Factors That Contribute to Cognitive and Neurobehavioral

1. Factors That Contribute to Cognitive and Neurobehavioral Deficits in Premature Graduates of Intensive Care Jeffrey Perlman MB Professor of Pediatrics Weill Medical College Cornell Medical Center New York

2. Background • The survival rates of VLBW infants including those born at the cutting edge of viability continues to increase. In addition there has been a concomitant reduction in the occurrence of known neurosonographic correlates of adverse outcome i.e severe IVH • However as follow-up has extended into school age and adolescence it has become apparent that a large number of graduates are exhibiting neurobehavioral problems in the absence of cerebral palsy.

3. Summary of Long Term Cognitive/Behavioral Deficits in in VLBW infants at Longer Term (6-14 years) Follow up • The academic achievement of approximately 30-50% of VLBW infants is in the subnormal range. • VLBW infants have IQ scores approximately 1 SD lower than full term controls. This has been documented worldwide and independent of social environment particularly in those countries with homogeneous populations. • The attention deficit hyperactivity disorder affects approximately 20-30% of VLBW infants as compared to 6-8% of full term controls. • Psychiatric disorders at adolescence affect from 25-30% of VLBW infants as compared 5-10% of full term controls.

4. Survival (%) of Very Low Birth Weight Infants Admitted to the NICU at Parkland Hospital for years 1980-2000. 1980- 1985 1986- 1990 1991- 1995 1996- 2000 % Survival

5. 18 month Outcome of VLBW infants < 1000g Birth weight in the NICHD for the period 1996-1998 • 55/220 (25%) with an abnormal CNS examination e.g. cerebral palsy • 103/220 (47%) with a MDI < 70

6. Birth Rates in the US - 2000 Births Number Total Births 4064948 < 2500g (7.6%) 308936 <1500g (1.42%) 56909 <1000g ( 0.65%) 26422 From Hoyert et al Annual Summary of Vital Statistics : 2000 Pediatrics 2001;108:1241

7. Outline • Describe vulnerable regions in developing brain that increase risk for cognitive injury • Review some medical complications and interventions association with prematurity that increase risk for cognitive injury • Review potential environmental factors that may contribute to the genesis of cognitive injury.

8. Factors/Events Increasing the Propensity for Brain Injury • Hemorrhagic-ischemic white matter injury • Disruption of one or more organizational events in brain development • Transient overexpression of glutamatergic receptors within basal ganglia • Hippocampal vulnerability to hypoxia/ischemia and /or stress

9. Severe IVH (Grade 4 IVH) Cystic PVL

10. Ultrasound Status and Global Cognitive Functioning Global Cognitive Total Normal IVH PL/VD Outcomes (n=597) (n=468) (N=83) (N=46) Normal Intelligence 529 (89%) 436 (93%) 73 (88%) 20 (43.5%) Borderline Intelligence 38 (6.0%) 26 (5.6%) 5 (6.0%) 7 (15.2%) Mental Retardation 30 (5.0%) 6 (1.3%) 5 (6.0%) 19 (41.0%) Normal Intelligence – Stanford Binet composite > 84, Borderline < 84, Mental Retardation < 68 IVH = germinal and intraventricular hemorrhage PL = Parenchymal lesion, VD = Ventricular Dilation From Whitaker et al. Pediatrics 1996;98:719

11. Factors/Events Increasing the Propensity for Brain Injury • Hemorrhagic-ischemic white matter injury • Disruption of one or more organizational events in brain development • Transient overexpression of glutaminergic receptors within basal ganglia • Hippocampal vulnerability to hypoxia/ischemia and /or stress

12. Lateral Ventricle Coronal Section of Brain Illustrating Potentially Vulnerable Areas of a Developing Brain Caudate Nucleus Periventricular White Matter Thalamus Lentiform Nucleus Claustrum Hippocampus

13. The Potential Importance of the Basal Ganglia to Cognitive Injury • The Basal ganglia (BG) and more specifically the corpus striatum play a central role in the feedback loop that modulates cortical function. Disruption of cortico-striatal function seem to be of particular importance with regard to neurobehavioral abnormalities. • The BG are vulnerable to injury during a restricted period during brain development. One important reason is that the neurons areenormously rich in glutaminergic synapses which emanate from the cerebral cortex • Several lines of evidence point to the importance of excitatory amino acids and in particular glutamate in the genesis of neuronal death with hypoxia and or ischemia.

14. Cranial Ultrasound Scan From an Infant with Linear Hyperechogenicity Supplying the Basal Ganglia

15. Linear Hyperechogenicity (LHE)within Basal Ganglia and Thalamus • LHE was observed in 10/193 (5%) infants < 1250g birth weight • The postnatal age to initial sonographic diagnosis was 4 weeks (range 1-11weeks) • Infants with LHE versus matched controls were more likely to have received: Antenatal Steroids 90% vs 45%, p= 0.02 Test positive for CMV 44% vs 0%, p= 0.02 Treated for hypothyroidism 30% vs 0%, p= 0.03 Chamnanvanakij et al Pediatr Neurol 2000:23;129

16. Bayley Scales of Infant Development assessment at 18 months adjusted age Data are presented as mean  S.D. BSID= Bayley Scale of Infant Development BRS = Behavioral Rating Scale

17. Lateral Ventricle Coronal Section of Brain Illustrating Potentially Vulnerable Areas of a Developing Brain Caudate Nucleus Periventricular White Matter Thalamus Lentiform Nucleus Claustrum Hippocampus

18. Hippocampal Vulnerability • The hippocampus is important to learning and memory • acquisition. • It is especially vulnerable to hypoxia and is a target of • stress hormones. • Vulnerability may be increased in developing brain in • VLBW infants in part as a result of: • a) Increased glutamate recognition sites • b) High dependency on thyroid hormone • c) Excessive glucocorticoid (GC)exposure secondary • to medications/stress

19. Hippocampal Volume and Everyday Memory in Very Low Birth Weight Children Test/Variable Preterms Full-Term N=11 n=8 p values Verbal IQ 90 (79-111) 108.5 (89-133) 0.02 Freedom from distraction 94 (66-106) 106.5 (84-140) 0.006 Mathematics reasoning 93 (79-110) 107.5 (93-124) 0.02 Numerical operations 81 (71-103) 107.5 (94-119) 0.001 Volumetric measurements Intracranial Volume 1436 (1284-1603) 1466 (1324-1650) NS Lt Hippocampus 3390 (3147-3812) 4080(3559-4291) 0.002 Rt Hippocampus 3379 (2949-3888) 4012 (3637-4297) 0.002 Values are median (range) Isaacs et al Pediatric Res 2000;47:713

20. Factors/Events Predisposing to Cognitive Injury in Developing Brain of VLBW Infants Vulnerable Brain RegionsPrimary Medical ProblemsGerminal Matrix   Chronic Lung Disease   Periventricular White Matter   Apnea and Bradycardia   Subplate Neurons   Nutrition   Thalamus/Basal Ganglia   Hypothyroidism  Hippocampus  Infections   Medications e.g. Steroids  Hyperbilirubinemia Environment  Parent-Child Interaction  Excessive Sound  Constant Light

21. Chronic Lung Disease (CLD) and Adverse Neurodevelopmental Outcome • Approximately 40% Of VLBW < 1000g develop CLD • CNS findings attributed to CLD include - - Progressive neurologic disease i.e seizures, neurologic deterioration and death; - Non progressive neurologic disease - often with associated IVH - Movement disorder • Neuropathology often demonstrates diffuse hypoxic and/or ischemic changes involving gray and white matter • CLD is an independent risk factor for abnormal neurologic outcome(OR:1.84;CI 1.28-2.61) • Most of these descriptions of CNS abnormalities preceded the use of postnatal steroids Campbell Clin Ped 1988;27:7, Perlman Pediatrics 1989 Vohr Pediatrics 2000;105:1216.

22. Recurrent hypoxia Hypercarbia  Acidosis Recurrent infections Medications - steroids - diuretics Nutritional compromise Potential Mechanisms of Injury in Infants who develop Chronic Lung Disease

23. Head Growth in an Infant with Bronchopulmonary Dysplasia Moore et al Pediatrics 1986

24. Glucocorticoids (GC) and the Risk for Brain Injury • Recent data suggest that GC are associated with  incidence of adverse neurodevelopmental outcome. • Sustained elevations of GC can modify the structure and function of the developing brain including: -  CBF to hippocampus -  white matter proteins, - delayed myelination of optic axons, -  activity of hypothalamic-pituitary-adrenal axis • CLD is associated with neurodevelopmental deficits

25. Recurrent Apnea and Bradycardia and the Potential for Cognitive Deficits • Apnea with associated bradycardia is a common problem and affects up to 90% of VLBW infants. • With prolonged bradycardia there is progressive hypotension with an  risk for a reduction in CBF. • Data linking apnea and bradycardia to abnormal outcome is conflicting. • Medications used to treat apnea e.g. theophylline may  risk for brain injury • A recent study reported an association of mental retardation ( MDI < 70) with the duration as well as the dose of doxapram Sreenan et al J Pediatr 2001;39:832

26. Factors/Events Predisposing to Cognitive Injury in Developing Brain of VLBW Infants Vulnerable Brain RegionsPrimary Medical ProblemsGerminal Matrix   Chronic Lung Disease   Periventricular White Matter   Apnea and Bradycardia   Subplate Neurons   Nutrition   Thalamus/Basal Ganglia   Hypothyroidism  Hippocampus  Infections   Medications e.g. Steroids  Hyperbilirubinemia Environment  Parent-Child Interaction  Excessive Sound  Constant Light

27. Foundation Fact Infants in a busy NICU are frequently exposed to stressful environmental conditions on a daily basis. Examples include attachment to multiple monitoring devices and intravenous lines that invariably limit positive caregiver or parental interactions, high noise levels, and variable bright light. Sustained stress in the NICU may have adverse effects on brain development.

29. Is stress bad for the brain? • Sustained exposure to stress with release of glucocorticoids can result in hippocampal degeneration. • Monkeys who died suddenly with gastric ulcers had marked hippocampal degeneration versus controls without ulcers. • Depressed patients with  GC secretion had bilateral reduced hippocampal volumes compared to age matched controls • Vietnam vets with posttraumatic stress disorder had smaller hippocampal volumes and had deficits in short term verbal when compared to controls • Premature infants < 30 wks GA examined at adolescence with MRI and neuropsychologic testing had comparable head circumferences and normal neurologic examinationsbut  hippocampal volumes and specific deficits in everyday memory and mathematics when compared to term controls Uno J Neurosci 93,1996.1989, Sapolsky Science 273,1996,Seline Proc. Natl.Acad Sci Brenner Am J Psychiatry 152,1995, Isaacs Pediatr Res 2000

30. Postnatal handling Increases Glucocorticoid Receptor expression and alters Corticotrophin Releasing Hormone response to stress Handling  Pituitary-Thyroid Activation Propylthiouracil Triodothyronine  Hippocampus Ketanserin  Serotonin   Cyclic AMP  Protein Kinase A  Nerve Growth Factor  Inducible Factor A  Activator Protein 2 (AP2)   GC receptor

31. Positive Impact of Handling in Newborn Rats • Rats handled daily from birth until weaning (DOL 22) had  basal GC levels and secreted less GC in response to stress at all ages tested when compared to non handled rats. • Non handled rats exhibited hippocampal cell loss and spatial memory deficits , findings that were almost absent in the handled rats • Handling had no effect on NGF1-A or AP2 expression in amygdala, hypothalamus or somatosensory cortex. Moreover handling had no effect on mineralocorticoid receptor expression in hippocampal neurons

32. Potential Mechanisms of Glucocorticoid Induced Hippocampal Injury •  Extracellular glutamate activity • Blockade of glucose entry into neurons thereby altering intracellular metabolism and increasing vulnerability during stress i.e. with hypoxia •  toxicity to oxygen free radicals

33. Environmental Enrichment Induces Experience Induced Neuroplasticity • Mice reared in an enriched environment demonstrate an increase in hippocampal granular cell layer and dentate gyral volume. • When subjected to spatial learning tasks “enriched mice” performed better with fewer errors than non-enriched mice •  GC and NGFI receptor expression was noted in “enriched” mice.

34. Hippocampal Volume and Everyday Memory in Very Low Birth Weight Children Volumetric Preterms Full-Term Measurements N=11 n=8 p values Intracranial Volume 1436 (1284-1603) 1466 (1324-1650) NS Lt Hippocampus 3390 (3147-3812) 4080(3559-4291) 0.002 Rt Hippocampus 3379 (2949-3888 4012 (3637-4297) 0.002 Values are median (range) Isaacs et al Pediatric Res 2000;47:713

35. Stress Glucocorticoid Release Hippocampal Injury Hippocampal Volume Loss

36. Environmental Stress and The Potential Impact on Cognitive Development • Parent-Child Interaction- Positive intervention - kangaroo care • Excessive Sound • Constant Light

37. Noise and Infant Development • Constant loud noise may impact upon neurodevelopment. • For example chicks that have a structural and auditory development similar to humans, stop peeping in response to a novel auditory stimulus. However when stimuli are repeated several times, the chicks habituate and no longer pause following a stimulus. • In the NICU loud noise (~ 80dB) is associated with  O2 and altered behavioral and physiological responses. • A recent survey of adult hospital employees indicated that noise levels > 55dB were high enough to interfere with work and appeared to affect comfort and anxiety.

38. Noise levels in Room 306 Isolette 50-60 Talking 70-80 on rounds Cleaning 60-80 Baby crying 60-100

39. Environmental Stress and The Potential Impact on Cognitive Development • Parent-Child Interaction • Excessive Sound - Positive Intervention- Music • Constant Light

40. Bright Light • The ability to modify light is critical to the development of circadian rhythms (CR). • CR are endogenously generated with a periodicity of approximately 24 hours and affect behavior and physiology e.g. sleep wake cycles. It is necessary to reset the clock each day, otherwise endogenous clock oscillations run free or out of phase with the external light dark cycle. • Although the fetal biological clock is capable of generating CR and responding to maternal signals, cyclical lighting does not appear to induce an earlier onset of postnatal circadian development.

43. Parkland NICU -Old Style NICU-State of the Art Cyclical Recessed Lighting Individualized Music Relaxed Atmosphere Average Noise Level 50-55dB

44. Complex Issues Related to Environmental Stimulation • The potential developmental impact of environmental enrichment or stimulation is complex, and influenced in part by factors such as the timing or mode of stimulation. • Thus premature visual stimulation of quail embryos before hatching is associated with earlier postnatal development of social preferences. However chicks with accelerated visual patterning, fail to demonstrate typical auditory responsiveness to maternal cues. • Furthermore it appears that a combination rather than a single stimulation is necessary for early intersensory functioning.

45. Medical and Environmental Factors Potentially Influencing Glucocorticoid Release and Hippocampal Injury CLD A+B Hypothyroidism Bilirubin Steroids Stress Environmental Stimulation Music Kangaroo care Hippocampal GC Receptor

46. Conclusions • A substantial number of VLBW graduates of intensive care develop cognitive and behavioral problems, even in the absence of neuro-imaging abnormalities. • Both medical complications of prematurity and therapeutic interventions coupled with a stressful environment greatly increase the risk for basal ganglia and hippocampal injury. • This talk is not all encompassing and there are additional prenatal (i.e. in utero stress, drug exposure), neonatal (i.e.infectious) and post discharge social and environmental contributing factors. • The design of any intervention strategy has to account for these multiple variables.