Thomas F. Newton

Regional differences in brain electrical activity in dementia: use of spectral power and spectral ratio measures ☆

The pathologic changes in dementia of the Alzheimers type (DAT) commonly affect selected brain regions. The cortical areas affected in multi-infarct dementia (MID) are less predictable and may be secondary to subcortical gray or white matter damage that is widespread in MID. We compared several types of quantitative EEG power measures (absolute and relative power, and ratios of power) to determine their regional distribution, and their association with changes in cognitive status and age. We examined 49 subjects with clinically diagnosed mild-to-moderate DAT, 29 with mild-to-moderate MID, and 38 elderly controls (CON). We used discriminant analysis to identify, for each parameter type, the brain region and frequency band where the parameter best distinguished between groups of subjects. The parameters showed regional differences in distinguishing between DAT and MID subjects, and in their association with age and cognitive status. All parameters were useful for detecting differences between normal and demented subjects and correctly identified comparable proportions of subjects as having dementia. Subjects who were abnormal on several parameters were much more likely to have dementia. The additive effects of these parameters in correct classification suggest that they may be monitoring different physiologic processes. Combinations of several types of parameters may be more useful than individual parameters for distinguishing demented from non-demented subjects.

Bupropion Reduces Methamphetamine-Induced Subjective Effects and Cue-Induced Craving

Bupropion is an antidepressant with stimulant properties, which inhibits the reuptake of dopamine (DA) and norepinepherine, and is purported to enhance DA neurotransmission. Bupropion is considered an appealing candidate medication for the treatment of methamphetamine dependence. The current laboratory study was set forth to assess the impact of bupropion treatment on the subjective effects produced by methamphetamine in the laboratory. We also assessed the effects of bupropion treatment on craving elicited by exposure to videotaped methamphetamine cues. A total of 26 participants were enrolled and 20 completed the entire study (n=10 placebo and n=10 bupropion, parallel groups design). Bupropion treatment was associated with reduced ratings of ‘any drug effect’ (p<0.02), and ‘high’ (p<0.02) following methamphetamine administration. There was also a significant bupropion-by-cue exposure interaction on General Craving Scale total score (p<0.002), and on the Behavioral Intention subscale (p<0.001). Overall, the data reveal that bupropion reduced acute methamphetamine-induced subjective effects and reduced cue-induced craving. Importantly, these data provide a rationale for the evaluation of bupropion in the treatment of methamphetamine dependence.

MDMA use and neurocognition: a meta-analytic review.

RationaleTo determine the association between MDMA misuse and neurocognition using meta-analysis.ObjectiveSeparate analyses were conducted based on two sets of inclusion/exclusion criteria. A relatively stringent set required that the subjects be matched on important moderator variables, whereas the other did not. The study participants’ performance in the following neurocognitive domains was reviewed: attention/concentration, verbal and nonverbal learning and memory, psychomotor speed and executive systems functioning.ResultsIn the 11 studies meeting the relatively stringent inclusion/exclusion criteria for this review, MDMA use was associated with neurocognitive deficits in each domain. Similarly, in the 23 studies meeting the relatively lenient inclusion/exclusion criteria for this review, MDMA use was associated with neurocognitive deficits in each domain. Small to medium effect sizes were generally observed. A comparison of the effect sizes across the two sets of analyses did not reveal significant differences.ConclusionsThe findings from this review reveal that MDMA use is associated with neurocognitive deficits. The implications of these findings are discussed.

Randomized, placebo-controlled trial of bupropion for the treatment of methamphetamine dependence

OBJECTIVE To compare bupropion to placebo for reducing methamphetamine (MA) use, increasing retention, and reducing the severity of depressive symptoms and MA-cravings. A secondary objective compared bupropion to placebo for reducing cigarette smoking among MA dependent participants. METHODS Following a 2-week, non-medication baseline screening period, 73 treatment-seeking MA dependent participants were randomly assigned to bupropion sustained release (150 mg twice daily; N=36) or placebo (twice daily; N=37) for 12-weeks under double-blind conditions. Participants attended clinic thrice weekly to provide urine samples analyzed for MA-metabolite, to complete research measures and assessments, and to receive contingency management and weekly cognitive behavioral therapy sessions. RESULTS There were no statistically significant effects for bupropion relative to placebo on MA use verified by urine drug screens, for reducing the severity of depressive symptoms or MA-cravings, or on study retention. In a post hoc analysis, there was a statistically significant effect of bupropion treatment on MA use among participants with lighter (0-2 MA-positive urines), but not heavier (3-6 MA-positive urines) MA use during baseline (OR=2.81, 95% CI=1.61-4.93, p<0.001 for MA-free week with bupropion among light users). Bupropion treatment was also associated with significantly reduced cigarette smoking, by almost five cigarettes per day (p=0.0002). CONCLUSION Bupropion was no more effective than placebo in reducing MA use in planned analyses, though bupropion did reduce cigarette smoking. Post hoc findings of an effect for bupropion among baseline light, but not heavy, MA users suggests further evaluation of bupropion for light-MA users is warranted.

Cocaine Dependence and Acute Cocaine Induce Decreases of Monocyte Proinflammatory Cytokine Expression across the Diurnal Period: Autonomic Mechanisms

Cocaine dependence is associated with an increased risk of infectious diseases. The innate immune system triggers effector pathways to combat microbial pathogens through expression of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). It is not known whether cocaine alters the capacity of monocytes to respond to a bacterial challenge in humans. In cocaine-dependent volunteers and control subjects, we analyzed monocyte TNF-α and IL-6 expression at rest and in response to the bacterial ligand, lipopolysaccharide (LPS), over a 24-h period. In addition, the in vivo effects of cocaine (40 mg) versus placebo on monocyte expression of TNF-α and IL-6 were profiled over 48 h. Cocaine-dependent volunteers showed a decrease in the capacity of monocytes to express TNF-α and IL-6 compared with control subjects. Moreover, acute infusion of cocaine induced a further decline in the responsiveness of monocytes to LPS, which persisted after cocaine had cleared from the blood. Heart rate variability analyses showed that increases of sympathetic activity along with vagal withdrawal were associated with decreases in monocyte expression of TNF-α. Cocaine alters autonomic activity and induces protracted decreases in innate immune mechanisms. Targeting sympathovagal balance might represent a novel strategy for partial amelioration of impairments of innate immunity in cocaine dependence.

Neurocognitive functioning is associated with employment status: a quantitative review.

Neurocognitive assessment is frequently used as a basis for making determinations regarding a person’s ability to work; yet, to our knowledge, a review of the association between neurocognition and employment status has not been conducted. For this review, we utilized meta-analysis to quantify objectively the association between eight neurocognitive domains and employment status. The meta-analysis revealed that performance in each domain was significantly associated with employment status, and that the associations were greatest for the following domains: intellectual functioning, executive functioning, and memory. These findings support the ecological validity of neurocognitive assessment.

Adherence to antiretroviral medications in HIV: differences in data collected via self-report and electronic monitoring.

Controversy remains regarding the reliability of methods used to determine adherence to antiretroviral medication in HIV. In this study the authors compared adherence rates of 119 HIV-positive participants during a 6-month study, as estimated via electronic monitoring (EM) and self-report (SR). Adherence for both short (4-day) and long (4-week, or intervisit) periods was examined, as well as factors that underlie discrepancies between EM and SR. Results showed that intervisit EM estimates were consistently lower than those of SR. SR estimates based on shorter periods (4 days) were closer to those of EM. Higher discrepancies between EM and SR estimates were associated with lower cognitive functioning and externalized locus of control. These findings lend support for using both EM and SR methods; however, study design (e.g., length) and other factors (e.g., cognitive status, cost) should be considered.

Presence and persistence of psychotic symptoms in cocaine- versus methamphetamine-dependent participants.

The primary objective of this study was to compare and contrast psychotic symptoms reported by cocaine- and methamphetamine-dependent individuals. Participants included 27 cocaine-dependent and 25 methamphetamine-dependent males, as well as 15 cocaine-dependent and 18 methamphetamine-dependent females. After screening, participants were excluded if they met criteria for any Axis I diagnosis other than nicotine dependence, or methamphetamine or cocaine dependence (ie, participants had to use either methamphetamine or cocaine but were excluded if they met dependence criteria for both). The participants were administered the newly developed Psychotic Symptom Assessment Scale (PSAS), which assesses psychotic symptoms. A high proportion of both cocaine- and methamphetamine-dependent men and women reported delusions of paranoia and auditory hallucinations. However, during the abstinent and intoxicated conditions, methamphetamine-dependent men and women were more likely than cocaine-dependent men and women to report psychotic symptoms. Future studies will compare psychotic symptoms reported by non-dependent recreational stimulant users to stimulant-dependent individuals.

Modafinil administration improves working memory in methamphetamine-dependent individuals who demonstrate baseline impairment.

Modafinil improves working memory in healthy subjects and individuals diagnosed with schizophrenia and Attention Deficit/Hyperactivity Disorder, though the effects of modafinil have not been evaluated on working memory in methamphetamine-dependent subjects. This double-blind, placebo-controlled study evaluated whether a daily dose of 400 mg of modafinil, administered over three consecutive days, would enhance performance on a measure of working memory relative to test performance at baseline and following 3 days of placebo administration in 11 methamphetamine addicted, nontreatment-seeking volunteers. The results revealed that participants demonstrating relatively poor performance on the third day of a 3-day washout period (ie, at baseline), showed significant improvement on measures of working memory, but not on measures of episodic memory or information processing speed. In contrast, for participants demonstrating relatively high performance at baseline, modafinil administration did not affect test scores. The findings provide an initial indication that modafinil can reverse methamphetamine-associated impairments in working memory.

Pharmacotherapeutics directed at deficiencies associated with cocaine dependence: Focus on dopamine, norepinephrine and glutamate

Much effort has been devoted to research focused on pharmacotherapies for cocaine dependence yet there are no FDA-approved medications for this brain disease. Preclinical models have been essential to defining the central and peripheral effects produced by cocaine. Recent evidence suggests that cocaine exerts its reinforcing effects by acting on multiple neurotransmitter systems within mesocorticolimibic circuitry. Imaging studies in cocaine-dependent individuals have identified deficiencies in dopaminergic signaling primarily localized to corticolimbic areas. In addition to dysregulated striatal dopamine, norepinephrine and glutamate are also altered in cocaine dependence. In this review, we present these brain abnormalities as therapeutic targets for the treatment of cocaine dependence. We then survey promising medications that exert their therapeutic effects by presumably ameliorating these brain deficiencies. Correcting neurochemical deficits in cocaine-dependent individuals improves memory and impulse control, and reduces drug craving that may decrease cocaine use. We hypothesize that using medications aimed at reversing known neurochemical imbalances is likely to be more productive than current approaches. This view is also consistent with treatment paradigms used in neuropsychiatry and general medicine.