Preparatory attention relies on dynamic interactions between prelimbic cortex and anterior cingulate cortex.

An emerging view of prefrontal cortex (PFC) function is that multiple PFC areas process information in parallel, rather than as distinct modules. Two key functions assigned to the PFC are the regulation of top-down attention and stimulus-guided action. Electrophysiology and lesion studies indicate the involvement of both the anterior cingulate cortex (ACC) and prelimbic cortex (PL) in these functions. Little is known, however, about how these cortical regions interact. We recorded single unit spiking and local field potentials (LFPs) simultaneously in rodents during a sustained attention task and assessed interactions between the ACC and PL by measuring spike-LFP phase synchrony and LFP-LFP phase synchrony between these areas. We demonstrate that the magnitude of synchrony between the ACC and PL, before stimulus onset, predicts the subjects' behavioral choice after the stimulus. Furthermore, neurons switched from a state of beta synchrony during attention to a state of delta synchrony before the instrumental action. Our results indicate that multiple PFC areas interact during attention and that the same neurons may participate in segregated assemblies that support both attention and action.

Distinct prestimulus and poststimulus activation of VTA neurons correlates with stimulus detection.

Dopamine neurons of the ventral tegmental area (VTA) signal the occurrence of a reward-predicting conditioned stimulus (CS) with a subsecond duration increase in post-CS firing rate. Important theories about reward-prediction error and reward expectancy have been informed by the substantial number of studies that have examined post-CS phasic VTA neuron activity. On the other hand, the role of VTA neurons in anticipation of a reward-predicting CS and analysis of prestimulus spike rate rarely has been studied. We recorded from the VTA in rats during the 3-choice reaction time task, which has a fixed-duration prestimulus period and a difficult-to-detect stimulus. Use of a stimulus that was difficult to detect led to behavioral errors, which allowed us to compare VTA activity between trials with correct and incorrect stimulus-guided choices. We found a sustained increase in firing rate of both putative dopamine and GABA neurons during the pre-CS period of correct and incorrect trials. The poststimulus phasic response, however, was absent on incorrect trials, suggesting that the stimulus-evoked phasic response of dopamine neurons may relate to stimulus detection. The prestimulus activation of VTA neurons may modulate cortical systems that represent internal states of stimulus expectation and provide a mechanism for dopamine neurotransmission to influence preparatory attention to an expected stimulus.

Neonatal encephalopathy: Focus on epidemiology and underexplored aspects of etiology.

Neonatal Encephalopathy (NE) is a neurologic syndrome in term and near-term infants who have depressed consciousness, difficulty initiating and maintaining respiration, and often abnormal tone, reflexes and neonatal seizures in varying combinations. Moderate/severe NE affects 0.5-3/1000 live births in high-income countries, more in low- and middle-income countries, and carries high risk of mortality or disability, including cerebral palsy. Reduced blood flow and/or oxygenation around the time of birth, as with ruptured uterus, placental abruption or umbilical cord prolapse can cause NE. This subset of NE, with accompanying low Apgar scores and acidemia, is termed Hypoxic-Ischemic Encephalopathy. Other causes of NE that can present similarly, include infections, inflammation, toxins, metabolic disease, stroke, placental disease, and genetic disorders. Aberrant fetal growth and congenital anomalies are strongly associated with NE, suggesting a major role for maldevelopment. As new tools for differential diagnosis emerge, their application for prevention, individualized treatment and prognostication will require further systematic studies of etiology of NE.

Placental contribution to neonatal encephalopathy.

Placental assessment, although currently underused, can inform our understanding of the etiology and timing of Neonatal Encephalopathy (NE). We review our current understanding of the links between placental dysfunction and NE and how this information may inform clinical decisions, now and in the future, emphasizing the four major placental lesions associated with NE. In addition, we discuss maternal and fetal factors that are hypothesized to contribute to specific placental pathologies, especially innate or acquired thrombophilias. We outline the importance of assessing placenta across trimesters and after delivery. As this field continues to evolve, currently available placental histopathological examination methods may need to be combined with advanced prenatal molecular and imaging assessments of placenta and be applied in well-designed studies in large representative populations to better define the links between placental dysfunction and NE.

Anterior cingulate neurons represent errors and preparatory attention within the same behavioral sequence.

The anterior cingulate cortex (ACC) has been implicated in both preparatory attention (i.e., selecting behaviorally relevant stimuli) and in detecting errors. We recorded from the rat ACC and medial prefrontal cortex (mPFC), which is functionally homologous to the primate dorsolateral PFC, during an attention task. The three-choice serial reaction time task requires a rat to orient toward and divide attention between three brief (300 ms duration) light stimuli presented in random order across nose poke holes in an operant chamber. In both the ACC and mPFC, we found that neural activity was related to the level of preparatory (precue) attention and subsequent correct or incorrect choice, in that the magnitude of the single units' response to the cue was lower on incorrect trials and was not different than baseline on unattended trials. This preparatory neural activity consisted of both excitatory and inhibitory phasic responses. The number of units responding to the cue was similarly graded, in that fewer units exhibited phasic responses to the cue on incorrect and unattended trials, compared with correct trials. Although preparatory activity was found in both the ACC and mPFC, activity after incorrect nose pokes, which may be related to error detection, were only observed in the ACC. Thus, during the same behavioral sequence, the ACC encodes both error-related events and preparatory attention, whereas the mPFC only participates in preparatory attention. The finding of substantial inhibitory activity during the preparatory period suggests a critical role for inhibition of pyramidal cells in PFC-mediated cognitive functions.

Unintended changes in cognition, mood, and behavior arising from cell-based interventions for neurological conditions: ethical challenges.

The prospect of using cell-based interventions (CBIs) to treat neurological conditions raises several important ethical and policy questions. In this target article, we focus on issues related to the unique constellation of traits that characterize CBIs targeted at the central nervous system. In particular, there is at least a theoretical prospect that these cells will alter the recipients' cognition, mood, and behavior-brain functions that are central to our concept of the self. The potential for such changes, although perhaps remote, is cause for concern and careful ethical analysis. Both to enable better informed consent in the future and as an end in itself, we argue that early human trials of CBIs for neurological conditions must monitor subjects for changes in cognition, mood, and behavior; further, we recommend concrete steps for that monitoring. Such steps will help better characterize the potential risks and benefits of CBIs as they are tested and potentially used for treatment.

Noradrenergic ensemble-based modulation of cognition over multiple timescales.

Cognition fluctuates over relatively faster and slower timescales. This is enabled by dynamic interactions among cortical neurons over similarly diverse temporal and spatial scales. Fast and slow cognitive processes, such as reorienting to surprising stimuli or using experience to develop a behavioral strategy, are also sensitive to neuromodulation by the diffusely-projecting brainstem noradrenergic nucleus, Locus Coeruleus. However, while a dynamic, multi-scale cortical ensemble code influences cognition over multiple timescales, it is unknown to what extent LC neuronal activity operates in this regime. An ensemble code within the LC may permit an interface with cortical ensembles allowing noradrenergic modulation of fast and slow cognitive processes. Alternatively, given that LC neurons are thought to spike synchronously, there may be a mismatch between LC and cortical neuronal codes that constrains how the noradrenergic system can influence cognition. We review new evidence that clearly demonstrates cell type-specific ensemble activity within LC occurring over a range of behaviorally-relevant timescales. We also review recent studies demonstrating that sub-sets of LC neurons modulate specific forebrain targets to control behavior. A critical target for future research is to study the temporal dynamics of projection-specific LC ensembles, their interactions with cortical networks, and the relevance of multi-scale coerular-cortical dynamics to behaviors over various timescales.

Febrile seizures and later intellectual performance.

The relationship of febrile seizures to later intellectual and academic performance was examined in a sibling-control study. Amont 431 sibling pairs tested at the age of 7 years, the mean full scale IQ on the Vechsler Intelligence Scales for Children was not different for children who had febrile seizures as compared with siblings who were seizure-free. Neither recurrent seizures nor those lasting 30 minutes or longer were associated with IQ deficit. Poor academic achievement, defined as Wide Range Achievement Test performance more than one grade level below school placement in children with IQs of 90 or above, was equally frequent in index cases and control patients. Febrile seizures were not associated with a decrement in IQ or early academic performance, as judged by comparison of affected children with their siblings.

Maternal seizure disorder, outcome of pregnancy, and neurologic abnormalities in the children.

Among 45,000 pregnant women, 21.4 per 1000 (2.1%) reported at least one seizure before or during pregnancy. During the study pregnancy, 4.4 per 1000 had a noneclamptic seizure, and another 4.5 per 1000 had one in the 5 years preceding the study. Stillbirth, microcephaly, mental retardation, and nonfebrile seizure disorders occurred with heightened frequency in the offspring of women with seizure disorders; low birthweight, neonatal seizures, and first-year deaths were not more common. Approximately 80% of the women with seizure disorders had infants with none of the unfavorable outcomes studied. The observational nature of this and other clinical studies on this topic makes it difficult to evaluate the role of medical therapy in the outcome.

The risk of recurrence of nonfebrile seizures in children.

In a prospective study, the risk of recurrence after a first postneonatal nonfebrile seizure was 61% by age 7 years. The risk of recurrence for nonsymptomatic seizures was considerably higher than for seizures attributed to immediate precipitating factors. Focal motor seizures were more likely than generalized motor seizures to recur. Children who had prior neonatal seizures were at greater risk for nonfebrile recurrence than children with no prior seizure. Family history and neurodevelopmental status were not significantly related to recurrence risk. Almost 90% of recurrences took place within 1 year, and 96% within 2 years.

Can magnesium sulfate reduce the risk of cerebral palsy in very low birthweight infants?

OBJECTIVES: To investigate whether in utero exposure to magnesium sulfate (MgSO4) was associated with a lower prevalence of cerebral palsy (CP) in infants born weighing < 1500 g. DESIGN: Singleton infants weighing < 1500 g at birth (very low birthweight, VLBW) and surviving to 3 years with moderate or severe congenital CP were identified among 155,636 children born 1983 through 1985 in four California counties. VLBW children with CP were compared with randomly selected VLBW control survivors with respect to whether their mothers received MgSO4 to prevent convulsions in preeclampsia or as a tocolytic agent, and other information abstracted from labor and delivery records. RESULTS: During the admission for delivery, 7.1% of the 42 VLBW infants with later CP and 36% of the 75 VLBW controls were exposed to MgSO4 (odds ratio (OR) .14, 95% confidence interval (CI) .05, .51). The overall association of MgSO4 with reduced risk of CP was also observed in the subgroup of infants born to women who were not preeclamptic (OR .25, CI .08, .97). Infants with CP were less often exposed antenatally to MgSO4 whether or not there was cotreatment with non-MgSO4 tocolytics (other tocolytics administered, OR for MgSO4 exposure .23, CI .06, 1.2; other tocolytics not administered, OR for MgSO4 .08, CI .02, .68), or antenatal corticosteroids (steroids given, OR for MgSO4 exposure .24, CI .06, 1.3; steroids not given, OR for MgSO4, .08, CI .02, .72). Apparent benefit of magnesium was observed in the presence or absence of a variety of characteristics of pregnancies, births, and infants. CONCLUSION: In this observational study, in utero exposure to MgSO4 was more frequent in controls than in children with CP, suggesting a protective effect of MgSO4 against CP in these VLBW infants.

Intrapartum asphyxia and cerebral palsy.

Signs of presumed hypoxia/asphyxia of the fetus are not uncommon and can be detected during labor, in the delivery room, and during the early neonatal period. Virtually no single sign or symptom has sufficient correlation to enable prediction of later cerebral palsy with a reasonable degree of medical certainty. To attribute cerebral palsy to prior asphyxia with reasonable certainty, there must be evidence that a substantial hypoxic injury occurred and that a sequence of events ensued which would prove the clinical impact of that hypoxic insult. Few cases of cerebral palsy meet these criteria.

Apgar scores as predictors of chronic neurologic disability.

Apgar scores were recorded at one and five minutes for approximately 49,000 infants, and at ten, 15, and 20 minutes for babies who did not achieve a score of 8 or higher at five minutes. These children were followed to the age of 7 years. Low Apgar scores were risk factors for cerebral palsy, but 55% of children with later cerebral palsy had Apgar scores of 7 to 10 at one minute, and 73% scored 7 to 10 at five minutes. Of 99 children who had Apgar scores of 0 to 3 at ten, 15, or 20 minutes and survived, 12 (12%) had later cerebral palsy; 11 of the 12 were also mentally retarded (in ten, IQ less than 50) and half had seizure disorders. Eight children who survived after having very low late Apgar scores and who did not have cerebral palsy had lesser but significant disabilities. Of the children who had Apgar scores of 0 to 3 at ten minutes or later and survived, 80% were free of major handicap at early school age.

Children who "outgrew' cerebral palsy.

A diagnosis of cerebral palsy was made for 229 one-year-old children enrolled in a large longitudinal study. Of these children, 118 were free of motor handicap at the age of 7 years. Mild early cerebral palsy, and the monoparetic, ataxic/dyskinetic, and diplegic forms of the disorder, resolved with high frequency. Normalization of motor signs was observed more frequently in black than in white children. However, 13% of white children and 25% of black children whose motor signs resolved were mentally retarded (IQ below 70) at 7 years of age. Nonfebrile seizures, abnormalities in speech articulation and extraocular movements, and certain abnormalities of behavior were more frequent among children who "outgrew" cerebral palsy than in the general population of the study.

Neonatal signs as predictors of cerebral palsy.

Signs of neonatal neurologic dysfunction, recorded in approximately 40,000 infants, were evaluated prospectively for their ability to predict later motor handicap. Tenfold to 33-fold increases in risk of cerebral palsy (CP) were observed in surviving children with any one of the following characteristics: birth weight less than 2,000 gm, head circumference more than 3 SD above or below the mean, five minute Apgar score of 3 or less, diminished activity or diminished cry lasting for more than one day, thermal instability, need for gavage feeding, hypotonia or hypertonia, single or multiple apneic episodes, or hematocrit less than 40%. Of worse portent, with relative risks exceeding 50, were neonatal seizures or Apgar scores of 3 or less at ten minutes or later. These characteristics were also markers of considerable risk of early death. For 0.5% of surviving infants, an overall impression of abnormality of brain function during the nursery period was recorded by the attending physician; there was a 99-fold increase in CP among these children.

Twinning and cerebral palsy: experience in four northern California counties, births 1983 through 1985.

BACKGROUND: Twinning is associated with heightened risk of cerebral palsy (CP) and is increasing in the United States and elsewhere. METHODS: Twins with moderate or severe congenital CP were identified in a cohort of 155,572 children born 1983 through 1985 in four northern California counties and surviving to 3 years. The prevalence of CP in twins and factors associated with increase in risk were examined. RESULTS: Among 2985 twins, 20 children in 18 pairs had CP. The prevalence of CP was 6.7 per thousand 3-year-old twin children (95% confidence interval [CI], 4.2 to 11), 12 per thousand twin pregnancies (95% CI, 7.2 to 19), and 1.1 per thousand singletons (95% CI, 0.97 to 1.3). Ten percent of all CP was in twins; 22% of CP in infants of less than 1500 g birth weight occurred in twins. Twins were over-represented among very low birth weight infants but their risk of CP was comparable with that of very low birth weight singletons. Twins born weighing 2500 g and more had a CP risk 3.6 times that of singletons of similar weight. In children who survived fetal death of a co-twin, CP was 108 times more prevalent (95% CI, 42 to 273) than in singletons and 13 times more prevalent (95% CI, 4.5 to 37) than in twins whose co-twin was born alive. The CP rate in unlike-sex pairs was 13 per thousand (95% CI, 4.8 to 32), not significantly different from 11 per thousand (95% CI, 5.7 to 19) for like-sex pairs. CONCLUSION: Twin pregnancies produced a child with CP 12 times more often than singleton pregnancies. The heightened risk was largely related to the tendency of twins to be low in birth weight and to a greater risk of CP in twins of normal birth weight compared with singletons of similar weight. Twins of unlike-sex pairs, necessarily dizygotic, were not at lower risk than like-sex pairs. The current increase in multiple births is likely to contribute more children with CP.

Phototherapy for neonatal hyperbilirubinemia: six-year follow-up of the National Institute of Child Health and Human Development clinical trial.

The National Institute of Child Health and Human Development Randomized, Controlled Trial of Phototherapy for Neonatal Hyperbilirubinemia was conducted to determine whether phototherapy used to control serum bilirubin is safe and is as effective in preventing brain injury as exchange transfusion. The study, conducted at six neonatal care centers, randomly assigned 1339 newborn infants to phototherapy or control groups by the following subgroups: (1) birth weight less than 2000 g; (2) birth weight 2000 to 2499 g and bilirubin level greater than 171 mumol/L (10 mg/dL); or (3) birth weight greater than or equal to 2500 g and bilirubin level greater than 222 mumol/L (13 mg/dL). Phototherapy was administered for 96 hours, and exchange transfusion was used to control hyperbilirubinemia at the same predetermined levels in both groups. Neurological and developmental examinations were conducted at 1 and 6 years of age, with follow-up rates of 83% and 62%, respectively. The two groups did not differ in mortality or diagnosed medical conditions. The phototherapy and control groups had similar rates of cerebral palsy (5.8% vs 5.9%), other motor abnormalities including clumsiness and hypotonia (11.1% vs 11.4%), and sensorineural hearing loss (1.8% vs 1.9%). The Wechsler Intelligence Scale for Children-Revised scores overall were not significantly different for the two groups (Verbal, 96.8 vs 94.8; Performance, 95.8 vs 95.1 for phototherapy and control groups, respectively). Phototherapy effectively controlled neonatal hyperbilirubinemia without evidence of adverse outcome at 6 years of age and was at least as effective as management with exchange transfusion alone.

Intelligence at six years in relation to neonatal bilirubin levels: follow-up of the National Institute of Child Health and Human Development Clinical Trial of Phototherapy.

Results of the National Institute of Child Health and Human Development Randomized Controlled Trial of Phototherapy were examined for the relationship of neonatal bilirubin level to neurological and developmental outcome at 6-year follow-up. This analysis focused on 224 control children with birth weight of less than 2000 g. Bilirubin levels were maintained below previously specified levels by the use of exchange transfusion only (24%). Rates of cerebral palsy were not significantly higher for children with elevated maximum bilirubin level than for those whose level remained low. No association was evident between maximum bilirubin level and IQ (Full Scale, Verbal, or Performance) by simple correlation analysis (r = -.087, P = .2 for Full Scale) or by multiple linear regression adjusting for factors that covary with IQ (beta = -.15, P = .58). IQ was not associated with mean bilirubin level, time and duration of exposure to bilirubin, or measures of bilirubin-albumin binding. Thus, over the range of bilirubin levels permitted in this clinical trial, there was no evidence of bilirubin toxicity to the central nervous system. Measures used to control the level of bilirubin in low birth weight neonates appear to prevent effectively the risk of bilirubin-induced neurotoxicity.

Selection of neonates for neuroprotective therapies: one set of criteria applied to a population.

OBJECTIVES: To estimate the proportion of children with cerebral palsy (CP) who had signs of birth asphyxia" in the early hours of life, and to examine the nature of the illnesses in those infants. DESIGN: Population-based case-control study. SETTING: All births in 4 northern California counties, 1983 through 1985. SUBJECTS: Eighty-four full-term singleton children surviving to age 3 years with spastic CP and 366 full-term control children. MAIN OUTCOME MEASURE: Moderate or severe spastic CP. RESULTS: Of 84 full-term children with spastic CP, 18 had 5-minute Apgar scores of less than 6, 20 required intubation for ventilation in the delivery room, and 5 had an initial blood pH of 7.00 or less. Three (3.6%) of the 84 children had all 3 signs evaluated, a prevalence of 0.019 per 1000 survivors. All 3 had neonatal seizures. When we relaxed the pH cutoff to 7.10 or less, there were 19 children with CP who met at least 2 criteria. Eight of these 19 infants were born in level I facilities. In these children there was evidence of maternal or infant infection (n = 7), abnormal coagulation factor, thrombosis, or thrombocytopenia (n = 8); or other complication predating birth (n = 9). CONCLUSIONS: Neuroprotective therapy offered to neonates with these early characteristics, even if perfectly effective, would be unlikely to prevent most CP. Most of these depressed infants with CP had nonasphyxial conditions that may have contributed to adverse neurological outcome.

Does cesarean delivery prevent cerebral palsy or other neurologic problems of childhood?

OBJECTIVE: To determine whether cesarean delivery can lead to fewer childhood neurologic problems. DATA SOURCES: We reviewed English language articles published between 1969 and 1993, obtained via MEDLINE search of the heading "delivery, abdominal." Bibliographies of book chapters and articles about cerebral palsy and other childhood neurologic disorders were also searched. METHODS OF STUDY SELECTION: We sought articles that dealt with vaginal versus cesarean delivery and the following outcomes: cerebral palsy, abnormal neurologic development, neonatal seizures, and neonatal intraventricular hemorrhage. Ten relevant studies were identified, only four of which were prospective, and only one of which (involving breech births) was a randomized trial. DATA EXTRACTION AND SYNTHESIS: No study found a significant difference in the rates of cerebral palsy, abnormal neurologic development, and neonatal seizures between those children born vaginally or by cesarean. The severity of handicap of infants born with myelomeningocele was less in those delivered via cesarean. Infants born by cesarean had a decreased risk for developing neonatal brachial plexus palsy. Cesarean delivery of mothers with human immunodeficiency virus (HIV) or with genital lesions and no history of herpes may benefit the infant. CONCLUSIONS: Cesarean delivery can reduce the risk of adverse childhood neurologic outcome for those born with myelomeningocele, and may reduce the rate of brachial plexus palsies and neonatal herpes and HIV infections. However, children born by cesarean have no documented reduced risk of other childhood neurologic problems or cerebral palsy.