neuropsychological implications of ucd

The The Neuropsychology Neuropsychology

of Urea Cycle of Urea Cycle DisordersDisordersM. Cullen Gibbs, Ph.D.M. Cullen Gibbs, Ph.D.

Pediatric NeuropsychologistPediatric Neuropsychologist

Children’s National Medical Children’s National Medical CenterCenter

Neuropsychological Neuropsychological Implications of UCDImplications of UCD

Inherited urea cycle disorders (UCD) Inherited urea cycle disorders (UCD) represent one of the most common groups represent one of the most common groups of inborn errors of metabolism; however, of inborn errors of metabolism; however, little information is available on the natural little information is available on the natural disease progression in persons with UCD. disease progression in persons with UCD.

In UCD the failure of the urea cycle to rid In UCD the failure of the urea cycle to rid the body of excess ammonia causes the body of excess ammonia causes hyperammonemia episodes.hyperammonemia episodes.

These episodes result in toxic effects on the These episodes result in toxic effects on the white matter of the central nervous system. white matter of the central nervous system.

The Importance of White The Importance of White MatterMatter

White matter is, in essence, the mechanism White matter is, in essence, the mechanism by which different regions of the brain by which different regions of the brain communicate with each other.communicate with each other.

White matter fibers in the brain allow White matter fibers in the brain allow communication between the left and right communication between the left and right cerebral hemispheres, within the cerebral cerebral hemispheres, within the cerebral hemispheres, and between the brain stem hemispheres, and between the brain stem and the cerebral hemispheres and the cerebral hemispheres

Damage to the white matter interferes with Damage to the white matter interferes with the ability of different regions of the brain the ability of different regions of the brain to communicate, resulting in cognitive to communicate, resulting in cognitive impairment. impairment.

Why is the Impact of Disease Why is the Impact of Disease Processes on Neuropsychological Processes on Neuropsychological Functioning Difficult to Identify Functioning Difficult to Identify

in Children? in Children? Opposing vectors of development and Opposing vectors of development and

deterioration mask effects of diseasedeterioration mask effects of disease The premorbid level of ability is a The premorbid level of ability is a

raterate of development, not a level of of development, not a level of performance.performance.

0 2 4 6 8 103

4

5

6

7

8

9

10

Developmental

status

Chronological age

Vector of normal development

Vector of disease effect

Resultant of vectors of development and disease in affected child

Hypothetical Effects of Disease and Normal

Development on Growth Trajectory

Courtesy of Dr. Elsa Shapiro; University of Minnesota Medial School.

Problems in the Assessing the Problems in the Assessing the Cognitive Impact of Disease Processes Cognitive Impact of Disease Processes

in Childhoodin Childhood

Unknown premorbid Unknown premorbid intellectual levelintellectual level

Difficult to identify cognitive Difficult to identify cognitive changes in early stages of changes in early stages of diseasedisease

Impact may vary according Impact may vary according to age of onsetto age of onset

Problems Assessing the Cognitive Problems Assessing the Cognitive Impact of Disease Processes in Impact of Disease Processes in

ChildhoodChildhood Because certain mental functions are Because certain mental functions are

not yet developed at the outset of the not yet developed at the outset of the disease and cannot be measured, the disease and cannot be measured, the extent of the impact may not be extent of the impact may not be detected until those functions are detected until those functions are developmentally ready to emerge.developmentally ready to emerge.

Presence of confounding factors, both Presence of confounding factors, both biological and environmental.biological and environmental.

What is What is Neuropsychology?Neuropsychology?

The study of learning and behavior in The study of learning and behavior in relationship to a child’s developing relationship to a child’s developing brain. brain.

A framework that draws from A framework that draws from cognitive sciences, neurology, cognitive sciences, neurology, neuroanatomy, and clinical, social, neuroanatomy, and clinical, social, developmental, biological psychology.developmental, biological psychology.

What is a What is a Neuropsychological Neuropsychological

Evaluation?Evaluation? Examination of external behavior to Examination of external behavior to

make inferences about internal brain make inferences about internal brain function and structure.function and structure.

Formal testing of abilities such as Formal testing of abilities such as memory and language skills assesses memory and language skills assesses brain functioning.brain functioning.

By comparing a child’s test scores to By comparing a child’s test scores to children of a similar age, it is possible to children of a similar age, it is possible to create a profile of the child’s strengths create a profile of the child’s strengths and weaknesses.and weaknesses.

What is the Purpose of a What is the Purpose of a Neuropsychological Neuropsychological

Evaluation?Evaluation? To understand, explain and predict To understand, explain and predict

behaviorbehavior Develop a profile of an individual's Develop a profile of an individual's

cognitive strengths and weaknessescognitive strengths and weaknesses Describe presence and degree of Describe presence and degree of

cognitive impairments and explain cognitive impairments and explain mechanisms responsible for their mechanisms responsible for their perpetuationperpetuation


Evaluation?Evaluation? Measure presence and degree of Measure presence and degree of

behavioral difficulties resulting from behavioral difficulties resulting from neurological basesneurological bases

Establish baseline of functioning for Establish baseline of functioning for systematic comparisons across timesystematic comparisons across time

Measure the cognitive or behavioral Measure the cognitive or behavioral impact of rehabilitation, impact of rehabilitation, pharmacological, surgical or pharmacological, surgical or therapeutic interventionstherapeutic interventions


Evaluation?Evaluation? Help formulate appropriate treatment Help formulate appropriate treatment

plansplans Guide remedial educational or Guide remedial educational or

vocational rehabilitation programs vocational rehabilitation programs Predict individual's ability to achieve Predict individual's ability to achieve

success in particular settingssuccess in particular settings Needs for settings to accommodate to Needs for settings to accommodate to

the individual versus individuals' the individual versus individuals' ability to adapt to the settingability to adapt to the setting

Left Right

Anterior

Posterior

Anterior - Posterior AxisAnterior - Posterior Axis

Anterior SystemsAnterior Systems---- Posterior SystemsPosterior Systems- Anticipates Anticipates - Receives - Receives - Selects GoalsSelects Goals - Encodes- Encodes- Organizes/ PlansOrganizes/ Plans - Stores- Stores- OrchestratesOrchestrates - Structure- Structure- OrganizationOrganization - Knowledge Base- Knowledge Base- MonitorsMonitors- ModulatesModulates

<----> <----> Complimentary RelationshipComplimentary Relationship

Lateral AxisLateral Axis

Left Hemisphere SystemsLeft Hemisphere SystemsPreferentiallyPreferentially involved involved

with:with: Building blocks of Building blocks of

languagelanguage Parts of complex materialsParts of complex materials Temporal processingTemporal processing Processing unimodal, Processing unimodal,

codable informationcodable information Executive of discrete Executive of discrete

motormotor

Right Hemisphere Right Hemisphere SystemsSystems

PreferentiallyPreferentially involved with: involved with: Spatial informationSpatial information Relationship between partsRelationship between parts Configuration of complexConfiguration of complex Processing multi-modal Processing multi-modal

novel informationnovel information Emotional tone in speechEmotional tone in speech

<-->

Domains of Domains of Neuropsychological Neuropsychological

FunctioningFunctioning

General cognitive functioningGeneral cognitive functioning AttentionAttention Executive-regulatory functionExecutive-regulatory function LanguageLanguage Visual/Nonverbal processingVisual/Nonverbal processing Memory& LearningMemory& Learning Sensory and MotorSensory and Motor AcademicsAcademics Social & emotionalSocial & emotional

What are the Potential What are the Potential Neuropsychological Implications Neuropsychological Implications of Damage to the White Matter?of Damage to the White Matter?

Impaired executive functionsImpaired executive functions Slowed speed of processingSlowed speed of processing Impaired spatial processingImpaired spatial processing Impaired coordinationImpaired coordination Dysarthric speechDysarthric speech Depressed moodDepressed mood

Cummings, 1990Cummings, 1990

What are the Executive What are the Executive Functions?Functions?

An “umbrella” term, encompassing… An “umbrella” term, encompassing… those interrelated skills necessary those interrelated skills necessary for purposeful, goal-directed for purposeful, goal-directed activity” activity” ((Anderson, 1998)Anderson, 1998)

““Capacities that enable a person to Capacities that enable a person to engage successfully in independent, engage successfully in independent, purposeful, self-serving behaviors” purposeful, self-serving behaviors” (Lezak, 1993)(Lezak, 1993)

Role of the ExecutiveRole of the Executive

ConductorConductor of the of the orchestra" orchestra"

““CEOCEO of the of the corporation”corporation”

““GeneralGeneral of the of the army”army”

““Domain Domain generalgeneral processes”processes”

Executive Functions as the “Conductor of the Orchestra”

Functions of the “Conductor”Functions of the “Conductor”

1. Initiate goal-oriented action

2. Working Memory

3. Plan & Organize

4. Self-monitor & evaluate

5. Inhibit

6. Flexibility

7. Emotional regulation

8. Self-awareness

Functional Domains of The Executive

Inhibit - stop an action or not react to impulseInhibit - stop an action or not react to impulse Shift - move from one task or situation to anotherShift - move from one task or situation to another Emotional Control - regulate emotional responseEmotional Control - regulate emotional response

Initiate - begin task, activity, attentionInitiate - begin task, activity, attention Working Memory - hold information actively in Working Memory - hold information actively in

mindmind Plan - anticipate future events and develop stepsPlan - anticipate future events and develop steps Organize - establish, maintain orderOrganize - establish, maintain order Self-monitor - attend to behavior/output; reviseSelf-monitor - attend to behavior/output; revise

Functions of the “Orchestra”

1. Perception

2. Conceptual thinking

3. Language processes

3. Visual-spatial processes

4. Memory

5. Sensory inputs

6. Motor outputs

7. Emotion

8. Knowledge & skills• social• non-social

Functions of the “Conductor”Functions of the “Conductor”

1. Initiate goal-oriented action

2. Working Memory

3. Plan & Organize

4. Self-monitor & evaluate

5. Inhibit

6. Flexibility

7. Emotional regulation

8. Self-awareness

Functions of the “Orchestra”

1. Perception

2. Conceptual thinking

3. Language processes

3. Visual-spatial processes

4. Memory

5. Sensory inputs

6. Motor outputs

7. Emotion

8. Knowledge & skills• social• non-social

Critical features of Critical features of Executive Control Executive Control FunctionsFunctions (Denckla 1995)(Denckla 1995)

Provide for delayed respondingProvide for delayed responding Future-orientedFuture-oriented Strategic action selectionStrategic action selection IntentionalityIntentionality Anticipatory SetAnticipatory Set Freedom from interferenceFreedom from interference Ability to sequence behavioral Ability to sequence behavioral

outputsoutputs

Demand Situations for Demand Situations for Executive FunctionsExecutive Functions

Multi-step tasks/ learningMulti-step tasks/ learning Novelty (lack of experience base) Novelty (lack of experience base)

vs Automaticity (familiar)vs Automaticity (familiar) High vs low stressHigh vs low stress Future vs present orientationFuture vs present orientation Intentional action selectionIntentional action selection

Outcome of “Good” Outcome of “Good” Executive FunctionExecutive Function

Purposeful, goal-directed Purposeful, goal-directed activityactivity

Active problem solving Active problem solving Self-controlSelf-control IndependenceIndependence Reliability and consistencyReliability and consistency Positive self-efficacy Positive self-efficacy Internal locus of controlInternal locus of control

The Frontal lobes: Strategic executive

ConductorOrchestraOrchestra

Neuroanatomic Organization:Neuroanatomic Organization:

Frontal lobes are densely connected with Frontal lobes are densely connected with other cortical and subcortical regionsother cortical and subcortical regions

Prefrontal system is highly, reciprocally Prefrontal system is highly, reciprocally interconnected with the interconnected with the limbic (motivational) system,limbic (motivational) system, reticular activating (arousal) systemreticular activating (arousal) system posterior association cortex (perceptual/ posterior association cortex (perceptual/

cognitive processes and knowledge base)cognitive processes and knowledge base) motor (action) regions of the frontal lobesmotor (action) regions of the frontal lobes

Interventions: General Interventions: General PrinciplesPrinciples

Teach Teach goal-directedgoal-directed problem-solving problem-solving processprocess,, within everyday meaningful routines,within everyday meaningful routines, having real-world relevance and application,having real-world relevance and application, using key people (parents/ teachers/ peers) using key people (parents/ teachers/ peers)

as models, “coaches” (Co-conductor).as models, “coaches” (Co-conductor).


External to internal processExternal to internal process External models of multi-step External models of multi-step

problem-solving routinesproblem-solving routines External guidance to develop & External guidance to develop &

implement everyday routinesimplement everyday routines Practice application/ use of routinesPractice application/ use of routines Fade external support to cueing Fade external support to cueing

internal generation & use of routinesinternal generation & use of routines


External to internal processExternal to internal process Internal control to generate & use Internal control to generate & use

specific problem-solving routinespecific problem-solving routine Generalization to new situation, Generalization to new situation,

requiring some external guidancerequiring some external guidance Accumulate experience, examine Accumulate experience, examine

conditions for selective use of conditions for selective use of various routinesvarious routines

Feedback throughout (i.e., reward)Feedback throughout (i.e., reward)

Structuring an executive Structuring an executive function intervention function intervention

program program

Use of everyday routines with Use of everyday routines with (e.g., Goal-Plan-Do-Review)(e.g., Goal-Plan-Do-Review)

Support working memory via Support working memory via “hard copy” of routine“hard copy” of routine

Allowing child to become Allowing child to become increasingly more active in increasingly more active in formulating plans and reviewing formulating plans and reviewing their performancetheir performance

What Do We Hope to What Do We Hope to Learn?Learn?

By using a developmental approach to By using a developmental approach to analyzing both natural history and response analyzing both natural history and response to treatment we hope to discover to treatment we hope to discover information about . . .information about . . .

neurobehavioral/neuropsychological neurobehavioral/neuropsychological associations with localized dysfunctionassociations with localized dysfunction

Age related differences in Age related differences in neurobehavioral/ neuropsychological neurobehavioral/ neuropsychological sequelaesequelae

Other phenomena such as how Other phenomena such as how intervention might change the trajectory intervention might change the trajectory of developmentof development

What Do We Hope to What Do We Hope to Learn?Learn?

Neuropsychological studies of UCD can help to Neuropsychological studies of UCD can help to identify specific effects on the brain associated with identify specific effects on the brain associated with UCD and correlate these findings with behavior and UCD and correlate these findings with behavior and outcome. outcome.

The impact of UCD occurring at different stages of The impact of UCD occurring at different stages of development will help us to better understand the development will help us to better understand the impact of the disease process on the developing brain. impact of the disease process on the developing brain.

The quantification of neuropsychological and The quantification of neuropsychological and neurobehavioral outcomes will be increasingly neurobehavioral outcomes will be increasingly important in determining the efficacy of interventions. important in determining the efficacy of interventions.

Efficacious educational/ behavioral interventions for Efficacious educational/ behavioral interventions for children with UCD based on their neuropsychological children with UCD based on their neuropsychological profile.profile.

neuropsychological implications of ucd

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