Background-Methamphetamine (MA)-dependent individuals prefer smaller immediate over larger delayed rewards in delay discounting (DD) tasks. Human and animal data implicate ventral (amygdala, ventral striatum, ventrolateral prefrontal cortex insula) and dorsal (dorsolateral prefrontal cortex, dorsal anterior cingulate cortex and posterior parietal cortex) systems in DD decisions. The ventral system is hypothesized to respond to the salience and immediacy of rewards while the dorsal system is implicated in the process of comparison and choice.

The relationships between immune and neural function are an increasingly important area of study for neuropsychiatric disorders, in particular depression. This is exemplified by the growing number of publications on cytokines and depression during the last 10 years, as compared to earlier decades. This review summarizes the current theories and novel treatment strategies for depression, with a focus on cytokine-induced depression. Neuroimmune mechanisms are now viewed as central to the development of depressive symptoms and emerging evidence is beginning to identify the neural circuits involved in cytokine-induced depression. The current diagnostic categories for depression, as defined by the Diagnostic and Statistical Manual of Mental Disorders, however, are not etiologically or biologically derived, and it has been proposed that "depression", likely reflects multiple pathogeneses leading to varying symptom constellations. As we move toward a better biological understanding of depression-related symptom constellations or syndromes, the term "depression" may prove inadequately broad, and an integration of interdisciplinary literatures will increase in importance. Future research should aim to characterize these depression-related symptom constellations or syndromes better with the goal of optimizing treatment strategies.

Methamphetamine (MA) is associated with behavioral and cognitive deficits that may be related to macrostructural abnormalities. Quantitative anatomical comparisons between controls and methamphetamine-dependent individuals have produced conflicting results. We examined local and global differences in brain structure in 61 abstinent methamphetamine-dependent individuals and 44 controls with voxel-based morphometry and tissue segmentation. We related regional differences in gray matter density and whole brain segmentation volumes to performance on a behavioral measure of impulsivity and group membership using multiple linear regression. Within the MA group, we related cortical and subcortical gray matter density to MA use history, length of abstinence and age of first use. Controls had greater density relative to MA in bilateral insula and left middle frontal gyrus. Impulsivity was higher in the MA group and, within all subjects, impulsivity was positively correlated with gray matter density in posterior cingulate cortex and ventral striatum and negatively correlated in left superior frontal gyrus. Length of abstinence from MA was associated with greater amygdalar density. Earlier age of first use of MA (in subjects who initiated use before age 21) was associated with smaller intracranial volume. The findings are consistent with multiple possible mechanisms including neuroadaptations due to addictive behavior, neuroinflammation as well as dopaminergic and serotonergic neurotoxicity.

Objective To evaluate the efficacy of cognitive rehabilitation therapies (CRTs) for mild cognitive impairment (MCI). Our review revealed a need for evidence-based treatments for MCI and a lack of a theoretical rehabilitation model to guide the development and evaluation of these interventions. We have thus proposed a theoretical rehabilitation model of MCI that yields key intervention targets - cognitive compromise, functional compromise, neuropsychiatric symptoms, and modifiable risk and protective factors known to be associated with MCI and dementia. Our model additionally defines specific cognitive rehabilitation approaches that may directly or indirectly target key outcomes - restorative cognitive training, compensatory cognitive training, lifestyle interventions, and psychotherapeutic techniques. Methods Fourteen randomized controlled trials met inclusion criteria and were reviewed. Results Studies markedly varied in terms of intervention approaches and selected outcome measures and were frequently hampered by design limitations. The bulk of the evidence suggested that CRTs can change targeted behaviors in individuals with MCI and that CRTs are associated with improvements in objective cognitive performance, but the pattern of effects on specific cognitive domains was inconsistent across studies. Other important outcomes (i.e., daily functioning, quality of life, neuropsychiatric symptom severity) were infrequently assessed across studies. Few studies evaluated long-term outcomes or the impact of CRTs on conversion rates from MCI to dementia or normal cognition. Conclusions Overall, results from trials are promising but inconclusive. Additional well-designed and adequately powered trials are warranted and required before CRTs for MCI can be considered evidence based.

Methamphetamine (MA) dependence causes serious cognitive impairments that can persist during abstinence and negatively affect recovery outcomes. Evidence suggests that immune factors, such as cytokines, chemokines, and cellular adhesion molecules, contribute to MA-induced immune dysfunction, neuronal injury, and persistent cognitive impairments, yet the role of MA-induced brain inflammation remains unclear. To address this question, we used a cross-species, translational approach. Thirty-two male C57BL/6J mice were administered MA (1 mg/kg) or saline subcutaneously for seven consecutive days. Mice were euthanized at 72 h or 3 weeks after the last drug dose, and blood and brain samples were collected. In addition, 20 adults in remission from MA dependence and 20 non-dependent controls completed neuropsychological assessments and a blood draw. Multiplex assays were used to measure cytokine, chemokine, and intercellular adhesion molecule (ICAM-1) expression in mouse and human samples. A number of significant MA-induced changes in neuroimmune factors were observed. Of particular interest were the chemokine monocyte chemoattractant protein 1 (MCP-1) and the cellular adhesion molecule ICAM-1, which were similarly increased in the plasma of MA exposed mice as well as humans. In human participants, MA-induced changes in the cytokine and chemokine milieu were accompanied by increased cognitive impairments. Mice showing MA-induced changes in peripheral immune molecule expression also had significant brain-region specific changes in pro- NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript inflammatory cytokines, chemokines, and ICAM-1. This cross-species, translational study suggests that chronic CNS immune dysregulationmay in part contribute to the longlasting neuropsychiatric consequences of MA dependence.

Studies suggest that cytokines have a role in the biology of depression. In this study, we evaluated depression and cytokine levels in patients with and without chronic hepatitis C (HCV) to better assess how chronic infection alters cytokines levels and may contribute to depressive symptomotology. Twenty-three adults with (n = 16) and without (n = 7) HCV were recruited through the Portland VA Medical Center. Research participants were excluded for current substance abuse, psychotic disorder, liver cirrhosis, or interferon (IFN) therapy. Participants completed the Beck Depression Inventory-II (BDI-II) and a blood draw to evaluate plasma cytokine levels [i.e., interleukin (IL)-1β, IL-10 and tumor necrosis factor (TNF)-α]. T-tests were performed to compare cytokine levels in patients with versus those without HCV. HCV patients showed higher TNF-α values compared to patients without HCV (group means = 7.94 vs. 3.41 pg/mL, respecitively, p = 0.047). There were no significant differences between the groups for the other cytokines assessed. In patients with HCV, TNF-α and IL-1β levels (but not IL-10) were correlated with BDI-II scores [r = 0.594, p = 0.020 and r = 0.489, p = 0.055 (trend), respectively]. Taken together, these results show an association between severity of depressive symptoms and expression of proinflammatory cytokines in patients with HCV. Future studies should investigate how inflammatory mediators play a role in the expression of specific Corresponding author: Jennifer M. Loftis, Ph.D., Phone: (503) ext. 57155, Fax: (503) 721-1053, Email: loftisj@ohsu.edu or Jennifer.loftis2@va.gov. 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 citable 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. NIH Public Access

Addiction is a worldwide public health problem and this article reviews scientific advances in identifying the role of neuroinflammation in the genesis, maintenance, and treatment of substance use disorders. With an emphasis on neuroimaging techniques, this review examines human studies of addiction using positron emission tomography to identify binding of translocator protein (TSPO), which is upregulated in reactive glial cells and activated microglia during pathological states. High TSPO levels have been shown in methamphetamine use but exhibits variable patterns in cocaine use. Alcohol and nicotine use, however, are associated with lower TSPO levels. We discuss how mechanistic differences at the neurotransmitter and circuit level in the neural effects of these agents and subsequent immune response may explain these observations. Finally, we review the potential of anti-inflammatory drugs, including ibudilast, minocycline, and pioglitazone, to ameliorate the behavioral and cognitive consequences of addiction.

Findings indicate that training in compensatory cognitive strategies facilitates behavioral change (ie, use of cognitive strategies) as well as both subjective and objective improvements in targeted cognitive domains.