CHILD DEVELOPMENT: BIOLOGY

Jonathan A. Slater, MD

Infancy: Development of Object Recognition I

Orienting of head/eyes toward objects reflects attention in early infancy

Infants follow movement at birth, but poorly discriminate objects

“Obligatory looking”—pathway from basal ganglia to superior colliculus at end of first month—gaze into eyes

Maturation of parietal lobe (increased metabolism seen) later allows disengagement (2-4 months) toward periphery

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Infancy: Development of Object Recognition II

Subcortical (mid brain) visual mechanisms develop before cortical

Novelty: Inhibition of return (IOR) favors searching in new locations: seen in newborns, not at 2-3 months, again at 4 months (reflects cortical development 4-6 months of visual system). Sustained fixation then declines, and ability to orient without shifting eye movement.

Superior colliculus lesion interferes

Development of Self-Regulation and Soothing

Caregiver behavior reflects how infant attention is used

Prior to 3 months: holding and rocking

3 months: distraction used, seen at time infants can disengage fixation from central objects and shift to periphery

Distress initially at overstimulation by light/sound, reduced when they orient toward novel stimuli

Learning

3-4 month olds can learn to anticipate the locations of visual stimuli by moving their eyes to them in advance of their presentation (triangle experiment: sequence of three successive spatial locations)

May depend on maturation of basal ganglia and parietal structures

Imaging Studies

Reduced cortical gray and white matter volumes/increased CSF in preterm infants, and are associated with poorer cognitive outcome.

Autism: temporal lobe, amygdala, medial/orbital subdivisions of frontal lobe affected

Volumetric imaging of infant brains (Brad Peterson)

Interpretation of facial expression and identifying facial identity—face related activation in fusiform gyrus along ventral surface of temporal lobe (Robert Schultz)

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Psychoneuroimmunology

Links b/t behavior, CNS, PNS, neuroendocrine hormones, immune system

Aversive stressors and disease susceptibility (viral, parasitic, neoplastic): shown in a variety of animal models

Effects depend on virulence of illness and psychosocial stressors: e.g. Macaque monkeys infected with SIV: leukopenia, wt loss and survival affected by rearing conditions (with mother or peers), number of changes in housing (familiar social group, unfamiliar group, or isolation).

Effects of Stressors on Immune Responses

Dose and time response of stressor influences immune effects, which in animals have affected lymphocyte responses, T-cell suppression, delayed hypersensitivity, GvH response, and NK activity

Social isolation: decreased proliferative responses, NKCA, macrophage-mediated cytotoxicity, increased tumor metastases.

Stressor predictability and control over stressor influence immune effects; fear determines level of immunosuppression.

Immunologic Consequences of Early Life Experiences (nonhuman primates)

Immune responses and cell numbers are sensitive to psychosocial stressors

Time at which immunity measured following stressor, environment, and age of animal influence mediate immune effects

Immunologic consequences may be long-term

Vulnerability may begin prenatally

Stress and Immunity: Clinical Studies I

Asthma and allergic rhinitis (mediated by humoral immune responses) occur more frequently in stressed children with limited coping abilities

Strep infections and ASLO titers in family members w/ high stress levels

Stress in children associated w/ recurrent colds, flu and lower salivary IgA

Separation and loss—one of multiple factors associated with childhood leukemia

Stress and Immunity: Clinical Studies II

Med students--lower NKCA and blastogenesis during finals, along with stress-related decreases in total T cells, helper T, suppressor T, and increases in IgG, IgM, IgA. Ab titers to EBV, CMV, HSV elevated and decreases in number and synthesis of IL-2 receptors on peripheral WBC’s.

Stress and Immunity: Clinical Studies III

Higher WBC, lymphs, reduced B-cell function in psychiatry trainees taking oral boards

Lifetime and past year adverse events predictive of lower NKCA in adolescents.

Parental divorce/separation associated with lower granulocyte killing of staph aureus.

Depression and Immunity in Children

Correlation b/t severity of depression and lower NKCA in hospitalized adolescents

Increased B cells, lower NKCA in CD pt’s c/w MDD and normals aged 11-18.

Depressed pre-pubertal children had lower NKCA c/w controls.

Stress and Immunity

Kindergarten Study: Children with increases in immune measures (CD4+/CD8+, response to PWM) following entrance into kindergarten had more respiratory infections following a concurrent earthquake.

Neuroendocrine
Axis and Stress

(Huizink et al, 2002)--Increased maternal prenatal stress associated with temperamental changes in infants at 8 months (new situations, unfamiliar persons, more behavioral problems); may be mediated by altered HPA axis reactivity found in prenatally stressed offspring

Pregnancy anxiety associated with decreased attention at 3 mos; PA and perceived stress—dec. attention at 8 mos.

May increase risk of future anxiety, mood and behavioral disorders

Effects of Early Handling and Maternal Deprivation

Adult rats subjected to neonatal handling

Decreased HPA axis responses to stress

mediated by up-regulation of glucocorticoid receptors in the hippocampus (Meaney et al)

Rat pups sep. from mothers in 1st 3 wks have higher corticosterone levels and greater cort responses to acute stress.

Chronic stress can result in damage to hippocampal neurons due to high circulating corticosterone levels

Increased CRF may result from maternal deprivation, increase risk of depression (found in adult monkeys whose mothers were subjected to variable foraging conditions—Coplan et al, 1996)

Alterations in Childhood Psychiatric and Behavioral Disorders I

In pathologically shy children, hypothalamic and amygdala-mediated responses to novel situations are hyperreactive

This may involve CRF, which is primary regulator of limbic sites, and may cause behavioral inhibition, increased HPA/ catecholamine/ CV responses.

Alterations in Childhood Psychiatric and Behavioral Disorders II

Cortisol hypersecretion occurs in severely depressed and suicidal children/adol requiring hosp., and during recurrence of MDD.

Increased urinary catecholamines and decreased urinary cortiosol levels seen in children/adolescents with PTSD

Autistic pt’s: decreased activity in serotonergic pathways, and alterations in DA system, GH responses and abnormal stress responses of HPA axis.

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	Orienting of head/eyes toward objects reflects attention in early infancy
	Infants follow movement at birth, but poorly discriminate objects
	“Obligatory looking”—pathway from basal ganglia to superior colliculus at end of first month—gaze into eyes
	Maturation of parietal lobe (increased metabolism seen) later allows disengagement (2-4 months) toward periphery


	Subcortical (mid brain) visual mechanisms develop before cortical
	Novelty: Inhibition of return (IOR) favors searching in new locations: seen in newborns, not at 2-3 months, again at 4 months (reflects cortical development 4-6 months of visual system). Sustained fixation then declines, and ability to orient without shifting eye movement.
	Superior colliculus lesion interferes


	Caregiver behavior reflects how infant attention is used
	Prior to 3 months: holding and rocking
	3 months: distraction used, seen at time infants can disengage fixation from central objects and shift to periphery
	Distress initially at overstimulation by light/sound, reduced when they orient toward novel stimuli


	3-4 month olds can learn to anticipate the locations of visual stimuli by moving their eyes to them in advance of their presentation (triangle experiment: sequence of three successive spatial locations)
	May depend on maturation of basal ganglia and parietal structures


	Reduced cortical gray and white matter volumes/increased CSF in preterm infants, and are associated with poorer cognitive outcome.
	Autism: temporal lobe, amygdala, medial/orbital subdivisions of frontal lobe affected
	Volumetric imaging of infant brains (Brad Peterson)
	Interpretation of facial expression and identifying facial identity—face related activation in fusiform gyrus along ventral surface of temporal lobe (Robert Schultz)


	Links b/t behavior, CNS, PNS, neuroendocrine hormones, immune system
	Aversive stressors and disease susceptibility (viral, parasitic, neoplastic): shown in a variety of animal models
	Effects depend on virulence of illness and psychosocial stressors: e.g. Macaque monkeys infected with SIV: leukopenia, wt loss and survival affected by rearing conditions (with mother or peers), number of changes in housing (familiar social group, unfamiliar group, or isolation).


	Dose and time response of stressor influences immune effects, which in animals have affected lymphocyte responses, T-cell suppression, delayed hypersensitivity, GvH response, and NK activity
	Social isolation: decreased proliferative responses, NKCA, macrophage-mediated cytotoxicity, increased tumor metastases.
	Stressor predictability and control over stressor influence immune effects; fear determines level of immunosuppression.


	Immune responses and cell numbers are sensitive to psychosocial stressors
	Time at which immunity measured following stressor, environment, and age of animal influence mediate immune effects
	Immunologic consequences may be long-term
	Vulnerability may begin prenatally


	Asthma and allergic rhinitis (mediated by humoral immune responses) occur more frequently in stressed children with limited coping abilities
	Strep infections and ASLO titers in family members w/ high stress levels
	Stress in children associated w/ recurrent colds, flu and lower salivary IgA
	Separation and loss—one of multiple factors associated with childhood leukemia


	Med students--lower NKCA and blastogenesis during finals, along with stress-related decreases in total T cells, helper T, suppressor T, and increases in IgG, IgM, IgA. Ab titers to EBV, CMV, HSV elevated and decreases in number and synthesis of IL-2 receptors on peripheral WBC’s.


	Higher WBC, lymphs, reduced B-cell function in psychiatry trainees taking oral boards
	Lifetime and past year adverse events predictive of lower NKCA in adolescents.
	Parental divorce/separation associated with lower granulocyte killing of staph aureus.


	Correlation b/t severity of depression and lower NKCA in hospitalized adolescents
	Increased B cells, lower NKCA in CD pt’s c/w MDD and normals aged 11-18.
	Depressed pre-pubertal children had lower NKCA c/w controls.


	Kindergarten Study: Children with increases in immune measures (CD4+/CD8+, response to PWM) following entrance into kindergarten had more respiratory infections following a concurrent earthquake.


	(Huizink et al, 2002)--Increased maternal prenatal stress associated with temperamental changes in infants at 8 months (new situations, unfamiliar persons, more behavioral problems); may be mediated by altered HPA axis reactivity found in prenatally stressed offspring
	Pregnancy anxiety associated with decreased attention at 3 mos; PA and perceived stress—dec. attention at 8 mos.
	May increase risk of future anxiety, mood and behavioral disorders


Adult rats subjected to neonatal handling
	Decreased HPA axis responses to stress
		mediated by up-regulation of glucocorticoid receptors in the hippocampus (Meaney et al)
Rat pups sep. from mothers in 1st 3 wks have higher corticosterone levels and greater cort responses to acute stress.
Chronic stress can result in damage to hippocampal neurons due to high circulating corticosterone levels
Increased CRF may result from maternal deprivation, increase risk of depression (found in adult monkeys whose mothers were subjected to variable foraging conditions—Coplan et al, 1996)


	In pathologically shy children, hypothalamic and amygdala-mediated responses to novel situations are hyperreactive
	This may involve CRF, which is primary regulator of limbic sites, and may cause behavioral inhibition, increased HPA/ catecholamine/ CV responses.


	Cortisol hypersecretion occurs in severely depressed and suicidal children/adol requiring hosp., and during recurrence of MDD.
	Increased urinary catecholamines and decreased urinary cortiosol levels seen in children/adolescents with PTSD
	Autistic pt’s: decreased activity in serotonergic pathways, and alterations in DA system, GH responses and abnormal stress responses of HPA axis.