Flexibility in Brain and Behavioral Functioning in ADHD: Implications for Treatment

• M.I.N.D. Institute • Department of Psychiatry & Behavioral Sciences

A Lack of Flexibility Is Consistent with Impairment in “Separating the Wheat from the Chaff” • Review behavioral and neural symptoms consistent with this model In separating the wheat from the chaff, you select what is useful or valuable and reject what is useless or worthless.

• Consequences of this impairment • Behavioral and pharmacological treatment implications

ADHD      Most prevalent childhood psychiatric disorder Greater than 2 million in United States 3% to 5% of childhood population 4% of adults 5 males to 1 females Females more inattention & cognitive problems; males more conduct & impulse problems Key symptoms Attention, hyperactivity (restlessness), impulsivity

Comorbidity

• Learning disabilities • Anxiety • Depression • Oppositional Defiant Disorder • Conduct Disorder • Autism

• ADHD Individuals Have Difficulty Matching Their Behavior and Brain Functioning to Current Task Demands

flex·i·bility (flex'i·bil'i·ty)

The ability to adjust readily to different conditions A lack of specificity for brain function symptomatic of lack of flexibility

Underlying Mechanism for Impaired Flexibility: One Hypothesis

• Intra-individual variability (IIV) – Measure of variability in performance within an individual – Usually measured via response time – Fluctuations occur over a period of seconds and is distinguished from systematic changes related to practice or learning – Observable in natural situations • Children with ADHD are “consistently inconsistent” • Appears to be heritable • Responds to medication

Example of IIV in Working Memory

– Predominant research in IIV in ADHD until recently has been in response inhibition – If IIV is a more general phenomenon expect to see in other areas of ADHD impairment – Working memory known to be impaired in ADHD • Working memory is the ability to maintain and

manipulate

information over short periods of time – Is there evidence for IIV differences between ADHD and controls in working memory?

• • No Group Differences in Working Memory Accuracy, Only Omission Errors

No group differences in accuracy Thus, no global impair ment in working memory

1.00

0.90

0.80

0.70

ADHD N=25 Controls N=24

0.60

0.50

•

Omission errors Differences in Group, Level, Group X Level

•

Omission errors reflective of “inattention” loss of focus

25 20 15 10 5 0 1 2

Level of Task Difficulty

3 Buzy et al., in press, Child Neuropsychology 1 2

Le ve l of Task Difficulty

3

IIV Group Differences in Working Memory Paradigm

ADHD significantly more IIV in response time

Group main effects 600 Tau (

d

= .90);

p <

0.01

500

ADHD N=25 Controls N=24

400 Buzy et al., in press Child Neuropsychology 300 200 100 0 1 2

Level of Task Difficulty

3

Measures of IIV Are Significantly Correlated with Hyperactivity & Restlessness/Impulsivity (n=25) CPRS–R:L Scales Cognitive Problems / Inattention Hyperactivity Accurac y Omis sion Errors .30

.41*

Restlessness-Impulsivity .28

ADHD Index .27

-.02

.27

.23

.04

Mu Sigma Tau .27

.54**

.35

.49* .40*

.22

.17

.16

.06

.37

.35

.13

Increased PreSMA Activation in ADHD Associated with > Variability; Opposite for HCs Are ADHD subjects using prefrontal & motor regions to compensate at the expense of availability for higher-order tasks?

Pre-SMA; Region significantly different in correlation between ADHD & HC Intrasubject Variability on No-Go Condition Suskauer et al., 2008

Default Network and Attention •Regions along brain’s medial wall that are deactive during demanding task performance (Raichle et al.,2001) •Regions are active when -monitoring the environment, body or emotional state - internal thought processes or mind wandering •Suppression of these regions (i.e., deactivation) during cognitively-demanding tasks is linked to successful performance Raichle et al., (2001) •Inability to suppress activation in this network is linked to distraction, errors or momentary attention lapses

Anticorrelation between Default Network and Task-Related Regions During Resting State Study in Adults with ADHD Castellanos et al., 2008: Bio Psych Decreased functional connectivity between dorsal ACC seed & posterior components of default-mode network (i.e., precuneus and post cingulate) in ADHD.

Relationship between Task Difficulty and Deactivation

• Degree of suppression in controls related to task difficulty, with greater deactivation associated with increasing difficulty McKiernan et al., (2003) • Our data (Fassbender et al., under review) suggest that in ADHD medial PFC activation is not different from baseline, with the exception to moderate deactivation in ACC/medial PFC.

• HC children display significant deactivation in medial PFC during control and WM tasks with increased deactivation during the more difficult WM task.

Deactivation in Default Mode Network during WM and Control Task Performance in ADHD and HC Groups x = -6 PC/precuneus x = -3

4

x = 0 x = 3 x = 6

1

ACC/mPFC

2 3 1 HC ADHD

4 0 -4 -8 -12 -16 *

AT

1 2 *

VSAT

*

2

4 0 -4 -8 -12 -16

3

4 0 -4 -8 -12 -16

4

4 0 -4 -8 -12 -16 * 1 Med PFC 1 * 2 2 * 1 Pc/cun * 2 * * * * Both groups deac

Correlation between IIV & Medial PFC Activity in Subjects with ADHD

Greater activity in the medial PFC linked to greater IIV on task. Thus, those ADHD participants with the greatest IIV are least able to suppress activity in medial PFC within the default attention network Fassbender et al., under review

Working-Memory Associated Task Performance Activation Reveals A Lack of Specialization for WM in ADHD HCs more likely to show different activation pattern between control (AT) & WM (VSAT) task; ADHD group does not. Schweitzer et al., under review

• Is lack of specialization of brain function consistent with greater activation than HCs in alternate regions?

Working Memory Related Changes In Adults with ADHD – Compensation?

HC > ADHD Control group demonstrates WM activation associated with verbal rehearsal strategies & inhibitory control ADHD > HC ADHD group demonstrates WM activation associated with motor & visual processing suggestive of compensatory brain regions and strategies.

Schweitzer et al, Biological Psychiatry, 2004

Grey Matter Difference Maps (A) and Statistical Maps (B) in Children with ADHD and Controls

ADHD subjects show a 20 – 30% increase in grey matter density in bilateral temporal & inferior parietal regions Sowell et al., 2003

Children with ADHD Demonstrate Delayed Cortical Maturation in Most Areas An exception is in the primary motor cortex where the ADHD group demonstrated earlier cortical maturation Shaw, P. et al. 2007, PNAS.

How Does ADHD Affect The Ability to Use Environmental Cues?

Wide Attention focus Take in both relevant arrow plus distracter arrows

<<><<

High Conflict

Narrow Attention focus Take in center arrow only

<<><<

Low Conflict

DSM subtypes Combined Inattentive Hyperactive Impulsive Is there any difference in how different ADHD subtypes perceive environment & cues?

Cognitive Control

Cued flanker paradigm Incongruent

<<><<

Uninformative Cue General Cue

(No information) (Prepare for an incongruent flanker)

Informative Cue conflict alerting

(Prepare to press with your right hand)

atten control/ preparation

CUE

100 90 80 70 60 50

NULL CUE

(No information)

RESPONSE WARNING CUE PREPARATION CUE

(Prepare for an incongruent flanker) (Prepare to press with your right hand)

ADHD-CO ADHD-IA HC TARGET

<<><<

IA not benefiting from specific cue

•

Performance Monitoring/Response Preparation in ADHD Subtypes

Treatment implications: Different subtypes may benefit more from one type of cueing than another e.g., IA with general cues

Effect of MPH on WM Brain Activation: Narrows the Focus

med frontal gyrus MPH may enhance performance by improving PFC’s ability to filter out distracters.

mid frontal gyrus precentral gyrus

Schweitzer et al, 2004

Conclusions/Future Directions

• Individuals with ADHD display greater IIV than HCs in behavior and brain functioning • Findings from IIV-brain imaging studies and general imaging studies suggest ADHD use alternate, wider range of activations suggesting – Lack of specificity for function – Lack of efficiency and utility in brain activation – Effect of behavioral/task strategies – Leads to lack of flexibility & ability to make use of environmental cues • Does inflexibility limit ability to generalize behavioral tx from one setting to another?

When you separate the wheat from the chaff, you select what is useful or valuable and reject what is useless or worthless.

(Wikipedia?)

Acknowledgements

University of California Davis/MIND Institute Catherine Fasbender, Ph.D

Joan Gunther, Psy.D.

Danielle Mizuiri, B.S.

Faye Dixon, Ph.D.

Sharon Coffey Corina, B.S.

Ron Mangun, Ph.D.

Cameron Carter, M.D.

University of Maryland Baltimore Wendy Buzy, Ph.D

Mark Cochran, Psy.D.

Carlos Cortes, M.D.

Rao Gullapalli, Ph.D

Deborah Medoff, Ph.D

Gloria Reeves, M.D.

Malle Tagamets, Ph.D.

Jiachen Zhuo, M.S. Thomas A. Windsor, B.A.

Disclosures

• NIMH • NIDA • UC Davis School of Medicine