Bench to trench

Bench to Trench Research support for the DIR速 model: from genetics and child development to blackboard mathematics, with clinical correlations and functional neurophysiology.

Joshua D Feder MD DFAPA Assistant Clinical Professor, Dept of Psychiatry, University of California at San Diego School of Medicine Faculty, Interdisciplinary Council on Developmental and Learning Disorders

Disclosures ICDL Faculty – minimal - review of clinical write ups, travel and room for summer institute NIMH/ Duke University – minimal – administrative time for pharmacogenetic research

Feder 411 Career – biomedical engineering and math, Navy – some operational medicine, psychiatry at NRMC San Diego, child and adolescent at Tripler, Clinic at Pearl, Chief of Child at NNMC, neurobeh med clinic at NNMC, USUHS faculty, Greenspan & Wieder in DC, back to San Diego in ‘96, UCSD volunteer faculty since 2000, ‘unejectible’ in Solana Beach since 2001, returned on ICDL faculty in 2007.

Research – perflorinated hydrocarbons Allied Chemical, mathematical models of mind and cognition (Grossberg), physician use of mammography (Korst), blood preservation (Valeri), relationship based interventions (Bradberry, Waldron), pharmacogenetics (March, Duke U) Autism Spectrum Disorders: 1980 Mass. Assn for the Blind (Congenital Rubella); 1982 teacher at school for autistic adults (Behavioral training); BUSM Pediatric Neurology 1985; Child Study Group – Tripler (Lee) 1990-1992; Neurodev. Clinic NNMC 1993 - 1996; Greenspan, Wieder et al ICDL 1993-present; AACAP Autism Committee 1997-2000 & ad hoc (Volkmar, Cook); AACAP Autism Medication Panels (Volkmar); AACAP Autism in the schools training 2006 (Chenven, Akshoomoff, Feder).

Practice – time 1/3 evaluation and case management, 1/3 therapy, 1/3 teaching and research; dx ½ developmental and learning disorders, ½ general psychiatric (ADHD, Bipolar, PTSD, Tourettes, Depression, OCD etc.); age range 1/3 infants and children, 1/3 older children and adolescents, 1/3 adults Community work: Rady Children’s Hospital San Diego Autism Research Workgroup, BRIDGE Collaborative (Bond Regulate Interact Develop Guide Engage), SDPS Ethics committee / resident training in ethics; ICDL Institute, F2F and online courses Outside life – coaching science and engineering, reading, care of chronically ill house pets…

What are we doing?

Learn about genetics and environment (GxE) research, and how it offers hope to persons with developmental disorders and supports the use of the DIR model.

Briefly review of the child development literature, and see how it rather directly supports the DIR model.

Learn about brain theory, the math behind co-regulation, perseveration, and tantrums, and how the DIR model makes sense in this conceptualization of autism spectrum disorders Hear the preliminary data on functional brain imaging of persons receiving a DIR approach Have a couple key ideas to take away.

That is‌we’ll look at: What you might not have heard about the interaction between genetics an environment, and how it offers hope.

What you may already have heard about child development, and underline it.

What you probably have not heard about brain theory, and how it offers a liberating understanding of what we do.

What we all know more and more every day: we are making fundamental changes in the people we treat.

Some of this will go fast Don’t Panic – just enjoy the ride Taking notes? Write down four words:

Hope, Engagement, Vigilance, and Timing Too much?: just write down

ENGAGEMENT All slides will be posted on circlestretch.blogspot.com

Assumptions You are familiar with the basics of DIR速 model, including coregulation and dual coding of affect and cognition.

You are familiar with current DSM conceptualizations of Autism.

You have a passing familiarity with the child development literature.

You recall your linear algebra, Fourier Transforms, and the Runge-Kutta method of numerical integration of ordinary differential equations for approximating solutions to iterative calculations.

Runge-Kutta 4th Order k1 =

hf(xn,yn)

k2 =

hf(xn+1/2h,yn+1/2k1)

k3 =

hf(xn+1/2h,yn+1/2k2)

k4 =

hf(xn+h,yn+k3)

y(n+1) = yn+1/6k1+1/3k2+1/3k3+1/6k4+O(h5)

Just kidding on the math part‌.

GxE

Genetics and Brain Structure in ASDs Oligogenic: the ‘50%’ finding Overpopulations in the brain Poor connectivity theories (Courchesne, et.al.)

Second trimester etiology Argues for more research and then screening in utero or before

Environment and the Brain: Animal Models - I  Delville, et al, gene expression: How was your hamster raised?

Subjugated hamsters attack the younger and weaker. Social experience in adolescence leads to permanent changes in brain chemistry, including a 50% reduction in vasopressin in the anterior hypothalamus.  Bester-Meredith, et al, species differences.Some mice are good dads, others are not.  Bester-Meredith, et al: cross fostering. Born to father, raised to flee.  Sugiyama, et al, impact of environment on transcription:Contact with pups makes rat moms transcribe long form receptor mRNA for prolactin and increases their maternal behavior. Pups make their mothers.

Environment and the Brain: Animal Models – II

Epigenetic programming: stable alterations in gene expression  Weaver, et al: Rat moms who crouch (nurture) their pups change the histone acetylation and transcription factor binding to the glucocorticoid receptor (GR) gene promoter in the hippocampus.  GR expression changes and so does the pup’s current and future response to stress via the Hypothalamic Pituitary Axis.  Pups of the more attentive moms have less reactivity to stress. That is, rat moms can change the genetic expression of their pup’s stress response.

Environment and the Brain: Human Models – I

Human Studies with Known Alleles (genotype and violence in maltreated children)  Caspi, et al: Low MAOA activity and history of maltreatment correlate with risk of violent crime.  Low MAOA activity may predispose to over-reacting to perceived threats.  Human version of the hamsters. ‘Stat’:1/3 of abused boys become abusers. Here 55 boys had low MAOA activity, 99 had high MAOA activity.  Should we check MAOA activity to find higher risk people?

Environment and the Brain: Human Models – II

Human Studies with Known Alleles (environment & stressful life events)  Caspi, et al: looked at polymorphism in promoter region of serotonin transport 5-HTT gene.  Three different groups with alleles l/l, s/l, and s/s.  It took 4 Stressful Life Events to see separation between groups.  33% depression risk with 4 SLE’s and either s/s or s/l allele. 17% risk with l/l and 4 SLE’s.

Environment and the Brain: Human Models – III

Human Gene x Environment Interplay Trait (disordered thinking)  Wahlberg, et al: Finnish Adoptive Family Study of Schizophrenia.  high vs. low genetic risk children adopted into low vs. high communicative deviance families  Only people at high risk and raised in high deviance families were at more risk for disordered thinking.  HGxE: Family might save

Environment and the Brain: Human Models – IV

Human Epigenesis in ADHD  Laucht et al, studied the DAT1 gene.  ADHD is up to 80% heritable.  Different studies found DAT1 alleles to be of great significance and others found none.  Turns out DAT1 is important when the person has been exposed to adverse family setting.

Environment and the Brain: Human Models – V

The Missing Link?  Smalley, et al: genetic linkage of on chromosome 16p13 a region implicated in autism.  A new trail linking what we do with our kids with autism to who they become in time?

The Importance of GxE: Bettleheim: parental inadequacy 'causing' the condition Shame and and guilt sap our families Treatment teams: 'this family just isn't cut out for this'.

But genetics do not always define destiny.

Our goal: help families to help their members develop to their fullest extent

“Never give up, never surrender!”

- Captain Peter Quincy Taggart Commander, NSEA Protector

So‌ just be nurturing?

Child Development‌

The role of affect in the modulation and modification of symptoms of ASDs

Importance of affective co-regulation in child development - I  Rene Spitz – Foundling homes. Hospitalism. (see also Roberts The Child in the Hospital)  John Bowlby – attachment, and later Mary Ainsworth strange situation (individual differences in attachment).  Selma Fraiberg – Ghosts in the Nursery. Affects of the child, of the parent, and the past history of relationships and their impact on relatedness.  Stella Chess and Alexander Thomas –temperament and goodness of fit (know your 7 dwarves!).

Do you know your Seven Dwarves?

Temperament and the Seven Dwarves  Sleepy - rhythmicity of sleeping, eating, etc.  Sneezy - threshold of reactivity to stimuli  Happy - quality of mood  Grumpy - intensity of reaction  Dopey - activity level, distractibility  Doc - persistence (attention span), adaptability  & Bashful - approach/withdrawal

The role of affect in the modulation and modification of symptoms of ASDs

Importance of affective co-regulation in child development - II  T. Berry Brazelton – importance of dyad and affect; Neonatal Behavioral Assessment Scale (1973).  Stanley Greenspan – from psychoanalysis to fussy baby clinics to ‘First Feelings’ to the Bayley subscale Functional Emotional Developmental Levels.  Allan Schore – Affect Regulation and the Origin [Disorders, Repair] of the Self.  Daniel Stern – mother-infant relationship therapy. Vitality affects: ‘musical’ co-regulation.

The role of affect in the modulation and modification of symptoms of ASDs

Importance of affective co-regulation in child development - III  Mundy, Charman, others – joint attention, language, and initiation.  John Medina – memory and affect.  Altschuler - Mirror neuron studies  Daniel Segal’s bottom line: ‘the brain is a social organ’.

The role of affect in the modulation and modification of symptoms of ASDs

Importance of affective co-regulation in child development – IV: Core DIR Concepts  Dual coding of affect and learning – you don’t really learn and adapt if don’t care about something or someone. ‘Buy in’ is critical to learning, problem solving, and development.  Co-regulation and counterbalanced regulation – helping each other be calm enough to engage.  Engagement – warm relating, beyond joint attention (note research on initiation and joint attention – Mundy).  Circles of interaction – building on emotional gestural interactions in a continuous flow of relating  FEDL - Functional Emotional Developmental Levels

Mathematical Models of the Mind Grossberg and Seidman –

NEURAL DYNAMICS OF AUTISTIC BEHAVIORS: Cognitive, Emotional, and Timing Substrates.

Psychol Rev 2006;113(3):483-525.

I: Basic Principles Nature finds the simplest way to do things Repetitive use of structures and concepts to build complexity Expect beauty

There are 10 kinds of people‌

Those who know binary and those who do not.

1012

Outstars: how to do things (praxis)

Learning Vector Quantization Network

Making the impossible possible

II: Pattern Activation and Matching

Category Formation  Input I activates STM pattern X at level F1 and activates the non-specific orienting system A  X inhibits A and creates specific output S  S becomes T, T activates STM pattern Y at level F2

PtternMIsmatch:  Pattern Y generates signal U, which is transformed into V and feeds back to level F1  When V and I don’t match, a new STM X* is formed  X* has less inhibitory output to orienting system A  If V and T are identical, it becomes dynamic LTM

Reset  If V and T don’t match, the inhibition to A drops, allowing it to release a non-specific arousal wave that resets F2  Then U and V quit and the gain inhibition to F1 is also shut off

The Search Continues  The system continues to look for a better match…

Vigilance: ρ The “ρ” in these models is ‘vigilance’, the intensity of affective tone in the system Vigilance determines how close a higher level pattern must be to an input to allow resonance to occur Vigilance is controlled by environmental feedback or internal volition (amygdala, etc.)

Vigilance and Dual Coding Affective tone in the system is required for dynamic resonant memory to exist We do not learn if we do not care

Vigilance and Category Formation Low vigilance permits learning of general categories with abstract prototypes (not getting reset so often) High vigilance forces many searches fir a category even when small mismatches exist Chronic high vigilance leads to : concrete, hyperspecific creation of categories, i.e. incredible concrete memory

Computer Simulation

Human Hyperspecific Category Formation:

Stanley Greenspan Steven Grossberg

Stuart Groenig?

Vigilance and Co-regulation Vigilance can be adjusted through environmental feedback Co-regulation in a relationship based intervention is a process that helps a person adjust vigilance Objective: reduce chronic high level of vigilance and help the person acquire an adaptive range of vigilance Goal: Allow the person to create a more balanced and useful mix of broad, abstract categories of thinking as well as specific ones

III: Timing

Adaptive Resonance Theory Resonant consciousness – Adaptive Resonance Theory predicts that all conscious states are resonant states In ASDs synchronous resonances may reset more frequently CogEM as a resonant system model

Stare hard at this, then close your eyes

Here’s Another -

Gated Dipole Field Effects

Consciousness in 3 cycles per second Allan Schore – backround orienting 3 cps waves, forming continuous but discontinuous consciousness Absence seizures are 3 cps too‌ Animation is discontinuous, but you see it as continuous as long as it is fast enough, even carrying affecive information

Clayman vs. Paperman

The Impact of Acting Out Clayman is angry and tends to act out‌ Paperman is frightened but also teases Do you have an affective reaction to this cartoon?

CogEM: Cognitive Emotion Motor model

CogEM allows 3 kinds of learning Conditioned Reinforcer Learning (CRL) allows sensory events to activate emotional representations (see dog, get scared) Incentive Motivational Learning allows emotions to bias cognitive processing consistent with the emotion (scared means the dog is dangerous) Motor learning allows sensory and cognitive representations to generate actions (RUN!)

CogEM system failure

What if your amygdala isn’t putting out a good enough emotional signal?

IML fails: You might be scared but this information is not transmitted PFC doesn’t communicate to sensory cortex: no way to set up a plan for when danger is detected Motor planning fails: you don’t run

Prefontal Cortex Gates Release of Properly Motivated Responses

Underaroused Gated Dipole Unexpected events create paradoxical amplification of activation in the ON channel instead of normal antagonistic rebound Leads to perseveration of attention on a given object or event, rather than flexible disengagement and shifting of attention Impairment of split attention, shifting attention, and joint attention A really strong arousal burst, however, creates an intense antagonistic rebound

Here’s the proof…

Given an arousal level I that exceeds the threshold, C, then x6 S+,J→J 2 ⎛ ⎝ ⎜ ⎞ ⎠ ⎟ = AB J 2(I−A−C) (D+I)(D+I+J), where D=A−C. By comparison, (A20) and (A25) imply that x5(S,J→0)= A 2 BJ (D+I)(D+I+J) and x6(S+,J→0)= ABJ(I−C) (D+I)(D+I+J) from which it also follows that x6 S+,J 2→0 ⎛ ⎝ ⎜ ⎞ ⎠ ⎟ = AB J 2(I−C) (D+I) D+I +J 2 ⎛ ⎝ ⎜ ⎞ ⎠ ⎟ and

x6(S + ,K→0) x5(S,K→0) =A −1 (I −C) for any K>0.

Comparing (A43) and (A46), shows that the relative rebound sizes satisfy x6 S+,J 2→0 ⎛ ⎝ ⎜ ⎞ ⎠ ⎟ >x 6 S+,J→J 2 ⎛ ⎝ ⎜ ⎞ ⎠ ⎟ , or that cutting J units in half is less rewarding than shutting off J2 units.

In addition, the ratio increases with I, as in the more general equation.

Substituting shows that x6 S+,J→J 2 ⎛ ⎝ ⎜ ⎞ ⎠ ⎟ =A 2 BJ 2[x5 −1 (S,K→0)x6(S+,K→0)−1] (D+I)(D+I+J)

IV: Putting it together‌

UnderarousedCogEM with Hypervigilant ART =

iSTART imbalance Spectral Timing Adaptive Resonance Theory

Neurophysiological Characteristics of iSTART Hyperspecific expectations – mismatches Non-specific arousal bursts Enhanced ON channel responses Enhanced storage of direct object representations in sensory and cognitive dipoles

Dynamic Systems iSTART Model

Clinical Manifestations‌ Perseverative behavior Large mismatches create severe negative reactions Affect may be flat because of an inability to represent others’ beliefs and intentions

Suggests Intervention If motivated attention and action are adaptively timed, then it is less likely that spurious resets of attention will occur This is necessary for development of social learning and communication

That is, we can hypothesize that..

When we pay attention to co/counterbalanced regulation, and engage people in well-balanced (well-timed) circles of interaction, we may be able to help the person manage internal vigilance and improve adaptive timing, allowing the person to develop a more adaptive set of expectancies, improving adaptive timing, and reducing the tendencies both to perseverate and to tantrum.

This kind of approach should prove helpful with a broad range of disorders of mood, mood instability, social learning, and learning, and communication.

The ‘rule of life’ When something happens the way we wanted it to, it’s a good thing Pretty much nothing happens the way we wanted The game becomes how different was it from what you wanted, and what do you want to do about it?

Suggested Research Clinical Amygdala PFC etc

Clinical Work Mundy and others – joint attention and initiation Greenspan and Wieder – 200 case report (1997) and follow up (2005); Greenspan and De Gangi FEAS validation studies Rick Solomon – The Play Project ICDL journal – see www.icdl.com Regular written case studies from clinicians in various fields (psychology, speech, OT, education, medicine, etc.)

Functional Imaging Studies John Stieben – York U. –  dense-array EEG appear as functional MRI images  post-treated ASD kids look similar to age-matched typically developing children in PFC (prefrontal cortex) and dorsal ACC (anterior cingulate cortex) function (i.e., executive function)  N170 ERP component was indistinguishable from controls so they have no fusiform (and related network) deficits  Successfully treated ASD group resembled high anxious individuals as they had heightened activation in the ventral or subgenual ACC (residual awkwardness)

Assessing Behavioral and Neurophysiological Outcomes of Intensive DIR Intervention for Children with Autism Lead Investigators: Devin M. Casenhiser, Jim Stieben & Stuart G. Shanker The Milton & Ethel Harris Research Initiative

Therapists: Amanda Binns, Narmilee Dhayanandhan & Nadia Noble Principal Clinical Advisors: Stanley Greenspan & Jake Greenspan with contributions from Yael Binya, Tim Bleeker and Cindy Harrison

ABSTRACT

Other Measures

TIMELINE

TITLE: Assessing behavioral and neurological outcomes of intensive DIR intervention for children with autism.

Parents will log hours spent providing DIR to their child each week.

The therapy phase of this study began October 30th, 2006.

November 2006

November 2007

November 2008

November 2009

Concurrent histories are taken every 6 months to document supplemental treatments children might be receiving

BACKGROUND:

To investigate the intervention at both the psychological and the neurophysiological level in an effort to document the effectiveness of DIR. METHOD: Participants: 50 children aged 2;1-5;2 with a diagnosis of an autistic spectrum disorder confirmed by ADOS and ADI-R criteria. 25 typically developing children who serve as a control group for the neurophysiological data (The typcially developing group receive assessments as with the treatment groups, but do not receive treatment).

Procedure: The participants were assessed to confirm a diagnosis of an autistic spectrum disorder using ADOS and ADI-R. They were subsequently assessed for cognitive functioning and assigned to one of two groups using a random blocking procedure based on age and cognitive functioning. One group was randomly selected as the immediate treatment group. The other group was selected as the 12-month delayed treatment group.

Both groups will receive a total of 24 months of DIR therapy. Groups did not differ statistically in terms of age or cognitive functioning at the time of the first round of assessments.

t ne mt aer T et ai de m m I

OBJECTIVE:

Therapy begins for Immediate Treatment Group

PreTre atm ent Assessments

t ne mt a er T deyal e D

Although ABA (Applied Behavior Analysis) models are the best studied and most popular forms of treatment for Autism, the DIR model (Developmental Individual-Difference, Relationship-Based Model is fast gaining popularity. While there is promising descriptive evidence for the success of DIR intervention, there remains a lack of controlled scientific studies to evaluate its efficacy. Furthermore, there has been no systematic attempt to determine whether interventions can have an impact on neurobiological functioning.

Bayley-III

0-42

WPPSI/WISC (preferred)

2;6-7;3

Diagnostic

Training of therapists, supervision and/or consultation is being provided by Stanley Greenspan, Jake Greenspan, Tim Bleeker, Cindy Harrison and Yael Binya.

Sensory

Although the program focuses on the child, therapists endeavor to treat the whole family in keeping with the DIR philosophy. Families with difficulties beyond the scope or skills of the therapists are referred for external services as needed (e.g., social worker).

ASSESSMENTS

Cognitive

Social Emotional Functioning

ELECTROPHYSIOLOGICAL ASSESSMENTS

Face, Emotion Gaze Task

We are conducting electrophysiological (ERP) assessments of face, emotion and eye-gaze encoding processes to look for treatment related changes in the brain. ERP components associated with face perception, emotion encoding and intentional eye-gaze behavior are known to be aberrant in children with autism. We expect to identify changes in both amplitude and latency of these face specific ERP components in children who successfully respond to treatment.

Therapy begins for Delayed Treatment Group

Age-Range

The treatment program follows the method and techniques of DIR as set forth in The Child with Special Needs, Engaging Autism, the ICDL Diagnostic Manual for Infancy and Early Childhood and the DIR FloortimeTechniques training videos.

Families meet each week for 2-3 hours with DIR therapists (certified SLPs and OTs) for ongoing coaching/ instruction, evaluation of progress and setting goals. Participants receive 1 Floortime session, 1 speech-language session (as needed), and 1 OT session (as needed) each week.

36-Month Assessments

Measure

Functional Skills

In keeping with the original model, primary caregivers are expect to conduct 20-30 hours of Floortime at home.

24-Month Assessments

Variable

Language

TREATMENT PROGRAM

12-Month Assessments

Pre-School Language Inventory

0-6;11

CASL (preferred)

3;0-26 years

Vineland

0-18 years

TABS

(used as process measure)

SEGC (Bayley subscale)

(used as process measure)

FEAS

(used as process measure)

ADOS

2 – adult

ADI

2 – adult

Sensory Profile

Early Social (used as process Communication measure) Scales Electrophysiological assessments are administered every 6 months.

Electrophysiology EEG/ERP All other assessments are administered at

We are also investigating the effects of treatment on Mu wave suppression during an action-observation task. Mu rhythms are believed to be related to “mirror neuron” systems which are known to be aberrant in children and adults with autism and may underlie theory of mind deficits in this population. Although exploratory, we expect to find increased Mu rhythm suppression during observation of action in our children who respond favorably to treatment.

EEG assessments are being carried out using a dense-array (128 electrode) recording system (Electrical Geodesics Incorporated).

Eye-tracking is monitored through a Tobii X-50 eye-tracking system fully integrated into the EEG recording data stream.

Children are provided with a 3 to 4 week training program to acclimate to the EEG nets and the testing format. Each family is provided with several “mock” EEG nets and are being trained to practice with net application procedures once per day prior to being tested in the lab. Children are also given a “mock” version of the tasks (using animations) to help acclimate to the testing environment.

N170 Face Specific ERP Component

PRIMARY ANALYSES In November 2007, we will compare the immediate treatment and delayed treatment groups to determine whether DIR intervention had a significant effect on any of the measures (assessments) we are recording.

Following 24 months of treatment, we will determine the magnitude of the gains made by children receiving intensive DIR intervention.

Analyses will be conducted between the parent treatment logs (which log the number of hours spent in treatment each week) and child outcomes to determine the strength of the correlation between the number of hours spent in treatment and a child’s outcomes.

Certain children may respond better to DIR treatment than others. Accordingly, a cluster analysis will be conducted to determine whether it is possible to establish a profile that might suggest how successful DIR intervention will be for a child matching that profile.

Social Reciprocity

Assessment Schedule

pre-treatment following 12 months of treatment

This research is made possible in part by a generous gift from Unicorn Foundation

following 24 months of treatment.

The delayed treatment group receives one additional assessment 12months prior to starting their treatment.

For additional information please contact: Devin Casenhiser (dcasenhi@yorku.ca) or Jim Stieben (jstieben@yorku.ca) The Milton & Ethel Harris Research Initiative York University

Summary Counter-regulate to manage VIGILANCE – Pay attention to Adaptive Timing Never Give Up, Never Surrender

References  Ainsworth, M. et al. Patterns of attachment: A psychological study of the strange situation. Hillsdale, NJ: Erlbaum (1975).  Bester-Merideth, J, et al. Species Differences in Paternal Behavior and Aggression in Peromyscusand Their Associations with Vasopressin Immunoreactivity and Receptors. Hormones and Behavior 36, 25–38 (1999).  Bester-Merideth, J, et al. Vasopressin and Aggression in CrossFostered California Mice (Peromyscuscalifornicus) andWhiteFooted Mice (Peromyscusleucopus). Hormones and Behavior 40, 51–64 (2001).

References….  Bowlby, J. (1969/1982). Attachment and loss: Vol. 1.

Attachment. New York: Basic Books  Bowlby, J. (1973). Attachment and loss: Vol. 2.

Separation. New York: Basic Books.  Bowlby, J. (1980) Attachment and loss: Vol. 3. Loss. New York: Basic Books.

References….  Brazelton, T. Infants and Mothers: Differences in Development. Dell, 1983.  Brazelton, T. The Earliest Relationship: Parents, Infants, And The Drama Of Early Attachment. Perseus Books, 1991.  Brazelton, T. Neonatal Behavioral Assessment Scale 3rd Ed.. Mac Keith Press, London, 1995.

References….  Caspi, A, et al. Role of Genotype in the Cycle of Violence in Maltreated Children. Science 297, 851 - 853 (2002).  Caspi, A, et al. Influence of Life Stress on Depression: Moderation by a Polymorphism in the 5-HTT Gene.

Science 301; 386-389 (2003).  Charman, T and Hudry, K. Interventions targeting joint attention and symbolic play can improve aspects of these skills in young children with autism. Evid. Based Ment. Health; 10; 21(2007).

References….  Delville, Y et al. Behavioral and Neurobiological Consequences of Social Subjugation during Puberty in Golden Hamsters. J Neurosci, April 1, 1998, 18(7):2667–2672.  Data Analysis and Center for Software, US Department of Defense. Artificial Neural Networks Technology. Available at: irrigation.rid.go.th  Diagnostic Manual for Infancy and Early Childhood. Interdisciplinary Council on Developmental and Learning Disorders, 2005.  Feder, D., The Bun. 2002. Video used with permission from Saltwaterblue productions.  Feder, J., A Study in Embedding Field Theory: Numerical Analysis of the NonRecurrent Gated Dipole, Boston University Archives, 1982.  Fraiberg, S., Adelson. E., Shapiro, V. (1975). Ghosts in the nursery: A psychoanalytic approach to the problem of impaired infant-mother relationships.

JAACAP, 14, 387422.

References…  Greenspan, S. Infancy and Early Childhood: The Practice of Clinical Assessment and Intervention with Emotional and Developmental Challenges. 1992. International Universities Press.  Greenspan, S, DeGangi, G, Wieder, S. The Functional Emotional Assessment Scale (FEAS) for Infancy and Early Childhood: Clinical and Research Applications. 2001The Child with Special Needs: Encouraging Intellectual and Emotional Growth. International Universities Press, 1997.  Greenspan, S.I. and Wieder, S. Developmental Patterns and Outcomes in Infants and Children with Disorders in Relating and Communicating: A Chart Review of 200 Cases of Children with Autistic Spectrum Diagnoses. The Journal of Developmental and Learning Disorders. 1:87-141 (1997).

References….  Greenspan, S. Building Healthy Minds: The Six Experiences that Create Intelligence and Emotional Growth in Babies and Young Children. Perseus Books.

1999.  Greenspan S. Greenspan Social-Emotional Growth Chart.

San Antonio, TX: Harcourt Assessment; 2004.  Greenspan, S and Lewis, D, The Affect-based Language Curriculum (ABLC): An Intensive Program for Families Therapists and Teachers. 2nd Ed. Interdisciplinary Council on Developmental & Learning Disorders, 2005.

References….  Greenspan, S, and Wieder, S. Engaging Autism: The Floortime Approach to Helping Children Relate, Communicate and Think.Perseus Books, 2006.  Greenspan, et al. Guidelines for early identification, screening, and clinical management of children with autism spectrum disorders. Pediatrics 121; 828-30 (2008).  Grossberg - Grossberg and Seidman - NEURAL DYNAMICS OF AUTISTIC BEHAVIORS:Cognitive, Emotional, and Timing Substrates.Psychol Rev 2006;113(3):483-525.

References….  Laucht, M, et al. Interacting Effects of the Dopamine Transporter Gene and Psychosocial Adversity on AttentionDeficit/Hyperactivity Disorder Symptoms Among 15-Year-Olds From a High-Risk Community Sample. ARCH GEN PSYCHIATRY/VOL 64, MAY 2007 (585-590).  Lewis, M, et al. Neurophysiological Correlates of Emotion Regulation in Children and Adolescents. Journal of Cognitive Neuroscience; 18; 430-443 (2006).  Lord, C, and McGee JP, eds. National Research Council, Division of Behavioral and Social Sciences and Education, Committee on Educational Interventions for Children With Autism. Educating Children With Autism. Washington, DC: National Academy Press; 2001.

References ….  Pollack, Jackson Number 1 (1948). Oil on canvas, 68 inches x 104 inches. The Museum of Modern Art, New York City.  Medina, J. Why Emotional Memories are Unforgettable.

Psychiatr Times, May 2008.  Mundy, P. J Autism Dev Disord; 27; 653-676 (1997).  Mundy, P. Attention, Joint Attention, and Social Cognition.

Cur Dir in Psychol Sci.; 16; 269-274 (2007).

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