty-two right-handed men (40 with CUD and 42 CON) were recruited by advertisement in local newspapers. All participants provided informed consent in accordance with the local institutional review board. Physical/neurologic, psychiatric, and neuropsychological examinations were conducted and included tests of intellectual functioning (Wide-Range Achievement Test 3 reading33 and the Matrix Reasoning subset of the Wechsler Abbreviated Scale of Intelligence34), Beck Depression Inventory (BDI)35 to assess symptoms in the past 2 weeks, the Addiction Severity Index,36 and the Structured Clinical Interview for DSM-IV Axis I Disorders (research version).37 All participants were healthy, were not taking any medications, and were excluded if they had contraindications to the MR imaging environment (eg, metal in the body or claustrophobia), history of head trauma or loss of consciousness (>30 minutes), other neurologic disease, abnormal vital signs at time of screening, history of major medical conditions (cardiovascular, endocrinologic, oncologic, or autoimmune diseases), major psychiatric disorders (other than cocaine dependence and alcohol abuse for the CUD group and/or nicotine dependence for both groups), and urine positive (by means of a urinalysis kit [Biopsych; Biopsych Triage, San Diego, California) for psychoactive drugs or their metabolites (phencyclidine, benzodiazepines, amphetamines, cannabis, opiates, barbiturates, and inhalants) except for cocaine in CUD.
All participants in the CUD group were current users: urine was positive for cocaine in all but 6 of the 40 individuals, and they reported use a mean (SD) of 2.1 (1.5) days before the study. Current use or dependence on other drugs was denied and corroborated by preimaging urine tests in all participants (urine was negative for all other drugs in all participants). Table 1 contains the demographic and clinical comparisons between the CUD and CON groups with nested genotype comparisons.
The DNA samples for MAOA genotyping were extracted from whole blood (PAXgene Blood DNA Kit; Qiagen Inc, Valencia, California) from each participant. The polymerase chain reactions were performed as previously described.27 In humans and primates, categorization of common genetic variability is based on a functional polymorphism in the promoter region of the MAOA gene; uVNTR, 3.5 or 4 repeats (ie, "high") and 2, 3, or 5 repeats ("low") is common in the population in whom 3 and 4 occur in a ratio of approximately 60:40 in men. Compared with the high variant, the low variant has relatively lower transcriptional activity in human nonneural cell lines.27,38 In this sample, alleles were observed in expected ranges by means of GeneScan version 3.7 and Genotyper version 3.6 software (both Applied Biosystems, Carlsbad, California). Genetic analyses resulted in 42 participants classified as having the low- MAOA -repeat alleles (22 CUD-L and 20 CON-L) and 40 as having the high-repeat alleles (18 CUD-H and 22 CON-H).
All participants underwent T1-weighted anatomic MR imaging on a 4-T imager (Varian/Siemens, Malvern, Pennsylvania), with Sonata gradient set. The MR imaging variables of the 3-dimensional modified driven-equilibrium Fourier transform39,40 sequences were as follows: echo time/repetition time, 7/15 milliseconds; 0.94 × 0.94 × 1.00 mm3 spatial resolution; axial orientation; 256 readout; and 192 × 96 phase-encoding steps, within a 16-minute imaging time. The modified driven-equilibrium Fourier transform sequence is particularly effective for white matter (WM)–GM tissue differentiation.41
All structural data were analyzed with MATLAB 7.0 (MathWorks, Inc, Natick, Massachusetts; http://www.mathworks.com) and statistical parametric mapping (SPM5; Wellcome Department of Cognitive Neurology, London, England; http://www.fil.ion.ucl.ac.uk/spm) with VBM5.1 toolbox (Christian Gaser, PhD, Department of Psychiatry, University of Jena, Jena, Germany; http://dbm.neuro.uni-jena.de/vbm/). Preprocessing (spatial normalization, tissue segmentation, and bias correction) was conducted by means of a unified model. Images were normalized to standard proportional stereotactic space (Montreal Neurological Institute). Tissue probability maps (International Consortium for Brain Mapping, European version) were subsequently applied, segmenting the images of all 82 participants into GM, WM, and cerebrospinal fluid (CSF) tissue classes for each individual following Bayesian rule.42,43 A hidden Markov random field44 was applied to minimize the noise level by "removing" isolated voxels of one tissue class that are unlikely to be members of this tissue class, thus increasing the accuracy of the individual participant tissue probability maps. Finally, Jacobian modulation was applied to compensate for the expansion/contraction that occurs during nonlinear transformation and to restore the original absolute GMV in the segmented GM images. The voxel resolution after normalization was 1 × 1 × 1 mm. Statistical analysis of the regional GMV was performed after smoothing the normalized and modulated segments by means of an isotropic 12-mm3 full-width at half-maximum gaussian kernel.
Total brain tissue was computed as a sum of the extracted GMV and WM volume (WMV) for each participant. We did not analyze WMV in this study because other methods, such as diffusion tensor imaging, are more sensitive for this purpose (VBM's WM T1 signal intensities are not correlated with the WM integrity).45 As in other studies,46-48 CSF was not used in the calculation for total brain tissue because the value outputs by SPM5 are susceptible to artifacts (eg, if voxels are not fully differentiated as GM or WM, they can be mislabeled as CSF). In addition, GM and WM tend to vary together; however, CSF is variable from day to day and may increase as GM decreases, misleading the total brain calculation.49
Statistical analysis for the demographic and drug exposure factors was performed by means of a general linear model with a 2 (diagnosis: CUD vs CON) × 2 (genotype: low vs high) comparison or t tests or χ2, as needed, in SPSS (SPSS, Inc, Chicago, Illinois),50 as documented in Table 1. In SPM5, general linear model 2 × 2 was used for the GM maps, controlling for total brain tissue and age, for the diagnosis main effect (CUD < or > CON) and the genotype main effect (MAOA*L < or > MAOA*H). Then, we conducted planned comparisons between CUD and CON of the same allele variation: CUD-L < CON-L and CUD-H < CON-H. Separate whole-brain regression analyses, controlling for total brain tissue and age, were then conducted to test associations between GMV and lifetime years of cocaine use (in the CUD sample [n = 40], small-volume correction was used51). Lifetime years of alcohol and cigarette use was evaluated in the whole sample (n = 82). All SPM5 analyses were performed controlling for age and total brain tissue, with extent threshold of 100 voxels and a threshold set at P < .05, corrected with a false discovery rate equivalent to a T threshold of 3.3. Labels for the resulting coordinates were inspected by means of software (Anatomy Toolbox; Institute of Neuroscience and Medicine, Jülich, Germany) and a coplanar stereotactic atlas of the human brain.52
The voxels of interest were extracted with SPM5 EasyROI toolbox (http://www.sbirc.ed.ac.uk/cyril/cp_download.html) with an isotropic volume of the whole cluster around the significant peak voxel coordinates of the main effect results (CUD < CON from Table 2). This approach resulted in raw GMV values for each participant in each of these regions, allowing the measures to be used for figures and in SPSS50 to conduct general linear model analysis, covarying for total brain tissue, age, race, verbal intelligence, and BDI symptoms (as documented in the "Results" section). These SPSS analyses were Bonferroni corrected for the 5 main effect regions, making the CUD × MAOA interaction results significant at P < .01. To understand the contribution to variability in GMV of all the variables studied and the potentially unique effects of long-term drug use, we used the voxels of interest in SPSS to conduct multiple regression analysis on each of the main effect coordinates. The model consisted of 2 hierarchical blocks: in the first block we entered total brain tissue, age, race, verbal intelligence, BDI, and MAOA. In the second block, we entered the lifetime drug use variables.
Individuals with CUD were significantly older than the CON group (mean [SEM] age, 45 [1] vs 39 [1] years), with no genotype effects (P = .28-.67). Additional differences included race (fewer whites in the CUD group than the CON group) and higher depression symptom score in CUD (9 [2]) than CON (3 [1]), with no genotype effects (P = .53-.89) and lower verbal intelligence (CUD, 90 [2]; CON, 97 [2]) and an interaction with the CUD-H group having lower scores than the CON-H group (P =< .002). There were no differences between the groups in years of education and socioeconomic status53 (Table 1).
In terms of drug exposure factors, all participants with CUD used cocaine (smoked crack) in the past 0 to 7 days before imaging and met DSM-IV54 criteria for current cocaine dependence. The participants with CUD reported use of a mean (SEM) of 1.7 (0.8) g of cocaine per occasion with no genotype effects (P = .82). The years of lifetime cocaine use was 19 (1), with no genotype effects (P = .97). The age at CUD onset was 26 (1) years, and participants with CUD-L tended to be younger at onset (by approximately 4 years; P = .09, 2-tailed) than those with CUD-H. In addition to long-term cocaine use, the CUD sample also had a substantial lifetime use of cigarettes and alcohol. A larger proportion of individuals with CUD (30 [75%]) than CON (9 [21%]) reported cigarette smoking, with no difference in the number of cigarettes smoked per day (CUD, 8 [1]; CON, 5 [2]) and with no genotype effects (P = .32). In addition, 70% of the CUD group were also diagnosed as having alcohol abuse; their age at onset was 16 (1) years and they consumed 60 (8) ounces per occasion, with no genotype effects (P = .21).
Total GMV was reduced with greater age across all participants (r = −0.30, P = .007) with no diagnosis or genotype effects (P = .85), and there were no main effects and no interactions in total WMV (P = .21). Controlling for age and total brain tissue, individuals with CUD had GMV reductions in the left OFC (Brodmann area [BA] 11) (F1,72 = 6.5; P = .002), right DLPFC (BA 9) (F1,72 = 27.5; P = .001), temporal cortex (BA 37) (F1,72 = 5.3; P = .02), and hippocampus and parahippocampal gyrus (F1,72 = 8.6; P = .002) compared with CON (CUD < CON; Table 2, Figure 1). The F values in parentheses throughout the "Results" section represent the main effects of addiction after controlling for the potential influences of total brain tissue, age, race, verbal intelligence, and BDI symptoms.
At this SPM threshold (P < .05, false discovery rate corrected), there were no regions of increased GMV in CUD compared with CON and no main effects of genotype as assessed with MAOA*L > or < MAOA*H contrasts. However, there was a significant CUD × MAOA interaction effect exclusively in the OFC (F1,68 = 5.2; P = .003).
After examining our planned contrasts and to investigate the source of the gene × disease interaction effect in the OFC, we matched the CUD and CON participants on allele variation (Table 2). Comparing CUD-H with CON-H (Figure 2, blue) demonstrated a diagnosis effect of GMV reductions in the hippocampus; however, this contrast did not produce significant results in any of the other main effect regions, including the OFC, even at a reduced threshold. Comparing CUD-L with CON-L (Figure 2, red) showed robust GMV reductions in the OFC, DLPFC, temporal cortex, and hippocampus, similar to the main effects of addiction. Here, however, the results not only included the OFC between the anterior branches of the medial and lateral orbital sulci (BA 11) but also encompassed the medial edge of the orbital surface, ie, gyrus rectus (Table 2). The general linear model SPSS analyses using our voxels of interest in these OFC coordinates in all participants, and controlling for the covariates as listed earlier, showed that the CUD-L group had significantly less GMV than the CUD-H group and both CON groups in the left OFC (MAOA × CUD; F1,68 = 4.2; P = .007) and bilateral gyrus rectus (MAOA × CUD; left, F1,68 = 10.6, P = .002; right, F1,68 = 14.8, P = .001) (Figure 2). This interaction was unique to the OFC (all other voxels of interest in Table 2, MAOA × CUD, P = .10-.76).
To understand the contribution of drug use duration in this sample, we conducted multiple regressions in SPM5 of GMV with years of drug use, controlling for age and total brain volume. In the CUD group (n = 40), with increasing years of cocaine exposure, there were more volume reductions in the OFC (r = −0.44, P = .003), DLPFC (r = −0.41, P = .008), and hippocampus (r = −0.46, P = .003); a similar pattern of results was obtained in the CUD group with lifetime alcohol (all r −0.34 to −0.65, P = .008-.001) and with cigarette smoking (all r −0.31 to −0.52, P = .008-.001) (Table 3, SPM results). In Figure 3, the whole-brain correlation results of all 3 drugs were overlaid, showing a visible overlap of the detrimental effects of all drugs on the hippocampus.
To understand the contribution of all the variables studied and the unique effects of long-term drug use, we conducted hierarchical regression analyses in SPSS. As documented in Table 4, total GM tissue was not significantly affected by any of the variables except for the known effect of reduced total GMV with greater age. As for the OFC, the block 1 variables contributed 21% to the GMV variance (driven by the MAOA genotype, age, and race). The drug use variables accounted significantly for an additional 19% of unique variance to the OFC GMV. This effect was driven by lifetime cocaine use. In the DLPFC, lifetime alcohol and cocaine use contributed the most unique variability to GMV, adding 24% to the 17% that was explained by the block 1 variables). In the temporal cortex, race and alcohol use were most predictive of GM differences between the groups. Results for the hippocampus were the most striking, showing that lifetime alcohol use contributed 30% of unique variance. Notably, in the hippocampus and DLPFC, alcohol and cocaine use contributed more variability than the block 1 variables.
These findings demonstrate a distributed pattern of GMV loss in participants with CUD compared with CON in the OFC, DLPFC, temporal, and hippocampal regions. Exclusively in the OFC, GMV reductions were driven by increasing years of cocaine use and by individuals in the CUD-L group having smaller GMV, showing a gene × disease interaction. The pattern of GMV in other regions was not affected by the genotype; rather, GMV loss in the temporal region and especially the DLPFC and hippocampus was driven primarily by drug use, especially by alcohol use.
Participants with CUD had reduced GMV in the right dorsolateral region of the prefrontal cortex, in BA 9, a region critical for monitoring information in working memory and in the controlled retrieval of information.55 Specifically in CUD, these regions showed a deficit in functional activation during a go/no-go task, and deficits in these regions were associated with poor inhibitory control.56 With the use of measures of cortical thickness, this precise DLPFC region was found to be thinner in participants with CUD than well-matched CON participants.8 Additional GMV reductions were found in this study in the inferior posterior temporal cortex, BA 37, associated with object naming and recognition memory, and found to have reduced GMV in opiate-dependent individuals.57 This temporal region is particularly sensitive to age-dependent damage in Alzheimer disease.58 This region is located immediately adjacent to the posterior parahippocampal gyrus and the hippocampus, also found to have reduced GMV in those with CUD compared with CON in this study. The hippocampus plays a role in extinction of currently nonrelevant but previously rewarding stimuli and in retrieval of information pertinent to these learning mechanisms; as such, the hippocampus is implicated in drug-context memory and in relapse to drug-seeking behaviors.59,60 Together with the hippocampus, the regions found to have reduced GMV in CUD in the current study are associated with drug-craving61 and drug-seeking60 behaviors. Because the hippocampus, in concert with DLPFC regions, has an important executive role in inhibiting previously acquired drug reward mechanisms,62 these GMV decrements may perpetuate the impaired response inhibition and salience attribution syndrome in drug addiction.2
The neurochemistry of these affected brain regions is modulated by tonic and phasic DA action.1,63,64 In humans, the in vivo concentration of DA receptors is related to neural volume, as demonstrated by a recent imaging study showing a voxel-wise relationship between DA D2 receptor availability (positron emission tomography with fallypride labeled with fluorine 18) and GMV in the DLPFC (BA 6 and 9) and temporal and parahippocampal gyrus,65 regions that were found to have reduced GMV in CUD in the present study. Medium spiny neurons are the principal targets of DA terminals, and DA depletion in animal studies results in neurons with shorter and fewer spines compared with nonexposed neurons.66 Because long-term drug use and addiction are associated with reduced DA D2 receptor availability,67,68 neuronal volume is predicted to be similarly reduced, as evident especially in prefrontal cortical DA projections from the ventral tegmental area.69,70 Studies in humans found a reduction of N -acetylaspartate (suggested as a putative marker for neuronal cell loss or damage) concentrations in CUD and increased levels of myoinositol (a marker of glial activation) in frontal cortical regions.71
The present results demonstrate reduced volume of the OFC in the left hemisphere, whereas the rest of the main effect regions were right lateralized. These results may support the notion of a disrupted regional laterality in drug addiction,72 which is posited to be inherited8; it may start developing before disease onset and may indeed contribute to its onset and progression together with the influence of particular traits, such as impulsivity.73
In this study, the CUD-L group had significantly smaller volume than the CUD-H group and both CON groups in the OFC and gyrus rectus (BA 11). The OFC has been implicated in a wide variety of externalizing behavior disorders, and patients with specific damage to the OFC demonstrate more impulsive behavior than patients with other prefrontal damage.74,75 The anterior part of the OFC consists of eulaminate (6-layer) cortex, including granular layer IV.76 Neurons in the OFC BA 11 of the macaque monkey code novelty, with rapid habituation,77 and BA 11 is strongly linked with DLPFC areas (also found in this study to have reduced GMV in CUD), which together may guide goal-directed motivation.78 The projections from the OFC to the entorhinal cortex, which innervates the pyramidal cells of the hippocampus, may underlie the process through which information about the emotional significance of stimuli is remembered.79 Limited GMV in the OFC may undermine its functional connections with dorsolateral and entorhinal regions, thereby impairing the ability to make advantageous decisions.69,80 Supporting poor connectivity is a study finding disruption in WM fiber tracts to the OFC in CUD, which may further impair the OFC connectivity to the DLPFC and hippocampus regions.81 The regional GM loss we documented herein may correspond to WM loss, which is more reliably documented in manual segmentation or diffusion tensor imaging studies than VBM.45
The selectivity of MAOA on DA degradation is not entirely known because MAOA influences other neurotransmitters that may affect GM.82 Although there is pharmacologic evidence that serotonin levels are enhanced after MAOA inhibition, immunohistochemical and autoradiographic studies have established that MAOA is predominantly localized in catecholaminergic neurons.83 The selectivity of MAOA specifically on DA degradation may also be relevant during prenatal development, when MAOA is crucial for catabolic degradation of DA, norepinephrine, and perhaps also serotonin.84 Indeed, recent studies have shown that MAO (A and B) regulates neural progenitor cells during brain development, an effect mediated through serotonin.85 Dopamine depletion in adults, as reliably documented in CUD,3 can trigger large-scale gene expression changes through multiple regulatory subunit changes in messenger RNA expression levels.86 Although the MAOA uVNTR polymorphism analyzed in this study is not directly indicative of brain MAOA activity,87 this genetic variant was linked to the differences in levels of the DA metabolite homovanillic acid in CSF.88
It remains unknown whether the mechanisms by which decreased transcriptional activity of MAOA might increase GM in the OFC in healthy controls28 but interact with cocaine use to selectively diminish OFC in the present study. The modulating effect of the MAOA genotype on structural variability may have started during early brain development, clearly before disease onset, and possibly continued its effect at adolescence at onset of the disease process. Interestingly, the CUD-L group in this study had a slightly younger age at onset of cocaine use. It is possible that these individuals who later developed CUD had reduced GMV in the OFC before disease onset because developmental factors, such as maternal smoking, are associated with increased likelihood of drug experimentation and decreased thickness of the OFC in adolescence.89 In this context, it is noteworthy that the MAOA*L genotype was associated with risk of alcoholism and antisocial alcoholism.31 It is also noteworthy that other factors in addition to the MAOA polymorphism affect the enzyme's expression. In a recent article, our group demonstrated that the MAOA gene is subjected to epigenetic modifications.90 This finding, together with the well-established evidence that the drugs of abuse cause epigenetic aberrations,91 led us to propose that the MAOA methylation pattern in CUD might be influenced by drug use, causing dysregulation of its expression.
Gray matter in the OFC, showing deficit in CUD-L, was uniquely driven by increasing years of cocaine exposure. In fact, the OFC was the only region affected specifically by cocaine and not years of alcohol use. It is possible that the OFC of individuals with CUD-L is more sensitive to the neurotoxic effects of cocaine than that of individuals with CUD-H exposed to similar amounts of the drug. Supporting this specificity is evidence from studies in rats showing that long-term stimulants limit spine density in the OFC (while long-term opiate use may increase spine density),92,93 perhaps making the OFC sensitive to morphologic changes depending on the drug of abuse.94 Additional morphometric damage can be caused by smoking exposure because long-term smoking inhibits MAOA95 and high-affinity nicotinic receptors in the human OFC increase after smoking.96 A recent VBM study showed that GMV in DLPFC and inferior frontal regions is reduced in cigarette smokers.97 However, consistent with the current results, nicotine administration to adolescent rats elicited less severe region-dependent effects than alcohol.98
Lifetime alcohol use was the major contributor of GMV deficit in the DLPFC, temporal cortex, and hippocampus of participants with CUD, contributing unique variability to GMV above and beyond the MAOA polymorphism and any of the other factors tested, more so than cocaine and cigarette smoking. In this study, we measured severity as the number of lifetime years of use. Animal models of binge alcohol administration, controlling for severity in a dose-dependent manner, support a direct link between high levels of alcohol consumption and neurotoxic effects in the hippocampus and surrounding dentate gyrus and associated entorhinal-perirhinal cortex during adolescence.98 Similarly, reduced hippocampal volume was found among adolescents with alcohol use disorders.99,100 Gray matter loss in the hippocampus may lead to more drug seeking, as demonstrated by animal studies showing that blocking neurogenesis in the adult rat hippocampus caused increased cocaine seeking and more self-administration,101 further facilitating a vicious cycle of cocaine use.101 The observed GMV reductions in the hippocampus, perhaps due to chronic alcohol use, may increase cocaine use through strong resistance to extinction of drug-seeking behavior.101
Our groups differed in age, ethnicity, verbal intelligence, and symptoms of depression. Demographic effects of difference in the lifetime trajectory of drug addiction are a source of variability and a contributor to the overall impact of the disease.102 Lower verbal intelligence could indicate compromised education due to drug use during adolescence (note that the differences due to genotype are partly supported by another study103). The BDI measure (reflecting symptoms in the past 2 weeks) cannot be separated from drug effects (such as acute withdrawal).104 Rather than excluding these effects, we studied their impact in explaining GMV differences between the groups, enhancing the generalizability of the current results.20 On the subject of enhancing generalizability, it is important to remember that our findings come from a male sample; women are largely understudied in drug addiction, a limitation of generalizability that needs to be addressed in future studies. Our sample of individuals with CUD also underrepresented whites compared with African Americans, and the latter show GM effects in the OFC and temporal cortex. This represents a confounding factor in this study, but it also highlights the evidence of racial differences in GMV that need to be accounted for beyond the clinical variable of interest. Indeed, in this study we demonstrated through hierarchical regression analysis that the MAOA and cocaine use effects contribute unique variability to GMV beyond other effects.
Similarly, additional factors affect GM reductions, including, for example, long-term lack of sleep (affecting the OFC)105 and acute depression affecting hippocampal volume.104 Both are common problems in CUD and should be further investigated in future studies. The present study had active, currently using participants with CUD (90% had urine positive for cocaine), and a case could be made for OFC reductions during acute use that may recover with abstinence. However, even after prolonged abstinence of 2 to 4 years, GM reductions were still found in comparison of substance-dependent individuals and controls, pointing to persistent and enduring GM deficits in the OFC.46,106
In a VBM study in healthy control participants, MAOA*L has had increased lateral OFC volume (BA 47) compared with MAOA*H.28 Conversely, in this study, the CUD-L group had significantly less GMV than CUD-H and both CON groups in the medial OFC and gyrus rectus. In the same previous study, healthy individuals with MAOA*L had reduced GM encompassing the entire cingulate gyrus and particularly in the anterior cingulate, a region not evident in the current results. While inspecting CON-L vs CON-H in our data, we could find a similar pattern including the anterior cingulate, using P < .05, uncorrected (results not shown). Differences in findings may stem from the use of varied methods with varied populations of controls and individuals with CUD. Other morphology studies found deficit in regions in which we did not find reduced GMV (eg, amygdala,13 anterior cingulate,11 and insula11); conversely, none of the studies found the hippocampus GMV deficits that we found in this sample, although we studied CUD with comorbid alcohol abuse, which has been associated with hippocampal volume loss. Future studies should continue to assess genotype differences within CUD because this study suggests CUD-L to be associated with potentially more extensive deficits than CUD-H (eg, earlier age at onset is a major risk factor for a more severe course of illness).
The extensive GMV loss in the OFC, DLPFC, temporal, and hippocampal regions in individuals with CUD underlies demographic, genetic, and drug use factors. Exclusively in the OFC, GMV reductions were driven by increasing years of cocaine use and by individuals with CUD-L having smaller GMV, showing a gene × disease interaction. The population we studied had already started using drugs, which constrains the ability to track causes and effects of the substance abuse.8,21 Addiction liability can be characterized dimensionally among already affected individuals insofar as indexes of severity.32 These results suggest that loss of GMV among individuals with CUD is multidetermined and can be assessed with a model that includes genetic, behavioral, and drug use factors that we speculate have interacted continuously throughout the lifespan. Studies are emerging in support of this notion, that gene × environment interactions take different forms at different ontogenic stages of development during the lifespan.32,107 Therefore, the next generation of neurogenetic studies will have to document complex interactions over protracted developmental trajectories to explain the effects contributing to multifaceted psychopathology as drug addiction.
Correspondence: Nelly Alia-Klein, PhD, Medical Department, Brookhaven National Laboratory, Medical 490, Upton, NY 11973-5000 (firstname.lastname@example.com).
Submitted for Publication: August 20, 2010; accepted October 7, 2010.
Financial Disclosure: None reported.
Funding/Support: This research was conducted at Brookhaven National Laboratory under contract DE-AC-298CH10886 with the US Department of Energy with infrastructure support from its Office of Biological and Environmental Research, and by the National Institute on Drug Abuse (R01DA023579, R21DA02062), the National Institute on Alcohol Abuse and Alcoholism (2R01AA09481), and the National Association for Research on Schizophrenia and Depression.
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21.32.010 Water Supply and Curtailment Policy.
It is the policy of the City of Portland through the Portland Water Bureau to provide clean, healthful, and plentiful water. Circumstances beyond the City's control, however, including weather conditions, natural catastrophe or the actions of others on the City's water supply system or sources may make it necessary to apportion the City's water. When a water shortage exists or is imminent or any other emergency arises or is imminent which threatens to disrupt or diminish the municipal water supply, the City may allocate water among users. In doing so, the City shall allocate water or curtail the use of water taking into account such issues as public health and safety, community economic conditions, the financial and operational needs of the water system, and existing wholesale contractual obligations. The Administrator of the Portland Water Bureau may, consistent with this section, adopt, amend, or rescind rules, procedures, and forms to establish a water allocation or curtailment program to be implemented in times of actual or imminent water shortage or emergency. Such rules shall be promulgated under the procedures described in City Code Section 21.24.080.

subset: commoncrawl


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The Standard Blog is written to give business owners a fresh and enthusiastic perspective on faith. We are committed to dispelling the myths and incorrect perceptions many people have of Christianity to demonstrate the supernatural realm of God's Kingdom when it comes to running our businesses.
Click the link below to subscribe to our RSS Feed or simply sign up to our Newsletters and well email you when a new article is published.


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ECU International Postgraduate Research Scholarship (ECUPRS Int)
The ECUPRS Int. scheme is both prestigious and highly competitive. ECUPRS Int. scholarships are offered each year for tenure at Edith Cowan University. The scholarships provide the recipient with tuition fee and health care cover for the duration of their research degree. In addition, each successful ECUPRS Int. recipient will be offered an ECU International Stipend (ECUIS) to meet living costs for the same period.
Application opening date: 3 August 2015
Application closing date: 30 October 2015
Method of application: Download forms
Amount: $27,000 per year stipend/living allowance plus tuition fees and overseas health cover paid
Frequency: Fortnightly
Method: Electronic funds transfer
- 1-2 years for a Master by research dependent on course length
- Up to 3 years for a Doctor of Philosophy (PHD)
Step by step guide to applying
You need to follow these steps to apply for a scholarship for a Masters by Research, Professional Doctorate or Doctor of Philosophy course (Higher Degree by Research):
- Before you apply for a scholarship, you must apply for admission into a Higher Degree by Research course
- We encourage all applicants to read the Scholarship Conditions: APA, ECU-PRS and ECU Research Excellence Awards (PDF) to understand the application process, selection criteria and the requirements on them as scholarship recipients
- Complete the Scholarship Application (.DOC), including:
- Outline of your research topic
- Information on your research publications or research grants you have received: Documenting Your Research Experience (PDF)
- Academic Referees to support your scholarship application, using the PG Academic Referee Report (PDF)
Send application to:
Submit your scholarship application and documentation by the closing date for the scholarship:
By email: firstname.lastname@example.com
Applicant information:
Information for Current Honours and Master by research students
Students currently enrolled in their qualifying Honours or Master by research degree must ensure that their thesis is submitted in sufficient time * for an examination result to be available for the scholarship round.
* Examiners take approximately 4 weeks to examine an Honours thesis and approximately 6 weeks to examine a Masters by research thesis, however, examination times may vary.
It is important to ensure your application includes as much information as possible together with the supporting documentation as following the closing date,additional documents cannot be added to an application.
Referee Reports - It is highly recommended that each applicant make arrangements for the provision of two (2) academic referee reports. Academic Referee Reports may be used in the assessment process of a scholarship application. It is the applicant's responsibility to ensure that referee reports are returned to the Research Scholarships Officer by the scholarship closing date.
Documents in a language other than English It is the responsibility of the applicant to ensure that all documentation presented in a foreign language is also accompanied by an authorised English translation. This means that applicants must provide copies of the qualification or documentation in the original language and an official English translation.
Selection for a postgraduate research scholarship is based on academic merit and research capability within the University's research strengths.
Successful applicants typically have first class honours or have completed a Master degree by research with additional research output such as research publications and/or successful research grant applications and research experience.


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When you are inspired by some great purpose, some extraordinary project, all your thoughts break their bonds. Your mind transcends limitations, your consciousness expands in every direction, and you find yourself in a new, great and wonderful world. Dormant forces, faculties, and talents become alive, and you discover yourself to be a greater person by far than you ever dreamed yourself to be
~ Patanjali, Yogi and Mystic
Nothing boosts productivity more than a healthy obsession. A healthy obsession can be a liberating and clarifying catalyst to your true calling and career direction—especially for people in the mid-life zone. With maturity comes renewed confidence and determination to pursue, and write about, the things they are truly passionate about.
Passion, some say, can be difficult to find, but if you're awake it will find you. Stay open-hearted and open-minded. Don't be like so many adults who fail to discover it all together, and in the absence of any encouragement, give up.
"People pride themselves upon their willpower, their indomitable courage, upon the fact that nothing frightens them," writes T. Lobsang Rampa, in his classic book You Forever. "They assured bored listeners that with their willpower they can do anything at all." But the truth is there is no greater power than imagination, passion, and the incredible power of love.
"The Last Supper soon became my obsession," writes Spanish author Javier Sierra in his book The Secret Supper, a dazzling historical thriller.
His novels all have a 'secret' common purpose: to solve historical musketries based on real documentation and extensive field research. Javier's passion and his obsession have made him a bestseller author throughout the world.
Similarly, Joe Medeiros, a writer, and producer, known for The Tonight Show with Jay Leno, developed an obsession for Leonardo da Vinci's iconic portrait of the Mona Lisa after reading about its theft from the Louvre.
Medeiros' obsession had a singular focus—discovering the truth. He first learned that the Mona Lisa was stolen when he was 25 and spent the next 30 years trying to discover the thief's motivation—a simple Italian immigrant named Vincenzo Peruggia who worked as a house painter in Paris.
When asked why he was so fascinated by the story, and why he devoted over 35-years to his quest Medeiros said, "The fact that that I couldn't solve the mystery. I wasn't able to write it as a [fictional] screenplay] but once we started to make the documentary, everything started to fall into place. And I always wanted to know, was he crazy? Did he do it for patriotism, did he do it for money, did someone commission him? I had all these questions and that's what kept me at it until I found the answers."
Because of my own obsession with The Mona Lisa, and also with discovering the truth, I came across Medeiros' wonderful documentary and have since reached out to him to help me with my research for my novel of historical art-related fiction set in Renaissance and modern-day Florence. (formerly known with the working title of Mona Lisa's Secret).
Learn more about Joe Medeiros's 35-year obsession here—http://www.monalisamissing.com/single-post/2015/07/19/The-Story-of-the-Film-A-35YearLong-Obsession.
Even better, visit his website and follow the links to view his fascinating documentary >>http://www.monalisamissing.com/
Passionate Obsessions Empower Your Productivity and Prosperity
A healthy obsession can lead you to many things, including:
• A state of divine flow—enabling you to write with mind-blowing productivity
• Your point of excellence—unleashing dormant talents and natural gifts
• Rocket-fuel tenacity to persevere and succeed
• Mentors, helpful allies and similarly obsessed people who will cheerlead and elevate your success
• A legion of devoted fans who are drawn to your impassioned writing
• Your passion and life purpose—spreading seeds of joy and inspiration and benefiting others
• Your life niche—creating a breath of fresh air and giving you a competitive edge
• True bliss—leading you to your vocation where being paid is the icing on the cake
New Zealand motorcycling legend Burt Munro proved that passionate obsession is the key to success. "All my life I've wanted to do something big," he said. In 1967 Burt achieved something huge.
At the age of 68, against all the odds, he set a world record of 183.586 mph with his highly modified Indian Scout motorcycle. To qualify he made a one-way run of 190.07 mph, the fastest ever officially recorded speed on an Indian.
Like so many inspiring people the road to success was not an easy one—it involved much personal hardship and numerous setbacks, but armed with his passion and a compelling desire to "go out with a bang," Burt Munro mortgaged his house and set out on the greatest adventure of his life.
His truly awesome achievements were brought to life in an inspiring and uplifting film, The World's Fastest Indian.
The World's Fastest Indian not only gives movie-goers an inside look at Munro's passion, but it also gives them an idea of New Zealand filmmaker Roger Donaldson's overwhelming desire to tell the story.
"This project has been a passion of mine since I completed a documentary about Burt Munro back in 1972," Donaldson said. "I have been intrigued by Burt's story for many, many years; some would say my obsession with this film matches Burt's obsession with his bike."
Donaldson's passion for his subject has won him international acclaim from Academy Award-winning actor Anthony Hopkins. "I thought it was a terrific movie. It is a unique script…it is just so well written, very well written, beautifully written, and so refreshing. I've worked with a lot of great directors, Steven Spielberg and Oliver Stone, and Roger Donaldson is there with that lot, you know. He really is," Hopkins said.
What Do You Collect?
Passionate obsessions, as you have begun to discover, go in all directions, and many times they are revealed in your collections. These could be as tangible as exotic butterflies, books, spoons, antiques, paintings, or as intangible as a dream or an idea.
I collect positivity and articles and stories related to people's extraordinary passions. My collections have inspired many of my self-empowerment books.
As I mentioned, I also have a passionate obsession with all things related to Leonardo da Vinci, but particularly his portrait of The Mona Lisa, and I have a burning desire to reveal the truth being the mysterious life of the woman in the painting, Lisa del Giocondo. I am sure I own every single book every written about both Lisa and Leonardo. My partner once laughed, "There are three of us in this relationship—you, me and The Mona Lisa."
It's true, I am obsessed and enthralled with my research for my historical novel Mona Lisa's Secret and with telling her story. Follow my obsession and sign up to my newsletter and be the first to know when this story will be published—http://eepurl.com/bEArfT. Sign up now and receive a welcome gift—your free 'Find your Passion' E-book.
Mining for Gold
Become audaciously obsessed. Real obsession is more than a fad or a fleeting enthusiasm. It can't be turned on and off like a tap. Answering the following questions will help you begin to clarify the things you have a burning obsession for:
What do you value? What do you need to experience, feel, or be doing to feel deeply fulfilled?
What do you collect? List all your obsessions and the things that interest you deeply. How can your passions fuel obsessive productivity?
Dive Deeper. . .
If you're struggling to identify your obsessions, you'll find some handy prompts and true stories in my book Find Your Passion and Purpose: Four Easy Steps to Discover A Job You Want And Live the Life You Love. You'll also find inspiration, including true transformational change stories by people like you in my Mid-Life Career Rescue series.
This is an edited extract from The Prosperous Author: How to Make a Living With Your Writing (Book Two: Productivity Hacks: Do Less & Make More) by Cassandra Gaisford. ORDER THE EBOOK TODAY, SAVE and SEND YOUR ORDER CONFIRMATION AND RECEIVE YOUR FREE BONUS GIFTS—Click the Amazon link here getBook.at/ProductivityHacksDoLessMakeMore
Do less and earn more today!
Although this book was written for writers, the principles and strategies can be embraced by business entrepreneurs, solopreneurs, actors, dancers, painters, photographers, filmmakers, and thousands of others around the world who want to enhance their productivity, do less and make more.


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It's always somewhat hilarious when school administrators get involved in wacky college traditions. At UCLA they're regulating the hell out of the Undie Run, the quarterly event to commemorate the Wednesday of Finals Week. Hey, that's tonight! Noticing that students seemed to be imbibing alcohol and generally behaving badly during the late-night scamper, the university has re-routed the event, and has warned participants to behave.
What? Behave at the Undie Run? Then what's the point of going to college? UCLA students have chafed at the interference; occasionally staging an Undie Ride, with presumably more rebel undie events in store. But that diodn't stop school administrators from changing tonight's route.
Students will run east on Strathmore Drive and turn north on Westwood Plaza, headed toward Bruin Plaza. However, instead of then charging up Bruin Walk toward Powell Library, students will be directed west to the Intramural Field. "We chose the IM field because it's a large, contained, well-lit space," said Birks, who along with Roth held several meetings with Director of Police Community Services Nancy Greenstein and Robert Naples, associate vice chancellor and dean of students.
"Oh no, we can't go with you Bluto, it's too dangerous! Well you can just kiss my ass from now on! Birks? Dead! Roth? dead! Niedermeyer? ...
Fun Undie Run photo gallery here, courtesy of LAist.


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What is the future; future events! Im now thinking about future events now! What are they!
I think about what Im going to dream about a few hours before I go to sleep!
What future events do I want! The Universe nows what I want and where it is! So, Im asking God and the Universe what I want and where they are!
What do I want! And I see a trail opening up! And through that trail it gets longer and steeper!, and at some point it gets better! And rockier and I end up in the vehicle of my choice; I put my mountain bike in the back and head up the hills to my house? I guess thats what I see!
Other stuff; the 12 step groups Im in; as I get better, they're getting rougher! Some of them are rough groups of people! I need to remember this; so, I play low key rolls to keep going! As soon as I start showing my real self; meaning, Ill get better; some of them see it as counseling! Meaning, Im using the place as concealing, and they get mad that Im not staying on subject of how to get off alcohol! I guess thats understandable! What I have to learn! Before I enter the room! I must remember; this is not kindergarden and no one is taking care of me in these places accept God! I must remember this!
The locals; Ive known people I grew up with in certain neighborhoods! IVe seen those people, and remembered them! They are now jerks to me! To the point that they Im nothing but a village idiot clown! Ive never seen anything like this before! Being treated like this! To be treated with this type of lack of respect! Im not sure what happened! However, I think I might now!
When young, I had to move in with my Grandmother! At her house, in her neighborhood was a new set of kids! And I became friends with them! But they were not good kids from a good neighborhood! But it was all I had! And some were good kids, but I meant nothing to them; no value!
Some of them I spent time with and we were friends! But not !;! Now when I saw one of them at the coffee shop! He treated me like I was an imbecile! Im not sure I understand! It hurt me deeply and shocked me! However, Ive been used by people before! So, what can I learn from this! One area Im looking at! Is it possible, that he was never safe to associate with in the first place! Considering the neighborhood! He might have been an idiot and I never knew it! Meaning, he was another scum back and I never knew it! He was not a nice kid like I thought he was! This is very possible! Im not friends with any of those people from that neighborhood! Not anymore!
It's sickening to walk up to someone and they spit in your face with contempt when you 10,000 miles might better then they will ever hope to be! Something went wrong, something is wrong! Many possibilities! However, in this area, this was not the first of this! In the original area I came from, I was blacked balled by the friends I thought I had! No one would talk to me, as if they had never met me! IT didn't work! Im getting the recovery I need! But I never would have thought any of this would happen!
ITs like the 12 step meetings I go to! Some meetings are not safe to start with! I must remember this! Im walking into a group of people that are not social safe and never ever were! Most people would not go into some of these meetings and share anything personal! I do, and it freaks out some people!; not all! I didn't care before, but it pisses of the social lites in the meetings; those that are building social status and trying to take over the meetings! Im getting caught up in this way to much! Their just meetings! I get used to being in these places and calling them home; they are not home!
I remember some friends when younger and calling them friends from home! They are not friends of mine now ! I mean nothing to them! Im looked at as a weird scumbag?! Its all for the better! The fact is; Im a real person, and they are not! I must stay away from them! They are not nice people!
How can this be?! But God is letting me know! They are of the world and not of God! They have no souls! Nothing associated with God! Arrogant; thats what they are!
Ive been dealing with arrogant creeps lately, and I must remember where Ive met them! Thats whats important! Its all very hard! I have to trust God and keep to the plan! And stay away from the other trouble makers!
Stay away from the women in these meetings! These 12 step meetings! IVe had about a zillion women like me from these meetings! Trouble! Find women outside of these places!
Ive been in someone meetings where the women are spoiled arrogant smart asses idiots! I want no part of it!
The problem with women; Im only seeing in my head, a specific kind of women; as if what Im looking for does not exist! Im not sure where ' my women" are! Im not sure! What group?!
Its possible that Im not looking in the right places, because I cant define those places! I see things as money! Middle class, upper middle class, lower street class! Who knows!
I don't see middle class people being interested in me because of lack of career and money! However, the women could find me interesting! But there is no money!
I think; Im not thinking! Im categorizing! In general; the idea is to attract the right women! So, what am I looking for in women! Thats what Im looking for!
This will be a new venture for me! IVe not been able to get close to women; physically close! But that is changing because Im getting closer to people naturally! My dissociative condition is lessening!
Im afraid in this town I grew up in; nothing! My name is dirt with a whole lot of people! And its all arrogant ignorance! None of it is true! Not even the best friends I grew up with are my friends anymore; I did nothing to them! Of course, they got rid of me years ago! But Im an honorable person! They are not! And that is part of the problem! The other problem is the sociopaths and psychopaths I had in this false family system! They ruined my name with many people! They do such things! Thats the way they operate! I had no idea this would happen! I would have never thought any of this would happen when a child! Nothing like this! Its all horrible!
I will get better and rely on God; where he wants me! Its ridiculous!
Other things;
The original family system! Its harder and harder to use this term; " family system"! This was not a family!
3 people were deeply against me when I was born! Hatred; deep sadistic demonic contempt and hatred! No remorse! No compassion! Just hatred! A pure form of hate! The other was my father! He protected me against the other three! However, he did not do this at a personal level; it just happened that way! My mother was not allowed to attack me when him in charge! But she would have done much worse then this if he wasn't involved! But I did not know this!
Im around these people! And do not have a clue, who or what Im around! Now as I see it with more clarity! I was not loved by anyone in this group! I was hated to the point of death or murder! A strange jealous hate! I don't know! Pathological hatred! I technically had brothers! They were not my friends! They hated me from the beginning or felt nothing and couldn't care less! Later it will be deep deep hatred!
My father is using the whole family system concept! He is exploiting the situation until he moves on to something else! He has no remorse or compassion! Nothing! And could careless about my survival! He's the type that will show up to an event your in and take credit for being the father; after he was completely absent from the seen and never helped or got involved! No conscious! Nothing!
I was protected! But my father could careless, it was not personal protection; it was a by product of the weird situation between these 2 sycophants! I was hated then on all sides! As soon as my father was not on the seen; it was over for me!
I never understood! Now I do! And this whole time I tried to flourish outside the home! I did not know anything was wrong! When I went home as a little boy! I thought I lived in a loving caring home with relatives and 2 brothers that I loved! Not so! Anything could have been further from the truth!
So, the whole idea is emancipation! And the beauty of forgiveness; and this is where it shines! You forgive all people and everything and everyone involved until you forget you ever met them! Its like backing out of a bad situation because your character was to good for it! Instead of being corrupted! You simply forgive everyone and go back to being a nice person again! You don't remember anything because you forgave everyone and everything over n over n over until they dislodged from you and your memories! If they don't owe you anything, why would you remember them! How can they owe you something if you forgave them the dept.!
Why would you forgive everyone! Because you don't want to see them again! You want to get the hill out of their in one piece! Count your losses and run and never come back! It and they are pure evil! And you don't want to remember! You forgive everything and go your own way! And thus is what Im doing! They can have their money and way of life! I get to keep my soul! This is extremely important because none of the other did!
Out of a whole community of people against me! None had their soul; it was always owned by Satan! Not mine! Lots of temptations! I never took it! I will give up the free money because, nothing is free! See!
Soon, I will be rid of them from my mind and nervous system!
Heres the point! They continue to have a hold on you through insanity! It is your insanity that continues to hold drudges against them and not forgive them and move on your way!
My way is the Universe and God helping me down my trail! I cant do this if my mind if filled with resentments from evil people! God has a plan for my future! It's not revenge! Its something much better!
Im trying to make a point! Through forgiveness; I win! I win against all of them! Its like surrendering to win! They won nothing if they cant harness my soul! But I get to leave and go away and never return! They are left with themselves! It is my soul they wanted all along! But they wont get it! I wont turn into one of them! I never have and never will! They can steal all they want from me! I stay with God and finally leave!
Why am I hanging on to them in the first place!
1. Denial; Im codependent! I was abandon young and need a parent!
2. Revenge and hate and contempt!
3. Money! Or land or things or what ever the temptation, also the temptation for family!
If I forgive all things, I wont need any of the above from any of them! I will get my needs met else where!


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Nicole Kidman says she has nothing but "respect" for her kids' Scientology beliefs, Selena Gomez holds hands with an old costar, and Jeremy Renner is going to be a proud papa: See Us Weekly's top 5 stories from Wednesday, Jan. 16 in the roundup!
1. Nicole Kidman on Connor and Isabella's Scientology: "I Respect Their Beliefs"
Nicole Kidman has no problem talking about peeing on Zac Efron in The Paperboy or filming rough sex scenes with John Cusack, but when it comes to matters of off-screen controversy, the Oscar-winning actress clams up. In a recent interview with The Hollywood Reporter, Kidman is asked about that most taboo of topics — her ex-husband Tom Cruise and the religion that's become synonymous with his name: Scientology.
2. Exclusive: Selena Gomez Holds Hands With Luke Bracey at Golden Globes Party After Justin Bieber Split
Jelena is so 2012. Former "It" couple Justin Bieber and Selena Gomez have gone their separate ways — "for good" this time, sources told Us Weekly — but 20-year-old Gomez isn't wallowing in self-pity. Insiders tell Us the newly single Spring Breakers actress was getting "super close" and holding hands with Australian actor Luke Bracey, who appeared with her in the 2011 movie Monte Carlo.
3. LeAnn Rimes: I Sometimes Worry Eddie Cibrian Will Cheat on Me
LeAnn Rimes, 30, shared her martial fears in an interview with Entertainment Tonight's Nancy O'Dell, who asked the country singer if she's ever worried Eddie Cibrian, 39, will cheat on her. "Everyone else would think I am a liar if I didn't say yes, and I have at times," Rimes admitted. "It's definitely creeped into my mind, as it would anyone's." The Playboy Club actor shares the same concerns about his wife, Rimes added.
4. Exclusive: Jeremy Renner Is Going to Be a Dad, Ex-Girlfriend Is Pregnant!
Jeremy Renner shared some big news with Eva Longoria on the smoking patio at the Golden Globes Jan. 13: He's going to be a father! The Bourne Legacy actor, 42, "was saying, 'I'm going to fly in when her water breaks,'" two witnesses tell Us Weekly exclusively. "Then Eva said, 'I'm so blown away.'" Shocking, but true.
5. Jenelle Evans Pregnant With Second Child
Jenelle Evans is pregnant again. The Teen Mom 2 star, 21, who is already a mom to son Jace, 3, is expecting her first child with new husband Courtland Rogers, a source confirms to Us Weekly. "I can't comment on anything — though I wish I could," Rogers tweeted Wednesday, Jan. 16.
For access to all our exclusive celebrity videos and interviews – Subscribe on YouTube!


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Why should you carry a second device just to control your computer?
Why should you need line-of-sight to do so?
You love the remote control which came with your Mac - so simple yet elegant, with easy control of Front Row, iTunes, Quicktime, DVD Player, Keynote, and more. You carry your iPhone, iPod Touch, or iPad wherever you go...
Enter Rowmote!
On one side, Rowmote is just like your Mac's remote control but over the wireless network. On the flip side, by tapping the Apps button, you get bonus abilities, switching between most controlled programs and toggling the iTunes Visualizer. Rowmote controls Front Row, Airfoil Video, Adobe Lightroom, Amarra, Aperture, Audirvana, BBC iPlayer, Beamer, Boxee, Decibel, DVD Player. Ecoute, eyeTV, Firefox, Hulu Desktop, iPhoto, iStopMotion, iTunes, Keynote '08 and '09, kJams Pro, Kodi, Last.fm, Logic Pro, Movist, mPlayer, OpenOffice Impress, PandoraBoy, PandoraJam, PandoraOne Desktop, Plex (Home Theatre, Media Center, and OpenPHT), Popcorn Time, Powerpoint 2004 and later, Preview, Prezi, Rdio, Quicktime, Safari, Skim, Songbird, Spotify, Squire, Tidal, The Tube, VLC, and XBMC. Rowmote can even sleep and wake your computer!
Rowmote Pro adds a wireless multitouch touchpad and keyboard - complete with landscape mode, two finger scrolling and right clicking, dragging, three and four finger gestures, accented / extended character support, and more - to the clean and powerful remote control of Rowmote! Rowmote Pro replaces the need for a separate mouse & keyboard to fully control your Mac.
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From Urusei Yatsura
Love has got me crazy
Oooh, yeah
*Love has got me crazy
So in love I can't see
Your love is no good for me
Love has got me dizzy
So in love I can't see
That I don't have time
I don't have time for this*
I know the sign
I'm on your mind
I know what you're looking for
But step by step
Deep in your heart
That my heart won't remember
You are dangerous
You know the sign
You've lost your mind
(When) you don't care what people will say
And step by step
Caught in your web
I'm trying to remember
That you are dangerous
I know the sign
I'm on your mind
I know what you're looking for
But step by step
(So) deep in your net
That my heart won't remember
That you are dangerous
Typed from the lyrics booklet for Dancemania DELUX 2
Contributed by James Edge (LockeVanish) <[email protected]>
[Submit an English translation for this song]
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My Little Pony Ties
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■ Joe Krentz, 81: President of the B.C. chapter of the charity Canadian Food for Children, which sends food to starving children in developing and disaster-struck countries. A former dairy farmer, he became involved with the volunteer organization at age 68, via wife and fellow CFFC volunteer Loretta, now 82.
What is the secret to your vitality?: I have been very active my whole life. My view on retirement is that a person needs to keep active to remain healthy. Good food, a positive attitude, helping others and my faith in God provide me with ample energy for day-to-day tasks. Being involved with CFFC is the destination that God has presented me with, and fulfilling this role as best I can is my duty as a child of God.
Anything that surprised you about growing older?: Loretta and I didn't make specific plans for our retirement and we just take life one day at a time. As far as being surprised about growing older, I'm surprised that I've made it this long!
What role do you envision seniors could and should play in our society?: The role seniors should play in our communities is one of service. If a person is healthy and financially able, they should participate in volunteer work to help and assist the less fortunate in our world.
■ Balwant Sanghera, 71: Longtime community advocate for multiculturalism and intercultural harmony and against youth violence; sits on the Punjabi Language Education Association, East Richmond Community Association and the South Asian Community Coalition Against Youth Violence.
What is the secret to your vitality?: I believe that staying active physically, mentally and socially takes on an added significance as we age. I am a strong believer in positive thinking. With proper attitude and the right frame of mind, a person can overcome any challenge. Also, serving one's fellow human beings is one of the greatest sources of happiness, energy and fulfilment. Positive reinforcement, even by strangers, is a great motivator and energizer for me.
What role do you envision seniors playing in our society and communities?: Seniors can play a very important role by guiding the youth, supporting them along the way and mentoring them. I find working with young people to be very rewarding. Making a connection with the youth goes a long way in gaining their trust.
Is age just a number?: For me, aging has been a gradual transition. If one feels young at heart, the years don't have much relevance. Eventually, everyone has to go through the aging process. This is a reality. So why not accept it and enjoy every moment of your life, no matter how old or young you are?
■ Lillian Zimmerman, "Over 80": Research associate, Simon Fraser University Gerontology Centre; co-founder of the women's studies program at Douglas College; author and researcher who specializes in issues facing older Canadian women.
What keeps you going?:
When I get right down to it, it is a deep sense of injustice. I don't like to see people mistreated, or policies which are not adequate to their needs. So many women of my generation did exactly what they were required to — they got married, raised a family — but surprisingly a lot of older women live in poverty.
You dislike the term "senior." Why?: It's simply outdated. When you use the word "senior," the picture you get is of someone on the margins of society. There is a whole new world of how older people are living their lives.
What surprised you about getting older?: First, that I'm having a good time. When I was a kid, old meant decrepit and everything awful. That's why I'm so upset at the stereotypes of older people who don't know which way is up or down. My 80s is one of the best decades of life.
What advice do you have for boomers?: Keep up with changes. Don't put yourself on the margins because you don't know what younger people are talking about.
■ Joe Segal, 86: President, Kingswood Capital; entrepreneur and philanthropist; former chancellor, Simon Fraser University.
Did anything surprise you about growing older?: Not really, no. It's a gift from God, growing older. People think that just because you are older you have to quit. When God says quit, you quit. He gives you the runway, you stay on the runway. I look at people who are 65 today and I say to myself, they're kids. If I was 65 today, I'd pick the world up and twist it a couple of times and put it down where I want it to be.
What is a senior?: I don't think that word should describe anybody over 65. Some of the greatest minds in the world were 70, 75 in their heyday. They had the drive, they had the desire, they had the experience, and they used it. Why waste an asset?
What is the secret to your vitality?: I think the mind controls the body to a large degree. If you are a positive thinker, then you are going to be excited. And you are going to look forward to new things every day.
You mentor young people. What is your advice to them?: There are many young people that say, "I don't know where I go next, or what to do next," or "I started a business and lost all my money. I'm bankrupt." Maybe they're 30 years old. They've tried and failed. So what do they do next? They have no assets. But they have a major asset — the fact they are 30 and not 86. I tell them very simply: I'll trade you places. I'll give you everything I have, every dollar I have, and you make me 30 on welfare. I'd rather be 30 and start over again than 86 and coming to the end of the runway. So they leave saying, "I have a runway." They don't give up. That's importa
■ Dal Richards, 93: Legendary Vancouver musician; still performs about 125 shows a year; has appeared at the PNE for 72 consecutive years; hosts a Sunday night radio show on AM 650.
What happened to retirement?: I've thought about it fleetingly from time to time, but I was having too much fun to seriously consider it.
What's the secret to your vitality?:
I am blessed with good health. That's the secret — plus the joy of performing and entertaining people. I get a lot of energy and love from the people I perform for.
What role do you envision seniors could and should play in our society?: I believe seniors can play an important role as mentors for young people. I am proud of having "discovered" some very talented young musicians who have played and sung with my band and become very successful. I am lucky to be able to share the excitement they feel as their careers develop.
In terms of performing, what do you know now that you didn't when you were in the bloom of youth, starting out?: I've learned how important audiences are. You must reach out to them, earn their respect by not only entertaining them, but by relating to them. If I should fall off my perch tomorrow, I can think of no better way to have spent my life.


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Countless images and videos have shown the frightening destruction caused by tornadoes that ripped through several Illinois towns on Sunday.
Perhaps none of them shows how instantaneously a home can be dismantled in a powerful tornado, but a video posted to YouTube this week comes close.
Surveillance video at a gas station-Dairy Queen combo in Diamond, Ill., shows cars being spun around in the street as the twister enters the area. Between the 29 second and 31 second mark in the video, a two-story home is wiped off its foundation and completely destroyed.
The video's description notes that the house was a model home and no one was inside at the time.
The phone at the gas station has since been disconnected, and employees there couldn't be reached.
Diamond was one of the towns most heavily hit by Sunday's storms. In all 22 tornadoes touched down in Illinois. Damaging and powerful storms also hit other parts of the midwest, including northwest Indiana.
In Washington, Ill., an EF-4 tornado with winds that forecasters said reached 190 mph affected more than 1,000 houses. A man was killed in the storm there and 122 people were injured.


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