Week 5 (Neural and Behavioral Development) Flashcards
Mental disorders where developmental abnormalities are likely to be involved
Autism Spectrum Disorders (ASD)
Attention deficit hyperactivity disorder (ADHD)
Schizophrenia
Fetal Alcohol Syndrome (FAS)
Note: may be due to genetic associations, exposure of toxins
When is the “risk period” for exposure of CNS to toxins?
All throughout pregnancy and even through childhood and adolescence (brain weight increases 3 fold from birth to young adulthood!)
Significant develomental changes occur in cerebral cortex and in myelination until end of 2nd decade
Note: different from other developmental problems where toxin exposure during first trimester is worst
Embryonic regions of neural tube and the parts of the brain they give rise to
Forebain (prosencephalon) –> telencephalon –> cerebral hemispheres
Forebrain (prosencephalon) –> diencephalon –> thalamus and hypothalamus
Midbrain (mesencephalon) –> Mesencephalon –> midbrain
Hindbrain (rhombencephalon) –> metencephalon –> pons and cerebellum
Hindbrain (rhombencephalon) –> myelencephalon –> medulla
Spina bifida
Abnormal closure of neural tube during weeks 3 and 4
1/1000 births in US
Lack of folic acid intake before conception and during pregnancy
Spina bifida occulta: vertebrae do not fuse across the top; dura intact and no structural hermiation; hairs or dimple at level of defect; usually seen at lower vertebral levels
Meningocele: vertebrae do not fuse across the top; meningial coverings of spinal cord enlarged and bulge out under skin but spinal cord itself still in place
Meningomyelocele: vertebrae do not fuse across the top; cord itself is bulging out into skin area (serious vulnerability for permanent damage to spinal cord)
How/where does massive cell proliferation occur during embryogenesis?
Massive cell proliferation occurrs primarily in periventricular germinal zones (on one side of the neural tube)
Periventricular regions contain neural stem cells (NSC) that generate neural progenitors (embryonic stem cells, transition “stem” cells, multipotent neural stem cells, committed neural progenitors)
Cellular differentiation during development
NSCs in a particular region initially generate neurons then astrocytes then oligodendrocytes
Cellular differentiation is regulated by molecular signals that include protein growth factors (FGF, EGF, IGF, BMP, NGF, etc), retinoic acid (accelerates maturation of stem cells too early which is bad!), transmitters
Environmental toxins that interfere with or mimic these signaling mechanisms can disturb cell division/differentiation and cause developmental abnormalities
Different processes going on simultaneously in diff regions so toxins or ischemia may affect one region and not another, or may affect different regions at different times
Periventricular Leukomalacia (PVL)
Failure to develop white matter secondary to periventricular ischemia during gestation
Highest vulnerability during 26-36 weeks gestation
Premature infants at particular risk
Periventricular ischemia leads to loss of oligodendrocyte progenitor cells in periventricular tissue (and other things)
Juvenile and adult neurogenesis
Multipotent neural stem cells in periventricular regions of juvenile and adult CNS can be propagated in tissue culture and give rise to neurons, astrocytes and oligodendrocytes
Function in vivo not yet well established: give rise to certain neurons and glia, replace cells after injury or disease, tumor stem cell hypothesis (are adult NSC a source of cancer stem cells for glioma?)
NSCs in hippocampal dentate gyrus
NSCs persist throughout life in hippocampal dentate gyrus
New neurons are born and incorporated there throughout life (total number of neurons stays stable though because neurons die)
Neurons may be important in: formation of certain types of new memories, certain types of seizure disorders
Behavioral effects of chemotherapy
“Chemobrain” when you get cognitive disturbances after chemotherapy
May be due to toxic effects on adult NSCs and reductions in adult hippocampal neurogenesis
Cell migration in the brain
Spatial organization in CNS is achieved by cell migration
Periventricular regions contain NSCs that generate neural progenitors that then migrate away
Cell migration guided by molecular cues (integrins, NCAMs, laminin, fibronectin, ephrins, semaphorins)
Neuroblasts and neurons migrate along processes of radial glia
Cell migration proceeds from inside (ventricular zone) to outside (surface of brain/pia) and occurs over a long period of time during gestation
Deeper layers of cortex (zone VI) form first, then V, then IV, then III, etc
When does generation of cortical neurons occur during gestation?
Cortical neurogenesis is from 2 months to at least 8 months of gestation
Radial glia
Guide neurons during development, then turn into astrocytes
Note: Alcohol causes premature transformation of radial glia into astrocytes, which disrupts migration of cortical neurons and disturbs cortical development
Growth of connections
Neural connections are formed by axonal migration
Axonal growth and migration are achieved by growth cones (contains machinery in it, and new membrane is added immediately behind the growth cone)
Direction of axonal migration controlled by positive and negative guidance cues that attract or repulse growth cones, in particular the filopodia
Guidance cues can be contact-mediated or diffusion-mediated
Synapse formation (synaptogenesis)
Mature synapses are complex structures with high densities of many different kinds of molecules (adhesion, structural, receptors, ion channels, second messengers)
Formation of individual synapses can occur quickly (minutes to hours) and begins with spine formation and interaction of adhesion molecules followed by accumulation of vesicles and other structural elements
Synaptogenesis begins during first trimester, continues throughout gestation and juvenile development, is ongoing to some degree throughout adult life (and aging) where it is an essential part of synaptic plasticity
Synapse density in cerebral cortex
Increases rapidly during 3rd trimester of gestation and first postnatal year
Peaks in visual and auditory cortices at 1 year postnatal
Peaks in frontal cortex at 4-5 years postnatal
Is subject to “pruning” after peaking
Myelination
In CNS, myelination achieved by oligodendrocytes
Oligodendrocytes derive from periventricular progenitors and migrate to where they are active
Very few axon tracts myelinated at birth, most occurs after birth and proceeds until end of teenage years
Many developmental milestones (walking, talking) correlate with myelination
Disturbances in myelination result in functional defects
Myelination can be assessed in vivo during childhood development using MRI
What happens to white and grey matter throughout childhood and adolescence
White matter increases and grey matter decreases
Not losing neurons, but losing synapses, which accounts for decrease in grey matter
Obesogens
Environmental toxins that may cause fetus to grow up to be obese
Pesticides (fungicides), phthalates (shampoos, cosmetics), BPA (in plastic), about 20 substances total
Developmental age groups
Infancy: 0-12 months
Toddlers: 12-36 months
Preschool: 3-5 years
School-age: 6-12 years
Adolescence: 13-18 years
Behaviorism
John Watson said “give me a dozen healthy infants…I can train them to become anything I want–doctor, lawyer, artist, thief, etc”
Emphasis on nurture over nature
Jean Piaget
Nature and nurture are interactive and inseparable
Cognitive development occurs in stages and each stage contingent on the one before
Each stage represents qualitative change in cognitive conceptual structures, not just an increase in knowledge
Schemas: building blocks of knowledge (dog is four legged and furry –> later on…that barks and slobbers)
Piaget’s cognitive stages
Sensorimotor (0-2 years): infant explores world through direct sensory and motor contact; object permanence and separation anxiety develop during this stage
Preoperational (2-6 years): child uses symbols (words and images) to represent objects but does not reason logically; has ability to pretend; is egocentric
Concrete operational (7-12 years): child can think logically about concrete objects and can add and subtract; understands conservation
Formal operational (12-adult): adolescent can reason abstractly and think in hypothetical terms
Erik Erikson’s stages of psychological development
Basic trust vs. mistrust (0-1 years): children develop sense of trust when caregivers provide reliable care; success leads to trust
Autonomy vs. shame and doubt (1-3 years): children need to develop a sense of personal control over skills; success leads to autonomy
Initiative vs. guilt (3-5 years): children need to begin to assert power and control over their environment; success leads to sense of purpose
Industry vs. inferiority (5-11 years): children need to cope with new social and academic demands; success leads to sense of competence
Ego identity vs. role diffusion (11-21 years): teens need to develop sense of self and personal identity; success leads to ability to stay true to oneself
Temperament in infancy
Way in which child interacts and responds to his/her environment
Can change over time with environment
Easy, slow-to-warm-up, difficult = 40%, 15%, 10%
Gross motor developmental milestones
Infancy:
6 weeks: controls head when held upright
4 months: rolls front to back
6 months: rolls back to front and sits unattended
9 months: pulls to stand
12 months: starts to walk unattended
Toddlers:
15 months: crawl up stairs, walk backwards
18 months: walk stairs with help and run
24 months: ball skills and walk on tip-toes
30 months: jump
36 months: alternate feet up stairs
Preschool:
3 years: use of utensils, broad jump, gallop (most show hand preference by age 3)
4 years: alternate feet down stairs, hop and skip
5 years: balance 10 seconds on one foot and print letters
School age: refined coordination for sports/fine arts
Fine motor developmental milestones
Infancy:
6 weeks: reaches for objects
4 months: grasps objects
6 months: transfers objects across midline and puts objects in mouth
9 months: plays pat-a-cake and uses refined pincer grasp
12 months: tower of 3 blocks
Toddlers:
18 months: scribble
24 months: put on garments
36 months: 9 blocks; bridge of blocks; R/L preference
School age: cursive, typing
Language developmental milestones
Infancy:
1 month: responds to directed call
3 month: coos
6 months: babbles (mama, dada) inappropriately
9 months: mama and dada appropriately
12 months: follows simple commands, at least 1 word
Toddlers:
2 years: 2 words; 50% intelligible; follow 2-step commands
3 years: 3 words (phrases); 75% intelligible; follow multi-step commands
4 years: 4 words (sentences); 100% intelligible
Preschool: conversation, feelings, talk about past
School age: inferences, jokes, sarcasm, reading
Adolescence: comprehend double meanings, make inferences
Social-emotional developmental milestones
Infancy:
3 months: responsive smile
6 months: sense of self and attachment with caregiver
9 months: separation and stranger anxiety
12 months: beginning of empathy
Toddler: increasing anxiety over separation and seek extra support when returning, but as comfort level with separation increases, length of separation increases
Preschool:
3 years: toilet trained, know own age and gender, play imaginative, take turns, share
4 years: interactive play in small groups, pretend social scenarios and role playing
4-5 years: simple board games, follow rules
School age: accomplishment, best friend, segregate by gender, sportsmanship
Adolescence: peer group sets standard, individuality from parents, romantic relationships, hobbies, etc
Cognition developmental milestones
Infancy:
0-4 months: modify/regulate primitive reflexes
4-8 months: manipulate objects meaningfully
7 months: attention span is 5 minutes
9 months: object permanence
8-12 months: goal-directed behavior
Toddlers:
12-18 months: cause and effect
15 months: functional play (push the car) and early representational play (toy phone)
18-24 months: symbolic representation and body parts
24 months: start of simple concepts (size, color, number)
Preschool:
3-4 years: identify colors
4-5 years: identify complex body parts
5-6 years: understand abstract symbols (letters, numbers)
School age: conservation, reasoning, organization (HW), active working memory, attn span 1 hour
Adolescence: abstract thinking, hypotheses, deductive reasoning, speculate and consider alternative possibilities (can lead to idealism)
Assessment tools
Parent questionnaires and examiner based assessments
Early development: Denver Developmental Assessment and Mullen scales of Early Learning (ages 0-5)
Cognitive assessments: WPPSI (ages 3-7), WISC-IV (ages 6-16)
How do neural circuits develop?
Incorporates mechanisms that are able to deal with targeting errors and with influences that derive from interactions with the environment
Regressive events
Prominent features of neural development
Naturally occurring cell death
Pruning exuberant connections and synapses (reduction in grey matter during childhood and adolescence)
Combinations of synaptic plasticity and regressive events during juvenile development allow interactions with the environment to “sculpt” neural systems in permanent or long lasting ways: “critical periods,” language, ocular dominance, colonization of “unused” cortex
Naturally occurring cell death
Plays central role in the formation of neural circuits
More neurons are born than are needed
Only those neurons survive that make connections to appropriate target neurons
Survival is determined by retrograde transport of trophic factor produced by target cells!
Neurotrophic growth factors (NTF) produced by target neurons
Neuronal survival is supported by neurotrophic growth factors (NTF) that are produced by target neurons and are retrogradely transported by input neurons
Afferent (signaler) neuron must be active in order to cause target neuron to secrete NTF though!
External (environmental) factors that influence target neural activity can alter trophic factor production and influence circuit development!
Pruning exuberant axonal connections
Pruning of connections plays a central role in the formation of neural circuits
More connections are made than are needed
Only appropriate connections are maintained
Maintenance of connections is determined by neural activity and by trophic factors produced by target cells
Axons can overshoot their normal targets by long distances and send out many exuberant branches that are either pruned or in some cases persist on the basis of activity dependent interactions.
How can environment affect neuronal survival?
Environmental factors that influence target cell activity and trophic factor production can sculpt circuit development by influencing afferent neuronal survival and the maintenance of connections
Environmental factors that influence target cell activity by the afferent neuron can regulate trophic factor production by the target neuron, which in turn can sculpt circuit development by influencing afferent neuronal survival and synaptic connections
If no activity, whole connection pruned
If weak activity, synapses may be pruned
If highly active, synapse strengthened
NGF
Founding member of the neurotrophin family
Can activate multiple signaling pathways that influence different cellular processes (PI3 kinase for cell survival and ras and PLC pathways for neurite outgrowth and neuronal differentiation)
Other molecules that act as developmental growth factors
BDNF, NT3, NT4/5
These are structurally related to NGF but also have other functions in mature animals (other than developmental growth factors)
Neurotrophins
NGF, BDNF, NT3, NT4/5, CNTF, FGFs, IGF, EGF, thrombospondin (produced by astrocytes)
Capable of complex signalling interactions that can influence many different cellular activities during development and after maturity (cell survival, neurite outgrowth and neuronal differentiation, activity-dependent plasticity, cell cycle arrest, cell death)
Different neurotrophins, alone or in combination, help to determine final pattern of connectivity of sensory neurons in the peripheral nervous system by mediating target effects on regressive effects that determine which neurons and terminals survive pruning
Molecules other than neurotrophic factors that have effects on developing nervous system
Steroids (sex and adrenal)
Thyroxin
Transmitters
Etc
Synapse plasticity and synapse formation
New growth in the form of terminal sprouting, dendritic branching and synapse formation are important aspects of juvenile neural development that add substantially to tissue volume
Synapse formation also “sculpted” by environmental interactions or influenced by exposure to hormones, toxins and other molecules
Note: neuropil fills space between neurons with dendritic branches and synapses, which is a lot of space, so changes in neuropil volume (which correlates with synapse density) can be measured in MRI scans
Synaptic pruning in adolescents with schizophrenia
Adolescents with schizophrenia have decreased grey matter in cortex
This loss may correlate with increased synaptic pruning and decreased synaptic density
Critical periods in development
Developmental windows in which anatomical connections and functional properties of neural cells and circuits can be modified by experience (AKA environmental interactions during juvenile development can have permanent effects on CNS structure)
Changes (increases or decreases) in activity during the brief developmental “critical periods” can cause permanent changes in CNS structure
Critical periods are windows of opportunity–activity that occurs after a critical period has passed will not be able to establish the normal adult pattern of structure
Loss of activity in adults does not alter the established structural pattern in adults in the same way as loss of activity during the critical period
The time of critical period varies with systems
Examples at the behavioral level: parent imprinting in birds, language in humans (learn language with no accent if 3-7yo)
Example at the cellular level: visual system
Critical period for primary visual cortex
Evidence for environmental regulation (pruning) of afferent axon terminals in ocular dominance columns in the primary visual cortex
During development, projections from both eyes initially overlap, followed by progressive segregation of projections into separated domains for each eye by pruning of exuberant collateral branches (this segregation requires stimulation in the form of light activation of the retina)
If light activation of retina and pathways is blocked in one eye during critical period of development (2-3 months), then the pathways of the activated eye survive, while those of the un-activated eye are pruned
Clinical therapy for amblyopia based on recognition of critical period importance
Amblyopia is abnormal development of visual cortex due to deprivation of vision in one or both eyes during childhood due to strabismus, congenital cataract or other causes
Untreated strabismus can lead to domination of visual cortex development by one eye, with consequent failure of development of binocular vision
Treatment consists of achieving binocular stimulation of the visual cortices by use of eye patches (over dominant eye) or glasses (or surgery to adjust extra-ocular muscles)
Treatment is most effective when initiated before 5 years of age, and is somewhat effective in teenagers and less so in adults
Colonization of “unused” cortex
In sighted people, V1 is the primary visual cortex
In the blind (from birth), V1 can be used for verbal memory
Mental disorders where developmental abnormalities are known or suspected
Autism Spectrum Disorders (ASD)
Attention deficit hyperactivity disorder (ADHD)
Schizophrenia
Fetal alcohol syndrome (FAS)
(Drugs of abuse)
Potential causes include genetic associations and exposure to toxins, the timing during development of which determines symptoms
Variety of developmental abnormalities in autism spectrum disorders (ASD)
Neuropathological evidence for multiregional dysregulation of neurogenesis (increased brain mass, increased regional cell densities, reduced neuronal size), neuronal migration (heterotopia (abnormal neuronal groups), dysplasia of cortical architecture (dyslamination)), synapse development (abnormal signaling in post-synaptic spines and dysregulation of glutamate signaling in Fragile X)
Imaging evidence for increased brain mass, abnormal myelination
Etiologies are not certain: evidence for complex genetic influences, but also ASD symptoms from single gene mutations (Fragile X syndrome with FMR1 and Rett syndrome with MECP2)
Similarities between ADHD and FAS
ADHD and FAS exhibit abnormalities of cerebral cortex development that result in certain cortical regions having either increased or decreased cortical thickness relative to controls
This suggests it may be possible to identify cortical changes associated with behavioral phenotypes and eventually may help with diagnosis or therapy
Environmental factors that may be essential to development during critical periods
Social interactions
Training and learning
Exposure to toxins
Essential nutrients
Hormones
The attachment relationship
Emotional or affective bond between infant and caregiver
Nature of attachment relationship is thought to reflect the quality of interaction between infant and caregiver, not to be reflective of attributes of either the infant or caregiver alone
Thus, each attachment relationship is unique to a particular dyad
Caregiver functions (ideally) as a secure base and as a safe haven
Secure base and safe haven
Caregiver functions (ideally) as both of these
Secure base: when a child trusts that (s)he has a sensitive, responsive, dependable caregiver, (s)he is able to venture out and explore the world around him/her
Safe haven: when a child trusts that (s)he has a sensitive, responsive, dependable caregiver, (s)he will seek comfort or reassurance from that caregiver when (s)he feels distressed or threatened
Attachment behavior
Organized system of behaviors (not just single behavior) that infant uses to maintain interaction, proximity, connection with caregiver
Activated under conditions of threat
Serves a protective function, evolutionarily adaptive
Attachment figures
Can be primary and secondary
Historically, mothers were considered a priori to be primary attachment figure, but now is increased recognition that other caregivers can be primary attachment figures (fathers, grandparents, child care providers)
As childcare duties are dispersed across more caregivers, child may develop more than one primary attachment figure
Attachment theory
John Bowlby’s assumptions
Early infant-caregiver interactions are viewed as a foundation for other social relationships established in childhood, adolescence, and adulthood
Patterns of dyadic regulation between infant and caregiver give rise to the child’s ability to self-regulate
Quality of attachment relationship (secure vs. insecure) reflects differences in these patterns of dyadic regulation
Quality of child’s early attachment relationships will have implications for patterns of adaptation throughout the life span, with regards to behavioral, social, emotional, cognitive functioning
Development as a relational process
Early development is inextricably embedded in the infant-caregiver relationship
The human infant relies on caregiver not just for sustenance but for external regulation of physiological states
Over time we learn to regulate ourselves, but this ability to self-regulate originates in large part in the context of earliest relationships with caregivers
Capacities of newborn infants
Just a few hours after birth, infants will show preference for mother’s face over a female stranger’s and that preference will occur even with relatively little viewing of the mother
By 1-2 days of life, infants can recognize mother’s smell
As early as 3rd day, infants can discriminate mother’s voice
Development of attachment relationship between mother and newborn infant
Mutual regulation: mothers and newborn infants help regulate physiological responses of one another
Ideally a synchrony develops between infant and caregiver: the “dance” that occurs between parent and child during brief, but emotionally intense, playful interactions
Notably, much of infant-caregiver interaction involves mismatched states: the key is not whether infant and caregiver are always in sync, but whether there are attempts to repair interactions
Strange situation
Lab procedure to develop methodology for assessing patterns of infant-caregiver interaction in order to provide empirical validation for attachment theory
Infant attachment classifications
Secure: 65%; actively explores environment, shares experience w/caregiver, visibly upset during separation (esp second separation), actively greets parent upon reunion; if upset, seeks proximity to caregiver and can be soothed by caregiver; once comforted, returns to exploration
Avoidant: 20%; readily explores environment, but minimal display of affect or using parent as secure base; minimal apparent distress during separations; little or no proximity seeking upon reunion, possible active avoidance; may stiffen, lean away, prefers to interact with toys
Ambivalent/resistant: 15%; exploration is of poor quality, often visibly distressed even before separation; extreme distress during separations; mixes proximity seeking with resistance upon reunion, cannot be soothed
Disorganized: 15%; behavior lacks any apparent goal or intention; displays of contradictory behavior, often simultaneously; incomplete, interrupted movements; odd postures, stereotypes, freezing, stilling, fear grimaces
Infant attachment, parenting and child’s emotional regulation
Secure: parent responds sensitively and consistently; child feels comfortable expressing range of emotions; child can be soothed, and learns to soothe self
Avoidant: parent is rejecting, minimizes child’s distress, may mock or express resentment at child’s expression of distress; child learns to suppress emotional needs
Ambivalent/resistant: parent is inconsistently available, may alternate between being neglectful and intrusive; may use threats of abandonment as a means of control; child learns to heighten, exaggerate distress
Disorganized: parent may be abusive, or caregiver has been traumatized themselves: frightening or frightened behavior; child has no clear consistent strategy for regulating emotions
Internal working models
Clear set of expectations about availability, responsiveness, and sensitivity of their primary caregiver(s)
Mechanism that provides for continuity in attachment across the life span
Are carried forward into other social relationships and used to appraise interactions and guide behavior in the context of those relationships
Infant attachment and childhood outcomes
Secure: better social skills, more elaborative play, more independent exploration, better cognitive skills and academic outcomes
Avoidant: more hostile and less empathetic with peers, more conflict in play, more easily frustrated
Ambivalent: more vulnerable to bully, show empathy but difficulty with boundaries, elicit nurturance from more competent peers and from teachers, more inhibited in play, restricted exploration during play
Disorganized: wary and withdrawn, views peers as threatening, play characterized by catastrophic themes, enhanced response to stress
Infant attachment and socioemotional well-being in adolescence and adulthood
Secure attachment in infancy predictive of greater social competence during adolescence
Disorganized attachment in infancy predictive of hostility in romantic relationships in early adulthood, two decades later and predictive of conduct disorder, self-injurious behavior, and dissociative symptoms at age 17
Ambivalent attachment in infancy predictive of anxiety disorders at age 17
Infant attachment and health outcomes in childhood and adulthood
Insecure attachment in toddlerhood related to obesity at 4 1/2 years old
Girls who were insecure as infants have shown an earlier onset of puberty then those who were secure as infants
Insecure attachment in infancy predicted higher rates of inflammation-based illness 30 years later
Evidence-based interventions to promote secure attachment relationships
Focus is on enhancing the quality of the caregiver-child relationship and the child’s environment
Fostering parental sensitivity
Teaching parent to read and respond appropriately to child’s emotional cues
Teaching parent how to help child develop emotional regulation skills
Increasing stability and support in the child’s environment
Tend to be relatively short term, focused, and with clearly defined goals
Targeted populations: maltreating families, parents with substance abuse problems, depressed mothers, adolescent mothers, preterm infants, children in foster care and adopted children, children with prenatal alcohol exposure
Perinatal mood and anxiety disorders (PMADs)
Onset during pregnancy and up to one year after delivery
Not to be confused with the “baby blues”
Major depressive disorder
Anxiety disorders (OCD, panic disorder, general anxiety disorder)
Bipolar disorder
Postpartum psychosis
How common is maternal depression?
MDD: 3-5%
Low-income or minority women: 30-40%
Incidence 3x higher in postpartum
Risks to mother of depression
Infrequent and late-entry prenatal care
Appetite disruptions
Sleep disturbances, fatigue
Increased risk of substance use and smoking
Suicidal thoughts and/or actions
Risks to fetus/neonate of depression
Pre-term delivery
Low birth weight
Lower Apgar scores
Elevated “stress hormones”
Risks to infant of depression
Increased crying and irritability
Decreased duration of breastfeeding
Increased risk of child abuse and neglect
Poor attachment to mother (emotional disconnection, less face-to-face, less skin-to-skin)
Long-term effects of disrupted attachment
Cognitive delays
Poor social/emotional development
Affect dysregulation
Behavior disorders
Anxiety/depression
Substance abuse
Poor adult relationships
High risk populations for PMADS in the hospital
Antepartum: high risk OB (particularly inpatient), infertility hx, perinatal loss hx, crisis pregnancy
Postpartum: traumatic delivery, adoption
NICU moms
PICU moms (child abuse/neglect)
Teen moms/single moms
Substance abusers
Domistic violence survivors
The universal message
“You are not alone”
“You are not crazy”
“With the right help, you will feel better”
What are the risks with SSRIs in pregnancy?
Birth defects? Paxil (paroxetine) has possible increased risk of heart defect (FDA black box warning); possible uptick in spontaneous abortion (miscarriage)
Medical risks? Increased risk of preterm delivery, HTN, poor neonatal adaptation (PNA), question of increased risk of persistent pulmonary hypertension of the newborn (PPHN)
Long-term developmental effects? Little data, but what we have is reassuring; autism data under investigation
Guidelines for perinatal antidepressant use
Use only when necessary and appropriate
Do not avoid if woman truly needs
Minimize number of exposures
Use lowest possible dose
Consider breastfeeding early and often
Guidelines for antidepressant use during breastfeeding
Consider early in pregnancy or even before
Safest medications are sertraline (Zoloft), paroxetine (Paxil) and nortriptyline
Use lowest possible EFFECTIVE dose
Sleep disturbance heightens risk for relapse
It’s OK not to breastfeed
Genetics of autism
60% monozygotic twin concordance
20% chance of having second child with ASD
However, 20% of individuals with AS have identifiable genetic disorders (Fragile X, tuberous sclerosis, Rett syndrome)
Neurobiology of autism
Early dysregulation of brain growth: rapid early growth (white and gray matter), plateaus at age 2-4, likely affects long range connectivity
Aberrant connectivity (local overconnectivity and regional underconnectivity)
30% have macrocephaly
Most brain regions implicated
DSM-IV TR criteria for autistic disorder
1) Qualitative impairments in social interaction
2) Qualitative impairments in communication
3) Restricted, repetitive and stereotyped patterns of behavior, interests and activities
4) Delay or abnormal functioning in at least one of the following areas, onset before age 3: social interaction, language as used in social communication, symbolic or imaginative play
5) Not better accounted for by Rett’s disorder or childhood disintegrative disorder
DSM-IV TR diagnostic criteria for Asperger’s disorder
1) Qualitative impairments in social interaction
2) Restricted, repetitive and stereotyped patterns of behavior, interests and activities
3) Disturbance causes clinically significant impairment in functioning
4) No clinically significant general delay in language
5) No clinically significant cognitive or adaptive delay
DSM IV-TR criteria for PDD (pervasive developmental disorder)-NOS
Severe and pervasive impairment in the development of reciprocal social interaction PLUS impairment in either verbal or non-verbal communication skills
OR
presence of stereotyped behavior, interests and activities
Autism Spectrum Disorder (ASD)
In DSM-V, will have only ASD instead of autistic, asperger’s and PDD-NOS
DSM-V ASD
A) Persistent deficits in social communication and social interaction across contexts
B) Restricted, repetitive patterns of behavior, interests, or activities
C) Symptoms present in early childhood (doesn’t have to be before age 3)
D) Symptoms limit/impair everyday functioning
E) Severity rating for each subdomain
F) Specifier for cause (ie Fragile X)
G) Modifier for other important factors (ie seizure disorder)
H) Assessment of overall impairment
DSM-V Social communication disorder (SCD)
Impairment of pragmatics
Diagnosed based on difficulty with social uses of verbal and nonverbal communication which affects functional development of social relationships and discourse comprehension (combined social and communication instead of separating them like DSM-IV)
Cannot be explained by low abilities in word structure, grammar or general cognitive ability
Symptoms must be present in early childhood
ASD must be ruled out for SCD diagnosis
Co-morbidities and clinical features of ASD
Core: social impairment, repetitive behaviors/restricted interests, speech/communication deficits (autism only)
Psychiatric sx: social phobia, ADHD, aggression, OCD
Cognitive?: expressive/receptive language disorders, intellectual disability
Other: immune dysfunction, sleep disturbance, motor problems (apraxia), macrocephaly, GI disturbance, epilepsy (EEG abnormalities)
Sleep impairment in ASD
Very common (80%)
Most commonly insomnia
Delayed sleep onset, night awakening, early morning awakening, reduced need for sleep
Longer sleep latency, increased duration of stage 1 sleep, decreased non-REM sleep (stages 2-4), abnormal REM sleep
“Bad sleepers” have worse cognitive ability, affective problems, hyperactivity, etc
Epilepsy in ASD
Abnormal EEGs in up to 50%
Epilepsy in 30%
No primary seizure type
Two peaks: early childhood and adolescence
ASD + intellectual disability = more likely to have epilepsy than ASD alone
More common in ASD girls
Motor impairment in ASD
Repetitive behaviors part of diagnostic criteria (both because of insistence on sameness and repetitive behaviors)
More severe over development
More predominant in children with severe language impairment
Motor delay, hypotonia (improves over time), incoordination, gait impairment (toe walking common), apraxia, motor planning, postural control
No studied treatments for motor impairments except Risperidone for repetitive behaviors
Infant motor data for ASD
Gross motor function at age 6 months significantly correlated with visual reception, receptive language and requesting at 12 months
Psychiatric comorbidities of ASD
ADHD (cannot formally diagnose in ASD): inattention, hyperactivity
Anxiety (particularly as children get older)
OCD
Excessive repetitive behaviors
Irritability/behavioral problems
Screening for ASD
At 18 months: M-CHAT, PDDST-II, Autism Screening Questionnaire
Immediate referral if: fails screening (“no” to 2 questions), no babbling/pointing by 12 mo, no spontaneous single words by 16 mo, no 2-word spontaneous phrases by 24 mo, any loss of language or social skills at any age, esp before 24 mo
Diagnostic workup for ASD
Neuropsychological to test IQ, behavioral or emotional problems, learning profile
Genetics: karyotype, Fragile X, MECP2 mutation, chronosomal microarray analysis
MRI only if abnormal neuro exam or global developmental delay
EEG only if concern for seizures or language regression
Treatment for autism
Treatment intensity more than 25 hrs/wk
High staff:student ratio
Teachers with special expertise
Individualized programs for each child
Behavioral treatment: ABA, PRT, DIR/floortime, JASPER
Pharmacotherapy: FDA approved for 5-16yo with ASD for irritability: Risperidone, Aripripazole (Abilify)
No medications shown to change social interaction or communication (core deficits)
Treatment for sleep impairment
Behavioral interventions: bedtime routines, reinforcement and extinction, parent training
Pharmacologic: melatonin (3-6mg at bedtime), clonidine, trazadone
Treatment for epilepsy
Because of heterogeneity, there is no gold standard treatment
Early recognition and treatment important
Anti-epileptics:
Leviteracitam: behavioral side effects
Valproid acid: liver toxicity
Benzodiazepines: drowsiness
Lamotrigine: SJS
What is the significance of reductions in synaptic density and increases in myelination that occur throughout childhood and adolescence?
Get increased efficiency at the cost of decreased plasticity
As we get older, less used connections die away (synaptic pruning) but more used circuits are insulated with myelin, which increases conduction speed
Are changes in the brain related to changes in cognitive functioning?
Yes!
Thick cortex = worse vocabulary
In kids with superior intelligence, their cortical thickness peaks later, which means they had more time for synaptic plasticity before pruning/making brain more efficient
Changes in functional activation (fMRI) over development
Children have more diffuse activation whereas adults have more focal organized activation
This is thought to reflect decrease in plasticity and increased efficiency, and maybe the synaptic pruning/increased myelination
Brain changes in FASD
Cortex is thicker in FASD (more is not better!)
Brain changes in autism
In general: distal brain regions don’t communicate well, and there is excessive local information processing
Time course of development is altered
Evidence for early brain overgrowth followed by reduced growth trajectory
Autistic children begin life with larger amygdala, then develop at reduced rate
Abnormal growth of white matter: late-myelinating white matter compartments overdeveloped while earlier myelinating deep/bridging zones and longer range pathways less developed –> problems in long-range connections in the brain
Abnormal cortical folding in inferior frontal gyrus, inferior sensory and motor strips, pars opercularis (containing mirror neuron system for immitating)
Lower response to reward
Brain changes in ADHD
Fronto-striatal network abnormalities
Increased prefrontal gray matter in hyperactivity in ADHD
Dyslexia
Difficulty with written language (reading and spelling)
Differences in how brain processes written and/or spoken language
Many brain regions involved in reading, and dyslexic patients show structural differences from controls in these regions
What does testosterone do to the brain?
Testosterone affects with cortex thickness
In boys, cortex gets thicker as testosterone increases
In girls, cortex gets thinner as testosterone increases
Criteria for ADHD
6 out of 9 of innatentive symptoms and/or 6 out of 9 of hyperactive/impulsive symptoms
Symptoms present more often than not; chronic course
Some sx begun before age 7
Diagnosing ADHD
No objective test
Several rating scales and questionnaires (Connors’ SNAP, SWAN) that are structured ways of asking about the DSM criteria
Must take developmental context into account
One 30 min encounter with a paient does not rule anything in or out
Prognosis of ADHD
30-60% of people diagnosed with ADHD as children will continue to meet criteria for disorder as adults
In short term, medication results in significant improvement in academic functioning
In long term, academic benefits of medication are modest and medicated children with ADHD still do not perform as well as neurotypical peers, on average
Hyperactive/impulsive symptoms tend to improve by adulthood, but inattentive symptoms remain
Co-morbidities of ADHD
Oppositional defiant disorder (ODD)/conduct disorder (25-33%)
Learning disorder/language disorder (25%)
Anxiety disorder (13%)
MDD (11%)
Substance abuse disorder (20-25%)
Why treat ADHD?
Patients less likely to engage in criminal behavior than unmedicated patients
Two main classes of ADHD medications
Stimulant: methylphenidate (concerta, ritalin) and mixed amphetamine salts (adderall, vivance)
Non-stimulant: atomoxetine, guanfacine, clonidine
Side effects of ADHD treatment
Most common is appetite suppression
Insomnia, mood changes, increase in tics, cardiac arrhythmias
Long term stimulant use associated with slightly decreased height in children
Non-pharmacological treatment for ADHD
Classroom or workplace modification, behavioral therapy, social skills training, psychoeducation
Learning disorders criteria
DSM definition: discrepancy between aptitude and achievement in a particular skill
Federal IDEA standards: if child does not meet grade-level standards for the categories listed below and does not respond to evidence based intervention
What does Federal law require if a child fails a state assessment exam?
Child must be given an evidence-based intervention in that area
If child does not respond to that intervention, evaluation is done and diagnosis of LD can be given
Co-morbidities of learning disorders
38% with LD have ADHD
50% with LD also have ASD
Other: anxiety, ODD, conduct disorder
Treatment for LDs
Tier 1: general classroom remediation
Tier 2: small group instruction
Tier 3: individual instruction, special education
No specific pharmacotherapy for LD, but treating co-morbid conditions always makes things better
Genetics of ADHD and LDs
Both ADHD and reading disorder seem to have heritability of 60%
Hundreds of risk genes for ADHD, and overlap between risk genes for ASD, schizophrenia and ADHD
Candidate genes exist for reading disorder, with some overlap for risk with speech disorders
Neurobiology of ADHD and LD
ADHD results from dysfunction of DA circuits in PFC, resulting in diminished executive function
Imaging studies have shown differences in L hermisphere occipito-temporal cortex and cerebellum between patients with reading disorder and controls; several candidate genes are involved in neuronal migration
Appetite regulation
Interplay of neurochemical signaling in homeostatic and reward pathways
1) Direct regulation by stimulation or suppression of appetite in the hypothalamus in response to molecular signals from viscera
2) Indirect regulation by influencing the reward value of food in the mesolimbic reward pathway
3) Indirect modulation by higher brain systems
Different signals that lead to appetite and feeding behavior
Cognitive input (desired body image, concepts of health, stress, etc) –> contextual information (cerebral cortex, amygdala, hippocampal formation) –> hypothalamus (compares input to biological set points) <–> mesolimbic reward pathways –> appetite and feeding behavior
Sensory inputs (visceral and somatic sensory pathways, chemosensory and humoral signs) –> hypothalamus (compares input to biological set points) <–> mesolimbic reward pathways –> appetite and feeding behavior
Note: biological set points are plastic and are established during development and can be influenced by habits and by environmental toxins
Hypothalamic homeostatic centers that regulate appetite
Ventro-medial areas drive satiety (lesions cause hyperphagia and obesity)
Dorso-lateral areas drive feeding (lesions cause hypophagia and starvation)
Orexigenic neuromodulators and anorectic neuromodulators in hypothalamic pathways
Orexigenic neuromodulators stimulate appetite: orexin, NPY, AgRP from hypothalamus; ghrelin from stomach
Anorectic neuromodulators inhibit appetite: histamine and alphaMSH from hypothalamus; leptin from adipocytes; insulin from pancreas
Appetite is directly regulated by neurochemical signaling in hypothalamic pathways
How do hormones released by viscera (leptin, insulin, ghrelin) influence appetite?
They travel via circulation to modulate hypothalamic circuits
Leptin and insulin act on hypothalamic arcuate nucleus to suppress appetite
How does leptin mediate “reward” associated with images of food?
If no leptin, nucleus accumbens activation by visual images of food is higher (will get more reward from looking at food)
Indirect regulation by influencing reward value of food by controlling DA release
Direct regulation by stimulation or suppression of appetite
Do other things modulate reward circuits and influence appetite and feeding behavior?
Yes, neurochemical inputs of many kinds and from many sources (including higher brain centers like cortex, amygdala, etc) modulate reward circuits
Histamine, GABA, leptin, insulin are inhibitory
Ghrelin, orexin, glutamate, endocanabinoids are excitatory
Exogenous neurochemicals (drugs, meds) can also influence these pathways
Negative feedback regulation of energy balance and glucose
Defects in negative feedback predispose to weight gain and insulin resistance
Fat mass and pancreas (producing insulin and leptin) feed back into hypothalamus which interacts with biological set points and reward system and perceived value of food and regulates food intake, energy expenditure and glucose production in the liver
Neurocentric model linking obesity, insulin resistance and T2DM: reduced neuronal insulin/leptin favors positive energy balance and hepatic insulin resistance
What mediates anorexia in cancer and infections?
Same neurochemical signaling in reward and homeostatic pathways, which are influenced by pro-inflammatory cytokines
Pro-inflammatory cytokines stimulate anorectic and inhibit orexigenic pathways
Key ponts about eating disorders
Eating disorders relatively rare among general population
Anorexia nervosa most common among young women
All eating disorders associated with increased risk of mortality
Binge eating most common in men and older people
DSM-IV criteria for anorexia nervosa
Refusal to maintain body weight at or above a minimally normal weight for age and height (more than 85% of what is expected)
Intense fear of gaining weight or becoming fat, even though underweight
Disturbance in the way in which one’s body weight or shape is experienced, undue influence of body weight or shape on self-evaluation, or denial or seriousness of current low body weight
In postmenarcheal females, amenorrhea (absence of at least 3 consecutive)
Types of anorexia nervosa
Restricting type: during current episode of anorexia nervosa, person has not regularly engaged in binge-eating or purging behavior
Binge-eating/purging type: during current episode of anorexia nervosa, person has regularly engaged in binge-eating or purging behavior
Medical signs of starvation
Bone: Ca2+ loss –> osteoporosis
Cardiac abnormalities, arrhythmia
Constipation (gut slows)
Orthostatic blood pressure changes
Amenorrhea
Electrolyte abnormalities (K+)
Renal compromise or failure
Body hair increases
Cognitive impairment
Cortisol regulation altered
Relationship between AN/BN and leptin, ghrelin, BDNF, endocannabinoids
These appetite modulators affect non-homeostatic cognitive, emotional and rewarding component of food intake as well as non food-related reward
AN/BN pathophysiologically linked to dysfunctions of reward mechanisms
Development and/or maintenance of aberrant non-homeostatic behaviors such as self-starvation and binge eating may be due to changes in appetite modulators
Epidemiology for AN
Incidence highest in females 15-19
Not clear if incidence is rising, although it might be in that age group
5 year recovery rate is 67%
Highest mortality rate of any mental disorder: 5% per decade
20% of those deaths are suicide
DSM-IV criteria for bulemia nervosa
Recurrent episodes of binge eating, characterized by:
1) Eating, in a discrete period of time (within 2 hour period) an amount of food that is definitely larger than most people would eat during a similar period of time and under similar circumstances
2) A sense of lack of control over eating during the episode
Recurrent inappropriate compensatory behavior in order to prevent weight gain, such as self-induced vomiting; misuse of laxatives, diuretics, enemas, or other medications; fasting; or excessive exercise
The binge eating and inappropriate compensatory behaviors both occur, on average, at least twice a week for 3 months
Self-evaluation is unduly influenced by body shape and weight
The disturbance does not occur exclusively during episodes of AN
Types of BN
Purging type: during current episode of BN, the person has regularly engaged in self-induced vomiting or the misuse of laxatives, diuretics, or enemas
Nonpurging type: during the current episode of BN, the person has used other inappropriate compensatory behaviors, such as fasting or excessive exercise, but has not regularly engaged in self-induced vomiting or the misuse of laxatives, diuretics, or enemas
Epidemiology of BN
Median onset at 12.4 years
Lifetime prevalence in US is 0.6%
88% report at least one other Axis I disorder
53% report suicidal thoughts
More prevalent in girls than boys
Binge eating disorder
New diagnosis in DSM-V
Common in US adolescents
Diagnosis requires binging at least once a week for 3 months
No compensatory behavior, so may be overweight
Eating disorder NOS
Very common diagnosis now using DSM-IV, but after DSM-V broadens AN and BN and adds binge eating disorder, won’t be used as much
Body dysmorphic disorder
Not about eating per se but appears related in terms of distortion of body image
Focus on some aspect of appearance which is seen as ugly
Fixed delusion
Has fMRI similar to those of AN
Can lead to plastic surgery, with chronically dissatisfied result
What causes eating disorders?
Way of coping with emotions and feelings of failure
Anorexia uses control of food, exercise and the body to combat a sense of losing control and to succeed
Binging uses food to try to soothe or get pleasure and then lose control
Both anorexia and bulimia have disordered focus on weight
Cultural expectations contribute to this, but certain temperaments will be more susceptible
Heredity is also a factor, as is learning in a family
“Typical” temperaments
Anorexia: hard-working, perfectionist, demanding of self; when confronted with challenges of adolescence feels a bit overwhelmed and works even harder; usually has lost weight on purpose or with an illness, and discovers the power of control over the body
Bulimia: emotional, somewhat impulsive, may have a history of loss or trauma; may have binged or purged with others who were doing it casually (very common at college)
Treatment of AN
Re-feeding is first, as this can be a medical emergency, but must be done gradually, even if by tube
Structured eating (learn to eat, but also tolerate feeling of fullness) and limited activity at first
Tolerative changes in body (which are not cosmetic at first)
Family therapy to change interactions about food and to change how family is controlled
Gradually add in appropriate activity
Work on self image about body, but only after patient is able to think clearly
Treatment of BN
Prevent purging by observing after meals
Teach emotional regulation techniques
Treat co-morbid disorders
Family therapy similar to that for AN
Fluoxetine has been found to be useful in decreasing binging by over 50% in an open trial
CBT has been found to be helpful, and may be the treatment of choice for adults
Stages of coming out
Sensitization: recognition of same-sex attraction (childhood - teens)
Identity confusion and experimentation
Identity assumption: self-ID as LGB and disclosure to friends, parents, family (late teens)
Identity commitment: LGB lifestyle and engagement in LGB community
Teen milestones
Girls:
First aware 10-11
First L sex 15-17
ID 14-17
Disclosure 16-19
Boys:
First aware 9-13
First L sex 13-17
ID 12-17
Disclosure 16-20
Sex-centered pattern vs. identity-centered pattern
Sex-centered pattern: may be associated with more internalized homophobia and risky sex, more heterosexual early experiences, M>F
Identity-centered pattern: childhood recognition, socio-historical change, F>M (80% L)
Gender differences in homosexuals
Females have later first awareness, same-sex experience, self-identification than males
Females have more heterosexual experience and bisexual identity
Females more identity-centered development
Recently more females with bisexual ID
Predictors of serious substance abuse in LGB
Parental physical abuse
Parents discourage gender-atypicality
Parents LGB insults
Gay verbal abuse
Gender atypicality in childhood
Family h/o SA
Being open with family (!)
Protective factors
Family support (PFLAG)
Friends’ support
Internet support
Project 10 and GSA at school
Supportive school administration
