Nicotine dependence (trait) and acute nicotinic stimulation (state) modulate attention but not inhibitory control: converging fMRI evidence from Go-Nogo and Flanker tasks.

Cognitive deficits during nicotine withdrawal may contribute to smoking relapse. However, interacting effects of chronic nicotine dependence and acute nicotine withdrawal on cognitive control are poorly understood. Here we examine the effects of nicotine dependence (trait; smokers (n = 24) vs. non-smoking controls; n = 20) and acute nicotinic stimulation (state; administration of nicotine and varenicline, two FDA-approved smoking cessation aids, during abstinence), on two well-established tests of inhibitory control, the Go-Nogo task and the Flanker task, during fMRI scanning. We compared performance and neural responses between these four pharmacological manipulations in a double-blind, placebo-controlled crossover design. As expected, performance in both tasks was modulated by nicotine dependence, abstinence, and pharmacological manipulation. However, effects were driven entirely by conditions that required less inhibitory control. When demand for inhibitory control was high, abstinent smokers showed no deficits. By contrast, acutely abstinent smokers showed performance deficits in easier conditions and missed more trials. Go-Nogo fMRI results showed decreased inhibition-related neural activity in right anterior insula and right putamen in smokers and decreased dorsal anterior cingulate cortex activity on nicotine across groups. No effects were found on inhibition-related activity during the Flanker task or on error-related activity in either task. Given robust nicotinic effects on physiology and behavioral deficits in attention, we are confident that pharmacological manipulations were effective. Thus findings fit a recent proposal that abstinent smokers show decreased ability to divert cognitive resources at low or intermediate cognitive demand, while performance at high cognitive demand remains relatively unaffected, suggesting a primary attentional deficit during acute abstinence.

A preliminary study suggests that nicotine and prefrontal dopamine affect cortico-striatal areas in smokers with performance feedback.

Nicotine and tonic dopamine (DA) levels [as inferred by catechol-O-methyl tranferase (COMT) Val158Met genotype] interact to affect prefrontal processing. Prefrontal cortical areas are involved in response to performance feedback, which is impaired in smokers. We investigated whether there is a nicotine × COMT genotype interaction in brain circuitry during performance feedback of a reward task. We scanned 23 healthy smokers (10 Val/Val homozygotes, 13 Met allele carriers) during two fMRI sessions while subjects were wearing a nicotine or placebo patch. A significant nicotine × COMT genotype interaction for BOLD signal during performance feedback in cortico-striatal areas was seen. Activation in these areas during the nicotine patch condition was greater in Val/Val homozygotes and reduced in Met allele carriers. During negative performance feedback, the change in activation in error detection areas such as anterior cingulate cortex (ACC)/superior frontal gyrus on nicotine compared to placebo was greater in Val/Val homozygotes compared to Met allele carriers. With transdermal nicotine administration, Val/Val homozygotes showed greater activation with performance feedback in the dorsal striatum, area associated with habitual responding. In response to negative feedback, Val/Val homozygotes had greater activation in error detection areas, including the ACC, suggesting increased sensitivity to loss with nicotine exposure. Although these results are preliminary due to small sample size, they suggest a possible neurobiological mechanism underlying the clinical observation that Val/Val homozygotes, presumably with elevated COMT activity compared to Met allele carriers and therefore reduced prefrontal DA levels, have poorer outcomes with nicotine replacement therapy.

Cue-induced cocaine craving: neuroanatomical specificity for drug users and drug stimuli.

OBJECTIVE: Cocaine-related cues have been hypothesized to perpetuate drug abuse by inducing a craving response that prompts drug-seeking behavior. However, the mechanisms, underlying neuroanatomy, and specificity of this neuroanatomy are not yet fully understood. METHOD: To address these issues, experienced cocaine users (N=17) and comparison subjects (N=14) underwent functional magnetic resonance imaging while viewing three separate films that portrayed 1 ) individuals smoking crack cocaine, 2) outdoor nature scenes, and 3) explicit sexual content. Candidate craving sites were identified as those that showed significant activation in the cocaine users when viewing the cocaine film. These sites were then required to show significantly greater activation when contrasted with comparison subjects viewing the cocaine film (population specificity) and cocaine users viewing the nature film (content specificity). RESULTS: Brain regions that satisfied these criteria were largely left lateralized and included the frontal lobe (medial and middle frontal gyri, bilateral inferior frontal gyrus), parietal lobe (bilateral inferior parietal lobule), insula, and limbic lobe (anterior and posterior cingulate gyrus). Of the 13 regions identified as putative craving sites, just three (anterior cingulate, right inferior parietal lobule, and the caudate/lateral dorsal nucleus) showed significantly greater activation during the cocaine film than during the sex film in the cocaine users, which suggests that cocaine cues activated similar neuroanatomical substrates as naturally evocative stimuli in the cocaine users. Finally, contrary to the effects of the cocaine film, cocaine users showed a smaller response than the comparison subjects to the sex film. CONCLUSIONS: These data suggest that cocaine craving is not associated with a dedicated and unique neuroanatomical circuitry; instead, unique to the cocaine user is the ability of learned, drug-related cues to produce brain activation comparable to that seen with nondrug evocative stimuli in healthy comparison subjects.

Effects of methylphenidate on functional MRI blood-oxygen-level-dependent contrast.

OBJECTIVE: The authors' goal was to determine potential hemodynamic consequences of methylphenidate on functional magnetic resonance imaging (MRI) blood-oxygen-level-dependent (BOLD) contrast. METHOD: BOLD and perfusion changes were recorded from the motor cortex of six healthy subjects while they performed flexion-extension movements of the right index finger (finger tapping) at varying rates before and after oral methylphenidate administration. RESULTS: Functional MRI signals increased monotonically with faster movement rates. Subjects' heart rates increased modestly after methylphenidate administration, but no changes in finger tapping performance or functional MRI signals were observed. CONCLUSIONS: Methylphenidate does not alter BOLD neural-hemodynamic coupling. Consequently, functional MRI can be used to map neural systems that subserve cognitive operations (e.g., attention and executive processes) in subjects taking methylphenidate.

Cocaine administration decreases functional connectivity in human primary visual and motor cortex as detected by functional MRI.

Functional magnetic resonance imaging (fMRI) was conducted to observe the effects of cocaine administration on the physiological fluctuations of fMRI signal in two brain regions. Seven long-term cocaine users with an average age of 32 years and 8 years of cocaine use history were recruited for the study. A T2*-weighted fast echo-planar imaging (EPI) pulse sequence was employed at 1.5 T to acquire three sets of brain images for each subject under three conditions (at rest, after saline injection, and after cocaine injection [0.57 mg/kg]). Cross-correlation maps were constructed using the synchronous, low frequency signal from voxel time courses after filtering respiratory, cardiac, and other physiological noise. A quantitative evaluation of the changes in functional connectivity was made using spatial correlation coefficient (SCC) analysis. A marked 50% reduction in SCC values in the region of primary visual cortex and 43% reduction in SCC values in the region of primary motor cortex were observed after cocaine administration. This significant reduction in SCC values in these cortical regions is a reflection of changes in neuronal activity. It is suggested that the observed changes in low frequency components after acute cocaine administration during a resting, no-task situation may be used as a baseline reference source when assessing the effects of cocaine on task-driven activation or on mesolimbic dopamine pathways.

Prenatal biopsychosocial risk assessment and low birthweight.

A double-blind prospective study was conducted to compare the predictive value of a prenatal biomedical risk scale (PBRS) and a prenatal biopsychosocial risk assessment (PBRAS) with respect to low birthweight. All obstetric patients at seven health centers located in Argentina, Colombia, Honduras, and Uruguay from November 1992 through January 1994 whose initial prenatal visits occurred between the 14th and 28th week of gestation were invited to participate. Information was obtained on 979 mother-infant pairs. High PBRS scores showed sensitivity of 62.1% and specificity of 81.3%, positive predictive value (PPV) of 45.3% and negative predictive value (NPV) of 89.5%, with respect to low birthweight. With the addition of the psychosocial factors (PBRAS), sensitivity of 75.7% and specificity of 76.1%, PPV of 55.1% and NPV of 88.9% were observed. The prospective cohort design of this study provides a strong basis for conclusion that an evaluation of the prenatal biopsychosocial risk (as operationalized by the PBRAS) adjusted for other variables such as length of gestation, neonatal APGAR, perinatal mortality, socioeconomic status, drinking and smoking improves the positive predictive value of the assessment of women who may give birth to newborns with low birthweight (P < 0.01).

Quantitative histological studies of primate corneas after excimer laser photorefractive keratectomy.

OBJECTIVE: To evaluate histological changes in the primate cornea after excimer laser photorefractive keratectomy (PRK) and to correlate them with clinical observations. METHODS: Sixteen African green monkey (Cercopithecus aethiops sabaeus) corneas were examined by light and transmission electron microscopy 6 weeks to 18 months after 1.5- or 3-diopter PRK. RESULTS: All specimens had a smooth stromal surface surrounded by a smooth, centrally tapered Bowman's layer. Epithelial thickness appeared to peak 12 months after PRK. The trend was for the epithelium to be thickest in the central-treated area; this phenomenon was more obvious in the 3-diopter-treated corneas. The numbers of activated keratocytes beneath the treated zone peaked at 4 months and decreased thereafter, while the numbers in the untreated areas decreased in the first 2 months after surgery, increased by 4 months, and did not change thereafter. Regenerated basal lamina averaged 86% intact over ablated areas; thickness was normal and no duplications were seen. Overall, the density of hemidesmosomes was significantly less in ablated areas compared with unablated areas. CONCLUSIONS: These findings support the relationship between clinical observations of corneal haze after PRK, reestablishment of the epithelial cell layer, and the potential for stromal remodeling by active fibroblastic keratocytes beneath the ablation zone. Overall, quantification of several morphological parameters indicated that the values for the treated zone tended, with time, to approach those of the untreated cornea after PRK.

Assessment of the long-term corneal response to hydrogel intrastromal lenses implanted in monkey eyes for up to five years.

The biocompatibility of hydrogel intracorneal lenses (ICLs) implanted in monkey eyes was evaluated for periods ranging up to five years. Seventy-three plus or minus powered ICLs made of Lidofilcon A (68% water) or Lidofilcon B (79% water) were implanted following lamellar dissection with a microkeratome. Ten sham surgical procedures were performed without ICL implantation as controls. Eyes were followed for up to five years by slitlamp biomicroscopy and specular microscopy. Light and transmission electron microscopic evaluations of enucleated eyes were performed at various intervals. Minimal tissue reaction was noted; both hydrogel materials appeared to be equally well tolerated. Failures usually occurred as a result of microkeratome problems encountered during surgery. Histopathological changes to the cornea included epithelial thinning anterior to the thickest portion of the ICL, fibroblastic activity along the ICL-stromal interface, and deposition of an amorphous extracellular material adjacent to the ICL. These observations did not appear to be clinically significant as the eyes were quiet by slitlamp examination. Removal of three ICLs eight to ten months prior to enucleation restored the normal histological characteristics of the cornea. The endothelial cell density of ICL-implanted eyes decreased by 4.3% (n = 17) six months after surgery but remained stable thereafter. The variation in endothelial cell area and percentage of hexagonal cells did not change over 50 months. The results appear to demonstrate that high water content synthetic ICLs can be well tolerated in the monkey cornea for up to five years.

Effect of excimer laser energy on the growth potential of corneal keratocytes.

To determine whether exposure to the excimer laser beam results in the oncogenic transformation of cornea cells, tissue-cultured corneal keratocytes and intact corneas from an inbred strain of rat were exposed to ablative and subablative energies of the excimer laser beam. No evidence for cellular transformation was found. Neither the corneas nor the stromal keratocytes exposed to the laser beam were transformed into cells with unregulated growth potential. Both treated keratocytes and corneas were implanted subcutaneously in the same strain of rats; neither developed into tumors. In tissue culture, cells from cultures exposed to the excimer laser beam exhibited normal growth patterns, growing at the same rate as control, unexposed cells and exhibiting the same capacity to respond to the contact inhibition of growth as the control cells. These results suggest that the 193-nm excimer laser beam does not transform corneal keratocytes and that the energies emitted by this beam will not cause cell transformation when the excimer laser is used as a surgical tool in human eyes.

Central photorefractive keratectomy for myopia. The blind eye study.

Prior to undertaking a study in sighted human eyes, we performed photorefractive keratectomy with the 193-nm excimer laser for the correction of myopia in nine legally blind eyes to evaluate safety, efficacy, predictability, and stability. In most cases, reepithelialization was complete by 5 days after surgery; no recurrent erosions were seen. By the end of the 6-month study, all of the corneas had a 0 or 1+ clarity score, on a scale of 0 (clear) to 5+ (opaque). Keratometry and pachometry demonstrated stable flattening of the corneas. One month after surgery, changes in refraction evaluated by retinoscopy showed fair predictability, with no significant increase in refractive or keratometric astigmatism, followed by some regression of effect by the end of the study, possibly caused by anatomical remodeling. The amount of regression appeared to be directly related to the amount of correction intended, suggesting that this effect would not be clinically important in the treatment of mild to moderate myopia.

One-year refractive results of central photorefractive keratectomy for myopia in the nonhuman primate cornea.

Photorefractive keratectomy for the correction of myopia was performed in 32 eyes of 16 green monkeys. The corneas healed satisfactorily, with normal formation of basal lamina and hemidesmosomal attachments visible in 14-week histologic specimens. No recurrent erosions were observed clinically. After a transient period of faint haze, all corneas were clear at 17 weeks and remained clear through the 1-year follow-up. In terms of accuracy, all corneas demonstrated a significant flattening compared with preoperative values, but no significant difference was seen between the groups with different intended corrections (1.5 and 3 diopters). The changes in corneal shape stabilized by 17 weeks, as measured by keratometry. The clinical results suggest that mechanical removal of the epithelium is preferable to laser ablation of the epithelium. Overall, the results demonstrate that excimer laser ablation of the corneal stroma can produce a stable diptric change in the primate cornea with good healing and long-term corneal clarity.

Refractive results of hyperopic hydrogel intracorneal lenses in primate eyes.

Hyperopic hydrogel intracorneal lenses were successfully implanted into 27 of 33 primate eyes. All eyes were evaluated preoperatively and postoperatively at monthly intervals for clinical appearance and refractive alteration. In a preliminary surgical series, several factors, such as tight sutures and implant design, resulted in a poor refractive yield. The final surgical series used a microkeratome with a pediatric microkeratome ring for smooth interface cuts, interrupted suturing with sufficient tension to align the wound without compression, a suture through the lens to prevent its dislocation, and intraoperative keratometry to reduce postoperative cylinder. The predicted vs measured refractive alteration for a range of 6 to 20 diopters had a correlation coefficient of .95. Keratometry changes correlated to the refractive changes with a coefficient of .97 but understand the change in refraction created by the surgery.

[Immunobiology of materno-fetal relations]. / Inmunobiología de las relaciones materno-fetales.

Normal development of pregnancy requires maternal immune system tolerance towards the fetoplacental allograft. Natural Killer (NK) cells can display spontaneous lytic activity against tumoral, and poorly differentiated cells, without a prior sensitization. Moreover this cytotoxic activity is not restricted by the Major Histocompatibility Complex (MHC). We investigated the existence of modifications in the NK activity mediated by peripheral blood mononuclear cells (PBMC) from pregnant women. A significant depression was found in this activity from the first trimester to the puerperium that cannot be ascribed to a defective number of NK cells among pregnant's PBMC. However this impaired NK activity can be reconstituted in vitro by incubation of PBMC with interleukin 2 (IL 2). Pregnancy is also associated with an absence of effectors and/or precursors which mediate other cytotoxic non MHC-restricted activities after long term incubation with IL 2, the so called Lymphokine Activated Killer (LAK) cells.