While animal studies suggest that neonatal pain experiences induce long-term alterations in pain sensitivity, no such data exist in humans. Changes in pain sensitivity in school-aged children (9-14 years) who were born preterm or fullterm, had been hospitalized for a prolonged period of time after birth and had undergone repeated painful procedures while being treated in a Neonatal Intensive Care Unit (NICU) were determined. A retrospective cohort study of 19 preterm (or=37 weeks gestational age) treated at least 3 days in a NICU at a University Hospital and 20 fullterm control children without NICU experience was performed. Perceptual sensitization to tonic heat and repetitive mechanical stimuli as well as heat pain and mechanical pain thresholds were obtained at the thenar and a trigeminal site. Length of hospitalization and NICU treatment was significantly higher in preterm than fullterm children. Nonetheless, both preterm and fullterm children with NICU experience showed greater perceptual sensitization to tonic heat and elevated heat pain thresholds at both sites. Mechanical pain threshold and perceptual sensitization did not differ between groups. Consistent with findings in animals, repeated pain experiences during the neonatal period were associated with alterations in thermal pain responsivity in school-aged preterm and fullterm children that was characterized by enhanced perceptual sensitization to prolonged painful stimulation and hypoalgesia to brief heat pain stimuli. Our findings suggest that repeated pain experiences in neonates may induce activity-induced changes in the functioning of pain pathways that persist well beyond infancy.

No abstract

Due to maturation-related plasticity of the developing nociceptive system, neonatal nociceptive input, as induced by medical procedures in the neonatal intensive care unit (NICU), may cause long-term alterations in pain processing. Using functional magnetic resonance imaging, this study investigated the cerebral pain response in school-aged children and adolescents (11-16 yr) with experience in a NICU after preterm (or=37 weeks gestational age, N=9) as compared to fullterm control children without early hospitalization (N=9). NICU children had been recruited retrospectively among former patients of the Children's University Hospital Mannheim. All children had participated in our previous studies [46,49] entailing psychophysical measurements. In response to tonic (30s) heat stimuli of individually adjusted moderate pain intensity, which were of comparable temperature across groups, the preterm but not the fullterm NICU children exhibited significant activations in a number of brain regions (thalamus, anterior cingulate cortex, cerebellum, basal ganglia, and periaquaeductal gray) that were not significantly activated in controls. The preterms showed significantly higher activations than controls in primary somatosensory cortex, anterior cingulate cortex, and insula. This exaggerated brain response was pain-specific and was not observed during non-painful warmth stimulation. Preterms' continuous pain ratings revealed a tendency for increased sensitization within and a lack of habituation across trials. In highly vulnerable children such as preterms, neonatal nociceptive input may, aside from other neurodevelopmental consequences, persistently increase the gain within pain pathways.

Recent studies showed an enhanced general sensitivity to painful stimuli in adult migraineurs during as well as between attacks. Yet, the influence of a prolonged pain history and potential sex differences has not been studied. We used quantitative sensory testing to examine 25 children with migraine between attacks and 28 controls (age 9-15). The assessment included the measurement of heat and mechanical pain thresholds as well as measures of perceptual sensitization in response to repetitive (mechanical) or tonic (thermal) noxious stimulation at both trigeminal and thenar sites. In addition, the mother was either present or absent during the measurements. Heat pain thresholds were not significantly different between the two groups. However, the child migraineurs showed significantly lower mechanical pain thresholds. Children and especially girls with migraine displayed significantly more sensitization to a tonic heat stimulus at the trigeminal site when the mother was present. The migraineurs also showed a trend towards higher sensitization ratings for mechanical stimuli. Overall, heat pain thresholds were significantly higher in the presence of the mother. In the migraine group only, mechanical pain thresholds were significantly higher when the mother was present. To summarize, an enhanced sensitivity to painful stimuli can already be observed in children suffering from migraine for an average duration of 4.4 years. This may be the result of sensitization in nociceptive pain pathways caused by frequent pain experiences. Girls with migraine were more prone to such sensitization, which may increase their risk for continuing to suffer from migraine throughout adulthood.

Previously, it was shown that school-aged (9-14 yr) preterm and fullterm children with neonatal pain exposure exhibit elevated heat pain thresholds and heightened perceptual sensitization to tonic painful heat when tested under standard conditions [Hermann C, Hohmeister J, Demirakca S, Zohsel K, Flor H. Long-term alteration of pain sensitivity in school-aged children with early pain experiences. Pain 2006;125:278-85]. Here, changes in the psychosocial context of pain responses in these children, who had been hospitalized >or=7 days after birth including >or=3 days of treatment in a neonatal intensive care unit (NICU), are reported. Nineteen preterm (or=37 weeks gestational age) with NICU experience, recruited retrospectively and selected based on strict exclusion criteria, and 20 fullterm control children participated. Preterm NICU children endorsed more pain catastrophizing as compared to controls. Mothers of preterm children, who had been more severely ill and had been hospitalized longer than fullterm NICU children, were more likely to engage in solicitous pain-related behavior. Maternal influence was also assessed by comparing heat pain thresholds and perceptual sensitization to tonic painful heat obtained in the presence versus absence (i.e. standard testing conditions) of the mother. In all three groups, maternal presence was associated with increased heat pain thresholds. Control children habituated significantly more to tonic heat when their mother was present. The NICU children showed overall significantly less habituation than the controls; there was no modulating effect of maternal presence. Especially in highly vulnerable children such as preterms, neonatal pain exposure and prolonged hospitalization may, aside from neuronal plasticity, promote maladaptive pain-related cognitions and foster parental behavior that reinforces the child's pain response.

Converging evidence has highlighted the association between poverty and conduct disorder (CD) without specifying neurobiological pathways. Neuroimaging research has emphasized structural and functional alterations in the orbitofrontal cortex (OFC) as one key mechanism underlying this disorder. The present study aimed to clarify the long-term influence of early poverty on OFC volume and its association with CD symptoms in healthy participants of an epidemiological cohort study followed since birth. At age 25 years, voxel-based morphometry was applied to study brain volume differences. Poverty (0=non-exposed (N=134), 1=exposed (N=33)) and smoking during pregnancy were determined using a standardized parent interview, and information on maternal responsiveness was derived from videotaped mother-infant interactions at the age of 3 months. CD symptoms were assessed by diagnostic interview from 8 to 19 years of age. Information on life stress was acquired at each assessment and childhood maltreatment was measured using retrospective self-report at the age of 23 years. Analyses were adjusted for sex, parental psychopathology and delinquency, obstetric adversity, parental education, and current poverty. Individuals exposed to early life poverty exhibited a lower OFC volume. Moreover, we replicated previous findings of increased CD symptoms as a consequence of childhood poverty. This effect proved statistically mediated by OFC volume and exposure to life stress and smoking during pregnancy, but not by childhood maltreatment and maternal responsiveness. These findings underline the importance of studying the impact of early life adversity on brain alterations and highlight the need for programs to decrease income-related disparities.

IMPORTANCE There is accumulating evidence relating maternal smoking during pregnancy to attention-deficit/hyperactivity disorder (ADHD) without elucidating specific mechanisms. Research investigating the neurobiological underpinnings of this disorder has implicated deficits during response inhibition. Attempts to uncover the effect of prenatal exposure to nicotine on inhibitory control may thus be of high clinical importance. OBJECTIVE To clarify the influence of maternal smoking during pregnancy (hereafter referred to as prenatal smoking) on the neural circuitry of response inhibition and its association with related behavioral phenotypes such as ADHD and novelty seeking in the mother's offspring. DESIGN, SETTING, AND PARTICIPANTS Functional magnetic resonance imaging was performed for the offspring at 25 years of age during a modified Eriksen flanker/NoGo task, and voxel-based morphometry was performed to study brain volume differences of the offspring. Prenatal smoking (1-5 cigarettes per day [14 mothers] or >5 cigarettes per day [24 mothers]) and lifetime ADHD symptoms were determined using standardized parent interviews at the offspring's age of 3 months and over a period of 13 years (from 2 to 15 years of age), respectively. Novelty seeking was assessed at 19 years of age. Analyses were adjusted for sex, parental postnatal smoking, psychosocial and obstetric adversity, maternal prenatal stress, and lifetime substance abuse. A total of 178 young adults (73 males) without current psychopathology from a community sample followed since birth (Mannheim, Germany) participated in the study. MAIN OUTCOMES AND MEASURES Functional magnetic resonance imaging response, morphometric data, lifetime ADHD symptoms, and novelty seeking. RESULTS Participants prenatally exposed to nicotine exhibited a weaker response in the anterior cingulate cortex (t 168 = 4.46; peak Montreal Neurological Institute [MNI] coordinates x = −2, y = 20, z = 30; familywise error [FWE]-corrected P = .003), the right inferior frontal gyrus (t 168 = 3.65; peak MNI coordinates x = 44, y = 38, z = 12; FWE-corrected P = .04), the left inferior frontal gyrus (t 168 = 4.09; peak MNI coordinates x = −38, y = 36, z = 8; FWE-corrected P = .009), and the supramarginal gyrus (t 168 = 5.03; peak MNI coordinates x = 64, y = −28, z = 22; FWE-corrected P = .02) during the processing of the NoGo compared to neutral stimuli, while presenting a decreased volume in the right inferior frontal gyrus. These findings were obtained irrespective of the adjustment of confounders, ADHD symptoms, and novelty seeking. There was an inverse relationship between inferior frontal gyrus activity and ADHD symptoms and between anterior cingulate cortex activity and novelty seeking. CONCLUSIONS AND RELEVANCE These findings point to a functional involvement of prenatal exposure to tobacco smoke in neural alterations similar to ADHD, which underlines the importance of smoking prevention treatments.

Background and Purpose-Differences between women and men in relation to stroke are increasingly being recognized. Methods-From July 2004 until June 2007, 237 acute ischemic stroke (AIS) patients were treated with recombinant tissue plasminogen activator (rtPA) within 3 hours after onset of symptoms in our stroke unit. Baseline characteristics, etiology, CT/MRI stroke patterns, clinical outcome, and complications of women were compared to those of men. Results-Of 237 AIS patients (mean age 70.7 years), 111 (46.8%) were women and 126 (53.2%) were men. Women were older (Pϭ0.001), but history of hyperlipidemia (Pϭ0.03), smoking (Pϭ0.03), and coronary heart disease (PϽ0.001) was less frequent than in men. Internal carotid artery disease occurred more often in men (Pϭ0.02), whereas atrial fibrillation was observed more often in women (Pϭ0.002). In men borderzone/small embolic and lacunar stroke was found more frequently (39.7 versus 27.2%), whereas women showed a higher percentage of large territorial stroke (72.8 versus 60.3%, Pϭ0.09). Baseline National Institute of Health Stroke Scale scores (12.5 versus 11.3), NIHSS score at discharge (11.0 versus 9.5), 3-month-outcome modified Rankin Scale score, thrombolysis-related (17.1% versus 13.5%) or independent complications (32.4% versus 30.2%), and mortality after 3 months (13.5% versus 9.5%) were similar. Conclusion-Differences of stroke lesion patterns in genders are paralleled by differences in etiology and risk factor profiles (women, cardioembolism; men, large and small vessel disease). Baseline characteristics, rates of rtPA-related and independent complications, as well as clinical outcomes were not different between women and men with AIS.