Katrin Zohsel

Long-term alteration of pain sensitivity in school-aged children with early pain experiences.

&NA; 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 (≤31 weeks gestational age) and 20 fullterm children (≥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.

Cerebral processing of pain in school-aged children with neonatal nociceptive input: An exploratory fMRI study

&NA; 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 (≤31 weeks gestational age, N = 9) or fullterm birth (≥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 Childrens University Hospital Mannheim. All children had participated in our previous studies [46,49] entailing psychophysical measurements. In response to tonic (30 s) 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.

Responses to pain in school-aged children with experience in a neonatal intensive care unit: cognitive aspects and maternal influences.

Previously, it was shown that school‐aged (9–14yr) 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 ≥7 days after birth including ≥3 days of treatment in a neonatal intensive care unit (NICU), are reported. Nineteen preterm (≤31 weeks gestational age) and 20 fullterm children (≥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 childs pain response.

Gender Differences in Acute Ischemic Stroke: Etiology, Stroke Patterns and Response to Thrombolysis

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 (P=0.001), but history of hyperlipidemia (P=0.03), smoking (P=0.03), and coronary heart disease (P<0.001) was less frequent than in men. Internal carotid artery disease occurred more often in men (P=0.02), whereas atrial fibrillation was observed more often in women (P=0.002). 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%, P=0.09). 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.

Quantitative sensory testing in children with migraine: preliminary evidence for enhanced sensitivity to painful stimuli especially in girls.

Abstract 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.

Do burn injuries during infancy affect pain and sensory sensitivity in later childhood

Abstract Studies in animals and humans suggest that neonatal and early infant pain or stress experiences can induce long‐term alterations in somatosensory and pain processing. We studied pain and sensory sensitivity in school‐aged children (9–16 years) who had suffered moderate (N = 24) or severe (N = 24) burn injuries in infancy (6–24 months of age) and 24 controls. Quantitative sensory testing entailing detection and pain thresholds for thermal and mechanical stimuli and perceptual sensitization to tonic heat and repetitive mechanical stimuli was performed. Two testing sites (thenar, trigeminal region), both not affected by the burn injury, were used to determine whether there are global changes in pain sensitivity. The result pattern suggests a differential impact of burn severity. Compared to controls, moderately burned children showed significantly higher mechanical detection thresholds (thenar) and significantly lower mechanical pain thresholds and significantly greater perceptual sensitization to repetitive mechanical stimuli (both testing sites). No significant alterations were observed for thermal stimuli. In contrast, severely burned children showed, compared to controls, primarily alterations in thermal pain sensitivity (elevated pain thresholds at both testing sites, significantly greater perceptual sensitization at the thenar). In these children, mechanical pain sensitivity and detection thresholds were not consistently altered. This differential pattern of altered sensory and pain sensitivity may reflect differences in experienced stress, pain and analgesic treatment between moderately and severely burned children. Most importantly, our findings suggest that early traumatic and painful injuries, such as burns, can induce global, long‐term alterations in sensory and pain processing.

In vivo clot lysis of human thrombus with intravenous abciximab immunobubbles and ultrasound

Abciximab immunobubbles have been introduced recently for ultrasonographic molecular imaging of human thrombus. This study investigates the potential of using these novel bubbles for enhancing sonothrombolysis. In particular, it addresses the question of whether ligand targeting of bubbles with abciximab improves the effectiveness of lysis with ultrasound. A partial thrombotic occlusion of the right common carotid artery of 16 rats was produced by insertion of human clot material via an external carotid artery catheter. Rats received abciximab immunobubbles, non-specific control immunobubbles or saline intravenously over 30 minutes in combination with pulsed 2 MHz ultrasound. Blood samples were taken at baseline and 5, 10, 20, 30 and 60 minutes after beginning treatment. Human D-dimer levels for quantification of thrombolysis were analysed by ELISA. Only animals treated with abciximab immunobubbles and ultrasound showed a significant increase of D-dimer levels over time (p = 0.043, linear trend p = 0.037), whereas in the other two groups, no significant increase over time was found. Overall, animals in the abciximab immunobubbles group showed higher plasma D-dimer levels than animals treated with non-specific immunobubbles (p = 0.049) and animals treated with ultrasound alone (p = 0.017). In histological sections, thrombi treated with abciximab immunobubbles and ultrasound showed clear signs of disintegration in contrast to thrombi in both control groups. 2 MHz ultrasound in combination with abciximab immunobubbles induces thrombolysis without lytic agents that is superior to insonation of non-specific immunobubbles.

Dimensions of pain-related parent behavior: development and psychometric evaluation of a new measure for children and their parents.

&NA; The development and maintenance of chronic pain are influenced by its social context, and especially by the responses of family members. For children, very few instruments are available that measure pain‐related parental behavior. Using the Multidimensional Pain Inventory for adults (MPI; [Kerns RD, Turk DC, Rudy TE. The west haven‐yale multidimensional pain inventory (WHYMPI). Pain 1985;23:345–356.]) as a model, we developed and evaluated a child and parent versions of the Pain‐related Parent Behavior Inventory (PPBI). Here, we specifically studied maternal pain‐related behavior as perceived by the child and self‐reported by the mother. As substantiated by exploratory factor analysis in a mixed sample of 193 children and adolescents (8–16 years) either suffering from recurrent pain of different origin or being healthy controls, both PPBI versions entail the identical subscale solicitousness, distracting behaviors and discouraging/ignoring responses. Child and parent PPBI subscales were internally consistent and were not substantially related to age or gender. Validity analyses yielded a pattern of correlations with measures of depression, trait anxiety, pain activity, and pain‐related cognitions that is consistent with the psychometric data for the adult MPI and findings on the social context of chronic pain. Child‐perceived maternal behavior was significantly related to overall parenting and to mothers’ actual behavior as observed during a cold pressor test. Finally, the PPBI was sensitive to differences in mothers’ responses depending on the specific nature of the child’s pain. Child and parent reports of parental behaviors were modestly correlated and were differentially related to the validity measures, hence supporting the importance of assessing the social context of pediatric pain independently of both the child’s and the parent’s perspectives.

Altered pain processing in children with migraine: An evoked potential study

In adults, evidence is accumulating that migraine is associated with altered central processing of pain stimuli and, possibly, changes in the allocation of attentional resources to such stimuli. In pediatric migraine, however, little is known about altered pain processing. We examined 15 children with migraine and 15 controls (age 10–15) in an oddball standards task. Children had to respond to rare targets (tones) and ignore frequent painful (pain threshold) or non‐painful mechanical standard stimuli while evoked potentials were obtained. Painful as compared to non‐painful stimuli elicited significantly larger N150, P260 and P300 components of the somatosensory evoked potential in all children. The pain‐evoked N150 and P260 components did not differ significantly between groups. However, in children with migraine, both painful and non‐painful standard stimuli were associated with significantly larger P300 amplitudes at significantly shorter latencies. Perceived intensity of the painful and non‐painful stimuli was comparable in both groups. The evoked potentials and reaction times to the target tones did not differ significantly between groups. Habituation across trials was similar in both groups. Hence, children with migraine may display an automatic attentional bias towards painful and potentially painful somatosensory stimuli. Consistent with the psychobiological perspective of chronic pain, such an attentional bias could constitute an important mechanism for migraine becoming a chronic problem.

Effect of Prenatal Exposure to Tobacco Smoke on Inhibitory Control: Neuroimaging Results From a 25-Year Prospective Study

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 mothers 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 offsprings 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 (t168 = 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 (t168 = 3.65; peak MNI coordinates x = 44, y = 38, z = 12; FWE-corrected P = .04), the left inferior frontal gyrus (t168 = 4.09; peak MNI coordinates x = -38, y = 36, z = 8; FWE-corrected P = .009), and the supramarginal gyrus (t168 = 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.