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Official websites use. Share sensitive information only on official, secure websites. An enduring question from cross-sectional clinical studies is whether the structural and functional differences often observed between cocaine users and healthy controls result from a history of drug use, or instead, reflect preexisting differences. What is needed to assess causality from drug exposure are true pre-drug baseline imaging and neurocognitive assessments. In the present study, we address this fundamental question of causality using longitudinal anatomical MR imaging and neurocognitive assessments in rhesus macaques. An MR only timepoint was also obtained following 2 years forced abstinence. We identified localized patterns of gray matter density GMD changes that were largely concordant with cross-sectional clinical studies. These included decreases in orbitofrontal cortex, insula, amygdala, and temporal cortex. There was also a prominent increase in GMD in the caudate putamen. In only select cortical regions were GMD decreases significantly correlated with cognitive impairments across individuals. Following abstinence, changes in GMD in some regions, including the orbitofrontal cortex, insula, and amygdala were persistent, and thus may play an important role in risk of relapse following extended abstinence. Cocaine use is causal in producing regional changes in GMD, and those changes appear to drive cognitive impairments. Keywords: cocaine, cognition, structural imaging, macaque, impairment, addiction. Structural brain alterations and cognitive deficits have been associated with stimulant use disorders 1 — 5. The structural changes in these areas have been hypothesized to underlie the differences in cognitive assessments that are frequently observed between stimulant dependent and healthy control individuals 6. An additional confound for determining causality is that of variable poly-drug abuse in clinical populations. Several studies have observed that the magnitude of structural differences correlated with duration of abuse, suggesting the magnitude of stimulant exposure drove the gray matter alterations. Specifically, decreased gray matter was related to duration of use in orbitofrontal, insular, parahippocampal and anterior cingulate cortices as well as the cerebellum 1 , 7 — Supporting the hypothesis that differences in structure could drive cognitive deficits are observations of significant correlations between gray matter density GMD and measures of cognitive performance among stimulant using populations 11 — Critical elements missing in these clinical studies are true baseline measures of GMD and cognitive performance prior to drug exposure. Upon extended abstinence, the extent of structural and functional recovery, or lack thereof, is also a fundamentally important question because it directly relates to what might be contributing to the enduring risk of relapse. It appears that some changes in gray matter exhibit at least a partial recovery with abstinence 10 , 11 , While recovery is obviously a good thing, it also complicates many cross-sectional comparisons between stimulant-dependent individuals with differing abstinence durations and control subjects. Herein, we address each of these critically important questions: 1 Does chronic cocaine intake produce GMD structural changes and if so, in which brain regions? We do so using neurocognitive performance-matched groups of rhesus monkeys coupled with longitudinal imaging acquisition at baseline prior to any drug exposure, following 12 months of drug or water self-administration, and finally after 24 months of imposed drug abstinence. Using the resulting structural gray matter interaction across time, we next determined if GMD changes from baseline were linked to the magnitude of any cognitive impairment observed in the same subjects The rationale for choosing those three cognitive domains in our earlier study was that cross-sectional clinical studies have observed significant differences in reversal learning, but not in stimulus discrimination The literature on working memory is mixed, as discussed previously We did not determine any relationship between structural changes and stimulus discrimination because cocaine exposure had no effect on it Scans acquired following the prolonged abstinence in a subset of the original cohort were contrasted with those obtained at the end of self-administration to determine GMD changes following abstinence. We also contrasted the post-abstinence scan with pre-exposure baseline scans to determine what differences between groups remained following self-administration and extended abstinence. This within subject design offers greater sensitivity to detect small but systematic changes within a relatively small number of subjects. Importantly, non-human primate NHP models of chronic drug exposure can offer critical insight to clinical observations due to similarities in brain structure, circuitry, and neuroanatomical assignment of function Moreover, compared to rodent studies, NHP models correspond more closely to the human condition in acute neurometabolic response 18 , and progressive neurochemical and neurometabolic adaptations upon drug challenge after a prolonged duration of exposure 19 — Finally, cognitive performance of NHPs can be assessed using tasks very similar to those used in human studies 15 , 16 , A cohort of 14 drug-naive, adult male rhesus macaques years old was trained to perform several cognitive tasks on a touch screen monitor for water reward 15 , Subjects received sufficient monkey chow Labdiet , PMI Richmond, IN to maintain a healthy body weight supplemented with daily fruit treats. A vascular access port was implanted midscapulae in all subjects prior to baseline cognitive assessments Subsequently, animals were divided into performance-matched groups and the experimental group of 8 subjects proceeded to self-administer cocaine intravenously via their vascular access port. Subjects typically would self-administer the maximum daily allotment of 6 infusions 0. All subjects performed cognitive testing reinforced by water reward on Mondays cocaine subjects were in a drug-free state, approximately 72 hrs after the last cocaine session Fig 1. A more detailed description of the self-administration and cognitive testing procedures has been reported previously Experimental timeline. Cocaine animals self-administered intravenously up to 3. A custom imaging processing pipeline was developed in order to maximize sensitivity for longitudinal comparisons The concatenated alignment parameters from these 2 linear steps were used to build an updated symmetrical GMD template. A GMD group X time interaction was analyzed with a general linear model using total intracranial volume as a covariate. Note that we focus on the group X time interaction analysis which reflects changes in structure with the passage of time that are not common to both groups. Ten iterations of permutations each were averaged. All maps are presented according to radiologic convention. The change in DMS performance was quantified as the difference in slope of the accuracy versus delay plot in DMS sessions before baseline and after cocaine self-administration as described previously Primary structural analyses determined the effect of cocaine self-administration on GMD by contrasting the post-self-administration scan with the baseline scan in a group X time longitudinal design. We then determined correlations between these GMD changes and cooccurring changes in cognitive performance. All structural changes combined were held to False Discovery Rate of 0. To determine persistent or compensatory structural changes following 2 years of abstinence, the scan at that timepoint was contrasted with the post-self-administration scan in 11 remaining subjects 6 cocaine, 5 controls using the same PALM with TFCE procedure as described above. At abstinence, only a subset of the original subjects was available due to an unexpected illness or loss of motivation Lastly, to determine if there were persisting differences between groups following self-administration and extended abstinence, a comparison between the abstinence and baseline scan time points was conducted. The first question posed in the Introduction was whether chronic cocaine intake produces GMD changes and if so, in which brain regions? From that contrast, sixteen regions greater than voxels voxel size 0. This threshold was arbitrarily chosen in order to avoid spurious correlations with regions too small to likely be functionally relevant. Effect of chronic cocaine on GMD. Regions in which the cocaine subjects showed relatively greater increases in GMD are colored in red. Numbers above sections represent distance in mm from the crossing of the anterior commissure. Brain regions with a greater relative decline in GMD in cocaine vs. In contrast, brain regions with relative increases in GMD in the cocaine vs. Supplementary Fig S1 is a compendium plot of the individual subject GMD values at baseline and post self-administration for each regional cluster. Although animals were assigned to each group to achieve matched mean task performance, comparison between the two groups at baseline indicated that 2 regions showed GMD differences that survived a Bonferroni-corrected t -test. One was in the left insula Fig. The second question we posed was whether any of the alterations in GMD shown in Fig 2 have functional consequences. We identified 3 regions with significant correlations. That large region encompasses multiple areas with distinct functionality that were connected by single voxels. Two of those six resulting subregions showed significant correlations that appear to drive the relationship shown by the larger cluster. Impact of structural changes on RevL performance. Within the cocaine subjects blue symbols , the impairment in RevL performance greater number of trials to criterion correlated with the magnitude of GMD decline in regions of the orbitofrontal cortex OFC; voxels. The lateral parietal area LIP; voxels also showed a significant correlation. Control subjects red are shown for comparison. Orthogonal views coronal, parasagittal, and axial indicate the location of the region of decreased GMD. For all regressions, only cocaine subjects were used. Impact of structural changes on DMS performance. Within the cocaine subjects blue circles , the impairment in DMS performance steeper decline in accuracy with delay correlated with the magnitude of GMD decline in a large region spanning the insula and the temporal lobe voxels. Within the larger contiguous region shown in A, a subregion within temporal cortex area TE voxels, lower panel was also highly correlated. To address the third question, namely, does extended abstinence reveal either further, or persistent changes, another structural scan Abstinence scan 3 was acquired in 6 subjects in the cocaine group and 5 subjects in the control group after two years of abstinence. A group X time interaction of Abstinence scan 3 contrasted with Self-administration scan 2 is shown in Fig 5. Between groups differences over the time following abstinence were: a decreases in GMD in frontal pole regions and b increases in GMD most prominently in the caudate putamen. Without it being conclusive, we note an absence of statistically significant change in some areas where there were significant decreases in GMD following self-administration Fig 2 , such as the amygdala and insula. Effect of abstinence on GMD. Regions in which the cocaine subjects showed a relative increase in GMD compared to control subjects are colored in red. Given that a lack of effect of abstinence in areas such as the amygdala and insula could be due to a lack of power, we asked a follow-on question: are there areas of significantly different GMD that remain following self-administration and extended abstinence? To answer this question, a group X time interaction contrasted the Abstinence scan 3 with the Baseline scan 1. There is also decreased GMD in the insula, amygdala, and left OFC in the cocaine group, relative to the controls, consistent with a lack of significant change in those regions in Fig. GMD differences remaining after chronic cocaine and abstinence. This demonstrates the changes that persisted after one year of chronic self-administration followed by a 2-year period of abstinence from cocaine. In this report, using performance matched groups of non-human primates, we show not only that one year of regular, yet relatively moderate cocaine exposure causes GMD structural differences similar to those observed clinically in human cocaine dependent individuals, but that in a few specific cortical regions, the magnitude of these structural differences correlates with accompanying cognitive deficits. Importantly, our results suggest a causal link between cocaine-induced structural changes and impaired cognition in the two cognitive domains examined. We also observed that despite long-term abstinence, some of the structural changes induced by cocaine remained, and therefore, may be implicated in long-term risk of relapse. Hence the need to address the question of causation by cocaine posed in the Introduction. Similar to findings from cross-sectional studies in human stimulant users 1 , 2 , 4 , 5 , 8 , 9 , 33 , 34 , we observed declines in GMD in the cocaine group relative to controls in the orbitofrontal, insular, and temporal cortices, as well as in the amygdala and thalamus. We also found several regions where the cocaine group showed increases in GMD relative to the control group following cocaine self-administration. In particular, the increase in caudate putamen GMD is reminiscent of the areas of increased gray matter observed in some cross-sectional studies in humans with stimulant dependence 7 , 35 — Increased gray matter in the temporal pole was previously demonstrated in cocaine dependent individuals as well The parallels between clinical data sets and the present one suggest that the structural differences between stimulant users and control subjects in clinical studies are caused, in large part, by exposure to stimulants. The strengths of this type of non-human primate longitudinal imaging approach has also been exploited to examine the structural impact of chronic ethanol consumption The second question we posed is that of whether functional consequences accompany the structural effects we observed. We previously reported deficits in RevL and DMS performance in the cocaine exposed animals 15 , which were similar to clinical observations of impaired RevL and DMS in cocaine using populations 6 , 11 , 16 , Impairments in cognitive performance subserved by neuroanatomical areas that also showed structural deficits in clinical studies suggests a link between them, but the lack of true baseline measures prior to cocaine exposure has precluded any inferences of causality. Our results fill that gap. In only a very limited number of anatomical regions do we see a significant correlation between the magnitude of structural change and cognitive impairment across individuals. Reversal performance has classically been associated with impaired OFC function 39 , 40 , and decreases in gray matter in the OFC as well as impairment on RevL performance have been frequently reported in stimulant abuse subjects 7 , While not classically associated with RevL, the lateral intraparietal cortex is associated with inhibitory control, an essential part of RevL performance 41 , which may explain the correlation with RevL in that region. Visual working memory has also been associated with function of the insula 45 and lesions of temporal cortex area TE impair matching performance We observed a significant correlation between changes in GMD and DMS performance in a large region that incorporated the insula and temporal cortex. The third general question we posed related to the effect of extended abstinence on cocaine-induced structural changes. The group X time interaction of scan 3 and scan 2 revealed a general pattern of results in which areas where cocaine had produced changes now showed changes in the opposite direction, suggesting that the GMD alterations resulting from cocaine self-administration might partially reverse. We previously reported a normalization of working memory and reversal performance in these subjects after approximately months abstinence Normalization of cognitive function and increases in gray matter have also been observed in abstinent cocaine users 6 , After a 6-month period of abstinence, cocaine users exhibited increased gray matter volume in occipital and frontal cortex compared to control subjects over a similar time period Moreover, the improvement in cognitive flexibility and decision making over the abstinence period correlated with increased inferior frontal gyrus GM in cocaine users Ideally, we would have also evaluated any relationship between cognitive performance after abstinence and changes in structure. Though we established recovery of cognitive function after approximately 5 months, at which time routine cognitive testing stopped, the lack of cognitive assessments extending to the time of the abstinence scan and the reduced number of subjects precluded a meaningful correlational analysis. Because we were not looking selectively at the regions defined by the group X time interaction in Fig. A future study could use our present results for hypothesis-driven predictions of how anatomically defined regions of interest change upon exposure and abstinence. However, the third group X time interaction we conducted, scan 3 contrasted with scan 1 does permit us to make definitive statements about what differences remain between the groups following self-administration and abstinence. As seen in Fig. These regions are part of functional networks implicated in impaired response inhibition and salience attribution that are affected in human addiction It is plausible these represent more permanent changes in GMD that may contribute to the long-lasting impact characteristic of drug addiction such as the increased risk of relapse. Such areas of lasting structural change could only have been identified with a true, pre-drug baseline measure, and further highlights the strength of NHP models of chronic drug use. The distribution of the regions of reduced GMD in the cocaine group are more widespread than simply brain regions with a dense monoaminergic innervation, known to be a primary target for stimulants. This interpretation is supported by observations that chronic cocaine administration selectively decreases neural spine counts in some brain regions such as OFC and hippocampus, but not in other regions 53 — Aside from neural loss, other factors potentially contributing to distributed alterations in GMD are activation of the innate immune response resulting in astrocyte activation, microgliosis, and glial hypertrophy, which all have been reported in response to stimulant drugs including cocaine 56 — In addition, cocaine-induced angiogenesis 59 and reductions in cerebral blood flow in insula, orbitofrontal cortex, and temporal regions, observed both clinically and in preclinical models 59 — 62 might contribute to the alterations in GMD observed. Our findings would suggest that cocaine use does increase GMD there, and that even after extended abstinence, Fig 6 demonstrates enduring increases relative to the control group. Why this region of the greatest dopaminergic impact of cocaine based on orders of magnitude greater innervation density shows such an opposite effect relative to others is unclear. Ersche and colleagues 7 discuss the literature relating increased regional volume to D2 antagonist effects, and also the well documented effects of cocaine at decreasing D2 levels, but the need for further exploration of mechanism remains. This study is uniquely informative to the large clinical literature of cross-sectional studies between cocaine users and controls. It conclusively demonstrates that use of cocaine can result in structural changes of both decreased, and increased GMD. Critically, it also strongly suggests that decreases in GMD in select cortical regions is linked to altered cognition. While abstinence appears to reverse some of the changes, there are striking exceptions that may contribute to the enduring risk of relapse commonly seen in addiction. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Financial disclosures: The authors report no biomedical financial interests or potential conflicts of interest. This section collects any data citations, data availability statements, or supplementary materials included in this article. As a library, NLM provides access to scientific literature. Biol Psychiatry. Published in final edited form as: Biol Psychiatry. Long term cocaine self-administration produces structural brain changes that correlate with altered cognition. Find articles by Hank P Jedema. Find articles by Xiaowei Song. Find articles by Howard J Aizenstein. Find articles by Alexandra R Bonner. Find articles by Elliot A Stein. Find articles by Yihong Yang. Find articles by Charles W Bradberry. Issue date Feb PMC Copyright notice. The publisher's version of this article is available at Biol Psychiatry. Open in a new tab. Include name of manufacturer, company, repository, individual, or research lab. Include any additional information or notes if necessary. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel. Add additional rows as needed for each resource type.

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Buy cocaine online in Mandeville

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