Neuropsychology & Cognitive
Neuroscience of ADHD
Michelle Benjamin
4/15/09
Cognitive Neuroscience of ADHD
•
•
•
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Neuropsychological assessment of attention
Theories from neuropsychology
Neuroanatomy overview
Neuroimaging
– Structural imaging findings
– Functional imaging results
• Genetics
• Future directions
Neuropsychological Perspective
BRAIN—BEHAVIOR relationships
• Neuropsychology is the “applied science concerned with the
behavioral expression of brain dysfunction” (Lezak, 1995)
• Questions to think about in neuropsychology:
– What brain regions are implicated in the behavioral
manifestations of attention problems and ADHD?
– How do we measure the functioning of those brain regions?
• Inattention
• Impulsivity
• Hyperactivity
Attention Assessment
Attention: Basic Definitions
• Selective or Focused Attention: vigilance in
monitoring information
• Divided Attention: ability to respond to more than
one task simultaneously
• Sustained Attention: ability to maintain attention
and respond consistently during a repetitive or
continuous activity
• Alternating Attention/Mental Shifting: mental
flexibility to shift from one task to another as
required
Baron, 2004
Attention: Measures
• Attention batteries:
– Test of Everyday Attention (TEA)
• adult battery
– Test of Everyday Attention for Children (TEA-Ch)
• Child extension of adult TEA
Attention: Measures
• Single instruments:
– Wecshler test examples: WISC-IV Letter-Number
Sequencing, Digit Span, Cancellation, WISC-III
Arithmetic
– Spatial Span tasks: e.g., Corsi blocks/WMS-III Spatial
Span
– Other span tests: Knox Cube (visual span),
alpha-, pattern- & word-span measures (discussed in
Baron, 2004)
– Continuous Performance Tests (e.g., CPT-II)
– Auditory Consonant Trigrams
Attention Measures
Single Instruments, continued…
– CHIPASAT (Children’s Paced Auditory Serial
Addition Test)
– Trail Making Tests: D-KEFS Trails, TMT,
Color Trails
– Symbol Digit Modalities Test
– Visual Search Cancellation Tests
– Underlining Test
– Progressive Figure Test & Color Form Test
Attention: Measures
• Behavioral report (covered already in class).
Examples include:
– Connor’s Rating Scales-Revised (CPRS)
– Specific subscales from parent/self report (e.g., BASC
Attention scale)
– BRIEF (2000)
– Brown Attention-Deficit Disorders Scales (2001)
– Diagnostic Rating Scale
– Attention Deficit Hyperactivity Disorder Rating ScaleIV – Home Version
Test of Everyday Attention for
Children (TEA-Ch)
• For children ages 6-16 years.
• Extension of Test of Everyday Attention (adult
attention battery).
• Published in 1999
• 2 forms: useful for re-testing situations
• Normed on 293 Australian children & adolescents
6-16 years.
TEA-Ch Subtests
• Sustained Attention:
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–
–
–
–
Score!
Sky Search DT
Score DT
Walk, Don’t Walk
Code Transmission
• Selective Attention:
– Sky Search
– Map Mission
• Attentional
Control/Switching:
– Creature Counting
– Opposite Worlds
Note. See handout for individual subtest descriptions
TEA-Ch
• Clinical populations reported in manual
– ADHD (N=24 boys)
• Out of 6 subtests, the ADHD group was worse that
age-matched controls for the following: Score!,
Score DT, Walk, Don’t Walk, Opposite Worlds
– Note: Creature Counting, Code Transmission and Map Mission were not given
– TBI (N=18)
• Out of 8 subtests, the TBI group was worse that agematched controls for ALL but the following:
Creature Counting (timing) and Score!
– Note: Walk, Don’t’ Walk was not given
Continuous Performance Tests
• Many different versions: (Riccio et al 2001 has
review & comparison)
• Handout explaining CPTs
E.g., CPT-II
• Visual vigilance measure.
• Individuals 4 years to adulthood.
• Press for all letters EXCEPT ‘X’
• Non-X and X stimuli are presented in blocks
varying from 1-, 2- and 4-second ISIs across
blocks.
• Task lasts for approximately 14 minutes.
CPT-II
• Normative data:
– N=1483 children 6-17 years. The smallest sample is 67 years (N=88).
– Total normative sample: N=1920; through adulthood.
• Oldest normative group is 55+, also small sample in this
subgroup (N=54).
– Total ADHD clinical sample: N=378.
• N=271 for ADHD children/adolescents 6-17 years.
Continuous Performance Tests
• CPT indices (see handout):
– Omissions: suggestive of inattentiveness. Measures
nonresponding
– Comissions: may represent an inability to withhold motor
responses (suggests impulsivity)
– Overall hit reaction time: average speed of correct
responses for entire test. Slowed RT and nonresponding
suggestive of inattention to task
– Overall standard error: attentional variability overall (e.g.,
high levels suggest inconsistency of speed of responses
(fluctuating attention from trial to trial)
Continuous Performance Tests
• Other CPT indices:
– Perceptual sensitivity (d’): whether difficulty in
discriminating perceptual features of targets vs. nontargets
– Response bias (B): individual’s response tendency.
e.g., cautious vs. risk-taking
Other CPT output (e.g., CPT-II) includes hit RT
block rate change, hit SE block change, hit RT ISI,
hit SE ISI change.
Other Attention Single Measures
• Trail Making Tests:
• Extension from adult measures (e.g., Army Individual
Test Battery (1944), Halstead-Reitan battery)
• Trail A: number sequencing (1-2-3-4…)
• Trail B: Number-letter sequencing (1-A-2-B..)
• Children 9-14 use versions with 15 items for each of
the above (some norms available from research extend
lower)
• Ages 15-adult use versions A & B with 25 items each
Other Attention Single Measures
• DKEFS Trail Making Test:
– normed for 8 to 89 years
– Better for teasing apart problems with TMT: e.g., if
problem is basic motor &/or visual problem vs.
cognitive shifting
– 5 separate conditions:
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1) Visual scanning
2) Number sequencing (similar to typ. Trails A)
3) Letter sequencing
4 Number-letter switching (similar to typ. Trails B)
5) Motor speed
– Maximum times: 150 sec for Conditions 1, 2, 3, 5; 240
sec for Condition 4
Other Attention Single Measures
• Color Trails Test:
– Instead of letters, colors are substituted to
minimize knowledge of English alphabet.
– Alternate between colors and 25 numbers.
Other Attention Single Measures
• Auditory Consonant Trigrams Test:
– Test of divided attention and rapid information
processing
– Normative data for ages 9-15 are reported in Baron,
2004
– Interval length for children: 0, 3, 9, and 18 seconds
– Person is given 3 letters to remember in any order.
– S/he is then told to count backwards from a certain
number until told to stop. (Children count backward by
1s; adults by 3s.)
Other Attention Single Measures
• Children’s PASAT (CHIPASAT):
– Test of divided attention, sustained auditory attention and
information processing speed
– Requires math calculation skills
– Normative data for ages 8-15 are reported in Baron, 2004.
(Note: very small N for 14-15 y.o.)
– Presentation is 1 digit every 2.8 (suggested for practice),
2.4, 2.0, 1.6 or 1.2 seconds. 61 digits per trial on tape.
– Person must add each new number presented to the one
heard immediately prior and say the sum aloud, continuing
to do this with each new number.
– Baron cautions against interpreting scores below 9.5 years
with this measure.
ADHD: Neuropsych Assessment
• NP assessment also traditionally includes measures of
executive functions, such as response inhibition, task
organization, planning abilities, reasoning, and working
memory. Example measures include:
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–
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Stroop Inteference
Verbal fluency
Tower tasks
WCST
Go/NoGo tasks
ADHD: Neuropsychological theories
• Executive Function Theory of ADHD
– ADHD symptoms arise from a primary deficit in
executive functions (neurocognitive processes for
maintaining an appropriate problem-solving set to attain
a later goal).
– Executive functions involves the prefrontal cortex,
basal ganglia & thalamus
– 4 factors of executive function tasks
1) Response inhibition and execution
2) Working memory and updating
3) Set-shifting and task-switching
4) Interference control
ADHD: Neuropsychological findings
• Meta-analysis on executive function
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–
–
–
Willcutt et al 2005
83 studies (N=3734 ADHD; N=2969 no ADHD)
Significant group differences in 109:168 (65%) comparisons
Mean weighted effect size=.54 (range .43-.69; medium effect)
ADHD vs. control differences most consistently seen in
• stop-signal reaction time (SSRT) (82% of 27 studies)
• CPT omission errors (77% of 30 studies)
– Less studies in working memory but promising
• 75% of spatial WM w/sign group differences
• 55% of verbal WM w/sign group differences
– WCST more weakly related to ADHD than other EF measures
ADHD: Neuropsychological findings
Executive measures (Willcutt et al 2005)
Executive Function Task
+95%
CI
Stop-Signal RT
Weighted
Mean Effect
Size
.61
+.09
No. studies finding
significant group
difference
22/27
% studies finding
significant group
difference
82%
CPT Commission Errors
.51
+.08
17/28
61%
CPT Omission Errors
.64
+.09
23/30
77%
WCST Persev. Errors
.46
+.09
11/24
46%
Trails B Time
.55
+.11
8/14
57%
Tower of Hanoi
.69
+.26
4/7
57%
Tower of London
.51
+.18
3/6
50%
Porteus Mazes
.58
+.19
4/5
80%
ROCFT Copy
.43
+.12
5/9
56%
Verbal Working Memory
.55
+.11
6/11
55%
Spatial Working Memory
.63
+.16
6/8
75%
ADHD: Neuropsychological findings
Nigg et al 2005
Nigg 2005
ADHD: Neuropsychological theories
• Problem with executive function theory
– Sensitivity and specificity of any single executive
deficit is not high enough to support EF as cause of
all ADHD cases.
• While 80% ADHD have deficit on at least 1 EF
measure, so do 50% of controls.
• Only 50% of ADHD children have deficit on most
sensitive measure (SSRT) compared to 10% of controls.
– Argue that an executive dysfunction subtype may
be distinguishable from other subtypes.
Nigg et al (2005)
ADHD: Neuropsychological theories
• Motivational dysfunction model
Sonuga-Barke (2005)
– Disruption in signaling of delayed reward
– Delayed aversion model of ADHD supported by human and
animal data
– Sonuga-Barke (2005)
• Executive dysfunction model: frontostriatal circuit
prefrontal—dorsal striatum
• Delay aversion model: orbitofrontal—ventral striatum
• Both circuits modulated by dopamine
• Dual or multiple deficits (versus single-deficit model)
ADHD: Neuropsychological theories
• Cognitive-Energetic Model
Sergeant 1999, 2005
– Overall efficiency of information processing is
determined by interplay between computation
mechanisms of attention, state factors &
management/executive function.
– Encompasses both bottom-up and top-down process
and approaches in ADHD at 3 levels.
– Attention to fact that ADHD causes defects at 3 levels:
• Cognitive mechanisms (e.g., response output)
• Energetic mechanisms (e.g., activation; effort)
• Management systems
ADHD: Neuropsychological theories
• Cognitive-Energetic model levels
• 1) 4 stages of the computational
mechanisms of attention
• 2) 3 distinct energetic pools
• 3) Overriding management or executive
system
ADHD: Neuropsychological theories
• Cognitive-Energetic model levels
• 1) 4 stages of the computational mechanisms
of attention
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–
–
–
Encoding
Search
Decision
Motor organization
– Stages all associated with experimental task
variables
ADHD: Neuropsychological theories
• Cognitive-Energetic model levels
• 2) 3 distinct energetic pools:
– Effort, arousal & activation
– A) EFFORT:
• Defined as energy necessary to meet task demands.
• Affected by cognitive load.
• Required when current organism state does not match
task demand.
• Encompasses motivation & response to contingencies.
• Associated with hippocampus.
• Functions to excite & inhibit arousal & activation.
ADHD: Neuropsychological theories
• Cognitive-Energetic model levels
• 2) 3 distinct energetic pools:
– B) AROUSAL:
– Defined as phasic responding to that is time locked to
stimulus processing.
– Typically influenced by signal intensity and novelty.
– Associated with mesencephalic reticular formation &
amygdala.
ADHD: Neuropsychological theories
• Cognitive-Energetic model levels
• 2) 3 distinct energetic pools:
– C) ACTIVATION:
– Association with the tonic physiologic readiness to
response.
– Affected by task variables such as preparation, alertness,
time of day, and time on task.
– Associated with basal ganglia.
ADHD: Neuropsychological theories
• Cognitive-Energetic model levels
• 3) Overriding management or executive
system
– Associated with planning, monitoring, error
detection & correction
– Associated with prefrontal cortex
ADHD: Neuropsychological theories
ADHD: Neuropsychological theories
• Cognitive-Energetic model levels
• Supported by the following:
– ADHD individuals are slower and more
variable in RTs than controls
– ADHD performance varies more than controls
as a function of event rate (e.g., faster rate
normalizes performance of ADHD groups)
ADHD: Neuroanatomy review
LATERAL VIEW
MEDIAL VIEW
Nadeau et al 2004
BA
BA99
BA 46
Dorsolateral
Prefrontal
Cortex
from Mai et al., 1997
Lateral
Orbitofrontal
Cortex
Medial
Orbitofrontal
Cortex
from Mai et al., 1997
SMA
Posterior BA 6
Pre-SMA
Anterior BA 6
Anterior
Cingulate Gyrus
BA 24
Rostral
Cingulate Zone
BA 32
from Mai et al., 1997
ADHD: Neuroanatomy review
Prefrontal cortex—general functional background
Frontal lobe region
Dorsolateral prefrontal cortex
Function
Organization, planning,
working memory
ADHD: Neuroanatomy review
Prefrontal cortex—general functional background
Frontal lobe region
Dorsolateral prefrontal cortex
Orbitofrontal cortex
Function
Organization, planning,
working memory
Social inhibition & impulse
regulation
ADHD: Neuroanatomy review
Prefrontal cortex—general functional background
Frontal lobe region
Dorsolateral prefrontal cortex
Function
Organization, planning,
working memory
Orbitofrontal cortex
Social inhibition & impulse
regulation
Medial frontal cortex
Fluency, initiation,
spontaneous behaviors
ADHD: Neuroanatomy review
Prefrontal cortex—general functional background
Frontal lobe region
Dorsolateral prefrontal cortex
Function
Organization, planning,
working memory
Orbitofrontal cortex
Social inhibition & impulse
regulation
Medial frontal cortex
Fluency, initiation,
spontaneous behaviors
Premotor cortex
Sequential motor movements
& motor planning
ADHD: Neuroanatomy review
Prefrontal cortex—general functional background
Frontal lobe region
Dorsolateral prefrontal cortex
Function
Organization, planning,
working memory
Orbitofrontal cortex
Social inhibition & impulse
regulation
Medial frontal cortex
Fluency, initiation,
spontaneous behaviors
Premotor cortex
Sequential motor movements
& motor planning
Motor cortex
Elemental motor movements
ADHD: Neuroanatomy review
Basal Ganglia
Striatum
Ventral Striatum (Archistriatum)
Nucleus Accumbens
Olfactory Tubercle
Neostriatum
Caudate Nucleus
Putamen
In most cognitive neuroscience articles, the striatum
refers to the caudate and putamen.
ADHD: Neuroanatomy review
Basal Ganglia (cont):
Globus Pallidus
Medial Globus Pallidus
Lateral Globus Pallidus
Ventral Pallidum (Archipallidum)
Subthalamic Nucleus
In cognitive neuroscience articles, the lentiform
nucleus refers to the putamen and globus pallidus
together.
ADHD: Neuroanatomy review
SUBCORTICAL STRUCTURES
Coronal view
Axial view
Nadeau et al 2004
Amygdala
from Crosson, 1992
ADHD: Neuroanatomy review
SUBCORTICAL STRUCTURES
NEUROREGULATORY FUNCTIONS
(Enhancement & Suppression)
BASAL GANGLIA REGULATORY BEHAVIOR
+
+
-
+
Cortex
+
Neostriatum
-
+/-
-
SNpc
LGP
-
MGP
Ventral Ant.
Thalamus
+
enhance
Direct
Ventral Ant.
Thalamus
suppress
Indirect
suppress
Hyperdirect
+
All 3
Modulate
• Neuroanatomical research suggests pathways involving
these brain regions known as the “Frontal-Striatal circuits”
cortex (PFC) striatum  globus pallidus  thalamus  cortex (PFC)
“Striatum” – caudate & putamen
(all part of the basal ganglia)
Cortical-subcortical loops
Dorsolateral
Prefrontal
Lateral
Orbitofrontal
Anterior
Cingulate
Motor
Oculomotor
SMA
FEF
DLPF
LOF
ACA
Striatum
PUT
BCN
dlHCN
vmHCN
VS
Pallidum
vlGP
cdmGP
ldmGP
mdmGP
rlVP
Thalamus
VLo
VLm
VAmc
MDpl
VApc
MDpc
VAmc
MDmc
pmMD
Cortex
Alexander, DeLong, & Strick, 1986
BA
BA99
BA 46
Dorsolateral
Prefrontal
Cortex
from Mai et al., 1997
Dorsolateral Prefrontal Cortex:
Basal Ganglia Connections
Dorsolateral
Prefrontal
(BA9) Loop
Dorsolateral
Prefrontal
(BA 46) Loop
Dorsolateral
PFC
Dorsolateral
PFC
Dorsolateral
Caudate Head
Dorsolateral
Caudate Head
rd Globus
Pallidus
dm Globus
Pallidus
VA
Thalamus
VA & DM
Thalamus
Lateral
Orbitofrontal
Cortex
Medial
Orbitofrontal
Cortex
from Mai et al., 1997
Orbitofrontal Cortex:
Basal Ganglia Connections
Lateral
Orbitofrontal
Loop
Medial
Orbitofrontal
Loop
Lateral
OFC
Medial
OFC
Ventromedial
Caudate Nuc.
Nucleus
Accumbens
Globus
Pallidus
Globus
Pallidus
Ventral Ant.
Thalamus
Ventral Ant.
Thalamus
SMA
Posterior BA 6
Pre-SMA
Anterior BA 6
Anterior
Cingulate Gyrus
BA 24
Rostral
Cingulate Zone
BA 32
from Mai et al., 1997
Medial Frontal Cortex:
Basal Ganglia Connections
SMA
Loop
Pre-SMA
Loop
Anterior
Cingulate
Loop
Rostral
Cingulate
Loops
SMA
Pre-SMA
Anterior
Cingualte Gyrus
Rostral
Cingulate Zone
Putamen
Striatal
Bridges
Nucleus
Accumbens
?
Globus
Pallidus
Globus
Pallidus
Ventral
Pallidum
?
Ventral Lat.
Thalamus
Ventral Ant.
Thalamus?
Dorsomedial
Thalamus
?
ADHD: Neuroanatomy & NTs
Curtolo et al 2008
Nigg 2005
ADHD: Neuroimaging
ADHD: Neuroimaging
• Structural imaging: CT & MRI
– MRI: region of interest (ROI)
– MRI: voxel-based morphometry (VBM)
• Functional neuroimaging
–
–
–
–
SPECT
PET
Functional MRI (FMRI)
Magnetic resonance spectroscopy (MRS)
• Electrophysiological techniques
– Quantitative electroencephalography (QEEG)
– Event-related potentials (ERP)
ADHD: Structural neuroimaging
• CT & structural MRI
– Both methods provide information on the
macroscopically visible brain
• Neuroanatomy of the skull, brain tissue and blood
vessels
– Structural imaging does not assess function,
e.g., cerebral metabolic rate and cerebral blood
flow
ADHD: Structural neuroimaging
Computed tomography (CT) or computed
axial tomography (CAT)
– axially acquired series of x-rays of the head to
determine brain structure
– Preferred radiological test in ER: quick, accurate,
widely available
– Used primarily to assess swelling, fractures, blood
products and ventricle size
– Poorer spatial resolution than MRI
ADHD: Structural neuroimaging
– Structural magnetic resonance imaging
(MRI):
• Uses magnetic fields and radio waves to image
brain structures without the use of ionizing
radiation (e.g, x-rays, CT, SPECT, PET)
• Superior resolution and better anatomic fidelity
than CT
• Different planes & types of MRI sequences can
be done to detect abnormalities
Structural neuroimaging
CT compared to MRI
CT
MRI
DWI
Silver et al 2005
Structural neuroimaging
structural MRI sequences
Silver et al 2005
Structural neuroimaging
MRI structural sequences
Silver et al 2005
ADHD: Structural neuroimaging
STRUCTURAL MRI METHODS
1) MRI region of interest (ROI)
–
Method of measures brain volumes for particular areas of
study and comparing size between subject groups.
–
Manual (or now semi- or fully automated) tracings of
particular cortical and subcortical areas in the brain.
–
Uses structural brain landmarks to define ROIs.
–
Most studies in ADHD (or patient populations) have used
this technique.
ADHD: Structural neuroimaging
STRUCTURAL MRI METHODS
2) Voxel-based morphometry (VBM)
– Method for simultaneously comparing, voxelby-voxel, where the major differences occur in
subject patient populations and healthy
controls.
– Differences between subject groups (regions of
reduced voxel density of either gray or white
matter) are plotted on a standard 3D surface
place of the brain.
ADHD: Structural neuroimaging
• Structural imaging findings in ADHD
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–
–
–
–
Total cerebral volume
Cortical areas
White matter (corpus callosum)
Subcortical regions
Cerebellum
ADHD: Structural neuroimaging
• Structural imaging findings in ADHD
–
–
–
–
–
Total cerebral volume
Cortical areas
White matter (corpus callosum)
Subcortical regions
Cerebellum
ADHD: Structural neuroimaging
• Total & lateralized cerebral volume reductions
– 7 of 12 studies with children thru age 19
• Total cerebrum, particularly the right hemisphere is 35% smaller.
• 1 study reported reduced intracranial volume.
– Smaller total gray and white matter also reported.
– NO studies report significantly larger volumes.
Seidman et al 2005 review
ADHD: Structural neuroimaging
• Structural imaging findings in ADHD
–
–
–
–
–
Total cerebral volume
Cortical areas
White matter (corpus callosum)
Subcortical regions
Cerebellum
ADHD: Structural neuroimaging
• Cortical regions
– Frontal hypothesis of ADHD focus on
dorsolateral (DLPFC) and orbitofrontal (OFC)
areas.
• Ability to maintain context relies on dopaminergic
tone in DLPFC.
• Behavioral inhibition may be associated with OFC
function.
ADHD: Structural neuroimaging
• ADHD prefrontal cortex findings:
– All studies measuring at least 1 part of PFC
reported smaller volumes in ADHD.
• 9 ROI studies in child ADHD reported smaller
DLPFC volumes in either right or left hemisphere.
• VBM study showed right superior frontal gyrus
reduction.
• Reduced brain surface extent in inferior DLPFC
bilaterally, using automated, computational image
analysis.
Seidman et al 2005 review
ADHD: Structural neuroimaging
• Dorsal anterior cingulate cortex (dACC):
– On medial surface of frontal lobe
– Strong connections to DLPFC
– Considered to play critical role in complex
cognitive processing:
•
•
•
•
target detection
response selection
error detection
reward-based decision making
ADHD: Structural neuroimaging
• Dorsal anterior cingulate cortex (dACC)
– Functional imaging in normals: dACC active in
number of cognitive tasks, particularly Stroop
and similar cognitive interference tasks.
– No structural ROI studies of dACC in ADHD.
– VBM study in ADHD children: significant
cingulate abnormalities.
• Reduction in right posterior cingulate volume.
Seidman et al 2005 review
ADHD: Structural neuroimaging
• Structural imaging findings in ADHD
–
–
–
–
–
Total cerebral volume
Cortical areas
White matter (corpus callosum)
Subcortical regions
Cerebellum
ADHD: Structural neuroimaging
• Corpus callosum
– Composed of mostly myelinated axons
– Connect homotypic regions of the 2 cerebral
hemispheres
– Essential for communication between the 2
hemispheres
– Size variations in the corpus callosum reflects
differences in number or size of axons that
connects regions (relates to extent of myelination)
ADHD: Structural neuroimaging
• Corpus callosum in ADHD
– Important role in attentional control in
neurologically intact individuals
– Critical role in distributing processing load
across hemispheres under high attention
demands, so that demands can be met.
Banich 2003 review
– Research in split brain patients suggests CC
important for sustaining attention & dividing
attention between tasks
ADHD: Structural neuroimaging
• Corpus callosum:
– Abnormalities in ADHD consistently found in
posterior regions linked to temporal and parietal
cortices
• Splenium
Seidman et al 2005 review
Valera et al 2006 meta-analysis
– By gender (meta-analysis of N=595):
• Splenium findings likely driven by splenium in ADHD
girls.
• ADHD boys exhibit smaller rostral body.
Hutchinson et al 2008 meta-analysis
ADHD: Structural neuroimaging
• Structural imaging findings in ADHD
–
–
–
–
–
Total cerebral volume
Cortical areas
White matter (corpus callosum)
Subcortical regions
Cerebellum
ADHD: Structural neuroimaging
• Basal ganglia: caudate, putamen, globus pallidus
– Part of discrete, somatotopically distributed corticalsubcortical circuits essential for executive functions
– Vulnerable to hypoxic complications (which occurs at
higher rates in ADHD)
– Animal models of striatal lesions suggest hyperactivity
and poor performance on working memory and
response inhibition tasks
– Striatum is one of the richest sources of dopaminergic
synapses
– Stimulant medications have effects on striatum
ADHD: Structural neuroimaging
• Basal ganglia ADHD findings (13 studies)
Seidman et al 2005 review; Krain & Castellanos 2006 reivew
– Caudate:
• 9 (69%) studies have shown smaller caudate total or the
head alone, either on L or R side.
• Small total caudate volumes in affected vs unaffected
identical twins.
• Significant findings between ADHD and controls in
caudate volume diminishes in mid/late adolescence.
This was the only area in their study to show
“normalization” over time.
Castellanos et al 2002
– Globus pallidus: 4 studies
• Smaller volumes either on the right or the left
ADHD: Structural neuroimaging
• Basal ganglia ADHD findings (cont)
– Putamen: no structural findings in ADHD versus controls
– TBI & secondary ADHD
• 2 severe ADHD cases with traumatic amniocentisis at 17
wks gestation with completed elimination of basal
ganglia.
• Lesions of right putamen & posterior ventral putamen
associated with higher incidence of S-ADHD & ADHD
respectively.
• Odds of developing S-ADHD 3.6 times higher for TBI
children with thalamic damage & 3.2 higher for children
with basal ganglia damage.
Krain & Castellanos 2006 review
ADHD: Structural neuroimaging
• Structural imaging findings in ADHD
–
–
–
–
–
Total cerebral volume
Cortical areas
White matter (corpus callosum)
Subcortical regions
Cerebellum
ADHD: Structural neuroimaging
• Cerebellum
– Associated with coordination of motor movements
– Also involved in non-motor functions such as timing
and attentional shifting
– Posterior-inferior lobules of cerebellar vermis appear to
differ from remaining cerebellar hemispheres and
vermis in selectively containing dopamine-transporterlike immunoreactive axons.
ADHD: Structural neuroimaging
• Cerebellum ADHD findings
Seidman et al 2005 & Krain & Castellanos 2006 reviews
– Smaller cerebellar hemispheres (up to 6%) in ADHD,
sustained through adolescence.
– Vermal volume smaller in ADHD.
– Decreased size of posterior inferior lobe of cerebellum
(specific to lobules VIII-X) in ADHD.
– Cerebellar volumes significantly negatively correlated
with rating of attention problems. (Castellanos et al 2002)
– Small right cerebellar volumes. (Durston et al 2004)
ADHD: Structural imaging summary
From Valera et al 2007
ADHD: Structural neuroimaging
New applications
Segmentation methods:
Cerebellum example
From Seidman et al 2005 review
ADHD: Structural neuroimaging
New applications
DTI
DWI
From Silver et al 2005
ADHD: Structural neuroimaging
Newer applications in structural imaging:
1) Diffusion-weighted MR
– Capitalizes on the molecular motion of water
– White matter pathologically altered in certain
injury conditions (e.g., TBI) which have
attentional impairments
ADHD: Structural neuroimaging
2) Diffusion tensor imaging (DTI)
– Another technique for evaluating integrity of white
matter (WM) in the brain
– Allows for more refined image analysis of subtle
brain differences associated in certain conditions
– Tracks aggregate groups of axons & their
projections within the brain
ADHD: Structural neuroimaging
DTI (cont.):
– Capitalizes on 2 biological principles of brain organization
• WM projections in brain follow orderly projection
routes (anterior-posterior, lateral, and inferior-superior
projects)
• WM integrity can be assessed by applying the principle
of anisotropy: water molecule diffusion rates are
dependent on direction of WM pathway, which can be
determined by physics & mathematics of vectors (or
tensors)
– FA (fractional anisotropy) maps & tractography
• FA maps: Created in which brighter voxels indicate
greater anisotrophy (greater directionality, integrity, or
coherence)
ADHD: Functional Neuroimaging
ADHD: Functional neuroimaging
• Functional neuroimaging
– SPECT: single photon emission computed
tomography
– PET: Positron emission tomography
– Functional magnetic resonance imaging (FMRI)
– Magnetic resonance spectroscopy (MRS)
ADHD: Functional neuroimaging
SPECT: single photon emission computed
tomography
– 1st emerged in 1950s as a technique.
– Requires the injection or inhalation of radiopharmacueticals
– These radioactive compounds distribute throughout the
body, including the brain, and emit single photon radiation
(typically gamma rays) as they decay.
– More highly active brain areas receive greater blood flow
(and therefore more of the tracer), which is then quantified
with SPECT imaging.
– Poor spatial and temporal resolution compared to FMRI.
ADHD: Functional neuroimaging
• SPECT
– In ADHD, numerous methodological concerns
with most studies done
• Qualitative analysis, minimal or no control groups,
comorbid conditions, poor subject matching, very
crude techniques (e.g., 17mm slices)
– Ethical concerns: radioactive tracers
(particularly for use in children & healthy
subjects)
ADHD: Functional neuroimaging
Current SPECT
capabilities
Silver et al 2005
ADHD: Functional neuroimaging
SPECT vs structural imaging comparison
Silver et al 2005
ADHD: Functional neuroimaging
• SPECT ADHD findings:
– Decreased striatal perfusion
Lou et al 1998
– Decreased right DLPFC, middle temporal, and cerebellar
cortex activity at rest in medication naïve subjects children &
adolescent. Increased rest activity in angular/postcentral and
occipital gyri.
Kim et al 2002
– Higher activity in dACC, motor and premotor cortices while
off methylphenidate.
Langleben et al 2002
– Methylphenidate increased regional cerebral blood flow in
DLPFC, caudate, and thalamus bilaterally in previous
treatment naïve ADHD children & adolescents. Kim et al 2001
ADHD: Functional neuroimaging
• PET: positron emission tomography
– Introduced in the 1970s
– Also requires the injection or inhalation of
radiopharmacueticals
– As the radioactive isotope decay (typically oxygen-15,
carbon-11, flourine-18) they emit positrons which are
detected by the PET camera.
– Some PET methods are flow dependent but others
measure cerebral metabolism rates.
ADHD: Functional neuroimaging
Silver et al 2005
ADHD: Functional neuroimaging
PET finding (summarized by Bush et al 2005):
– Global cerebral glucose metabolism 8.1% lower in
ADHD group.
• 6.1% lower in ADHD vs control men
• 12.7% lower in ADHD vs. control women
– Regional metabolism remained lower in dACC,
premotor & somatosensory areas after
normalization for global decreases.
Zametkin et al 1990
ADHD: Functional neuroimaging
PET findings (cont.):
• Series of drug studies of acute stimulant use in
ADHD:
– No consistent acute or chronic stimulant effects on the
brain
– Caveat: more recent data suggests full stimulant effects
may take up to 4 wks to manifest
• FDG-PET: with CPT tasks, may not have enough
power to detect drug-related differences detected
with SPECT & FMRI.
• PET: working memory & gambling tasks
– Consistent for frontal-striatal conclusions in ADHD.
ADHD: Functional neuroimaging
– While both SPECT and PET are still useful in
certain areas (e.g., measuring dopamine
transporter level), FMRI has become choice for
functional studies.
– Functional MRI (FMRI): uses magnetic fields
and radio waves to image brain structures
• Noninvasive; no exposure to ionizing radiation.
– Repeated scanning
• Better spatial and temporal resolution
• Tasks can be either block or event-related, allowing
more flexibility in task design.
ADHD: Functional neuroimaging
• FMRI: dACC findings
– dACC: important role in attention, cognition (e.g., error
detection), motor control & reward-based decision making.
– Hypofunctional in ADHD adults: Counting Stroop task.
Bush 1999
– Medial prefrontal hypoactivity in dACC during stop-signal
& motor timing tasks.
Rubia et al 1999
– No activity or hypoactivity in dACC of ADHD versus
control child/adolescent subjects on Go-NoGo tasks.
Durston et al 2003; Tamm et al 2004
ADHD: Functional neuroimaging
• FMRI: striatal findings
– Lower left caudate activity in ADHD Durston et al 2003
– Lower putamen blood flow in ADHD using T2
relaxometry. Methylphenidate increased perfusion in more
hyperactive ADHD boys and decreased perfusion in more
normoactive ADHD boys.
Teicher et al 2000
– Lower left caudate power in ADHD adolescents during
stop-signal task
Rubia et al 1999
ADHD: Functional neuroimaging
• FMRI: lateral frontal findings
– Less consistent than other findings
– Stop signal task: reductions in ADHD in ventrolateral
PFC.
Rubia et al 1999
– Go/NoGo: normal subjects but not ADHD activated
ventrolateral PFC.
Durston et al 2003
– Counting Stroop: ADHD subjects activate ventrolateral
PFC bilaterally whereas controls did not. Robust
activity in insula bilaterally in ADHD (not controls).
Possibility for compensatory use of accessory response
pathways.
Bush et al 1999
ADHD: Functional neuroimaging
Magnetic resonance spectroscopy (MRS):
• Noninvasive, MRI-based method for quantifying
various chemicals
• Not all chemicals are visible with MRS
• Drawback: only able to study a few restricted
ROIs during a session
– Focus on 1 or 2 sites during a single study
– E.g., unilateral DLPFC, cingulate or caudate.
ADHD: Functional neuroimaging
• Compounds commonly studied with MRS:
– N-acelyspartate (NAA): marker for neuronal integrity
• Low values indicate neuronal dysfunction or death
• May also be marker for myelination
– Glutamine/glutamate/-butyric acid
• Elevations associated with neuronal destruction
– Choline
• Increases associated with myelin breakdown
– Creatine/phosphocreatine
• Creatine most often used as an internal control
ADHD: Functional neuroimaging
• Compounds commonly studied with MRS
Nuclei
measured
Compound studied
Parameter measured
Comments
1H
Creatine
Energy use
N-acetylaspartate
(NAA)
Decrease when neurons/axons
damaged or lost
Provides reference point for
measurement of other metabolites
Measures neuronal integrity
Choline
Neuropathology (suggestive)
Lactate
Glycolysis or failed oxidative
metabolism (suggestive)
Phosphocreatine
Energy storage
Adenosine triphosphate
High-energy phosphate
metabolism
Local tissue pH
MRS
31P MRS
Inorganic phosphate
Phosphomonoesters
Phosphodiesters
Membrane phospholipid
metabolism
Membrane phospholipid
metabolism
Becomes “visible” to MRS when cell
intregrity is compromised
Only present in pathological state
References for chemical shift of other
peaks in spectrum
--Calculated based on the chemical shift
of inorganic phosphate
-----
Adapted from Silver et al 2005
ADHD: Functional neuroimaging
• ADHD MRS findings:
– NAA depletion in left DLPFC but not left striatum in
ADHD, compared to control and ADD subjects.
Hesslinger et al 2001
– Lower NAA/creatine ratio bilaterally in globus pallidus
in adolescent boys; no change with single dose
methylphenidate.
Jin et al 2001
– Differential effects of methylphenidate and atomoxetine
in striatum and medial PFC.
Carrey et al 2002
– Decreases in striatal glutamate but not NAA, creatine or
choline with treatment.
Carrey et al 2003
ADHD: Functional neuroimaging
• ADHD MRS findings (cont):
– Elevated glutamate (but not NAA, creatine, or
choline) in right medial frontal PFC and left
striatum. (N=9 ADHD) MacMaster et al 2003
– Comparison of bilateral DLPFC (N=24
ADHD): no overall neurometabolite
differences.
• Low NAA levels ADHD girls.
Yeo et al 2003
ADHD: Neuroimaging
• Electrophysiological techniques
– Quantitative electroencephalography (QEEG)
– Event-related potentials (ERP)
ADHD: Electrophysiology studies
• Quantitative EEG:
– Computer-assisted spectral analysis of the EEG signal.
– Quantification of the alpha, beta, theta and delta frequencies.
– Signal generators are not localized to specific neural
structures with precision.
– ADHD characterized by “theta excess” and “alpha slowing”
as compare to controls.
• Caveat: Patterns of “theta excess” and/or “abnormal alpha” can be
indicative of other disorders (e.g., dementia, schizophrenia, mood
disorders, OCD, learning disorders, and TBI, to name a few).
ADHD: Electrophysiology studies
• Event-related potentials (ERPs):
– Measured from multielectrode arrays placed over the scalp
–
– Represent the averaged electrical response of the brain over
many trials (e.g., 25-100 trials)
– Good temporal resolution but poor spatial resolution
• Millisecond temporal resolution
– “inverse problem”
• no unique solutions when determining the position of
sources within the head
• Extremely difficult to localize brain activity with certainty
Genetics Research
1) Family, twin & adoption studies
2) Molecular genetic studies
ADHD genetics: family studies
• Increased risk among 1st and 2nd degree
relatives of affected individuals.
– Risk of ADHD among parents of ADHD kids is
increased by two- to eightfold.
– Similar elevated risk among siblings of ADHD
subjects.
Faraone & Biederman 2000
• Familiarity of ADHD confirmed when gender,
family intactness, and SES controlled.
Faraone et al 1992, 2000; Biederman et al 1990, 1992
ADHD genetics: adoption studies
• Basic premise: if genes contribute to ADHD risk,
biological relatives should be at greater ADHD risk
than adoptive relatives of ADHD kids.
• Two studies (1970s): biological relatives of
hyperactive kids were more likely to have
hyperactivity than adoptive relatives.
• More recent study: ADHD rates greater for biological
relatives of nonadopted ADHD kids than adopted
relatives of adopted ADHD kids.
ADHD genetics: twins studies
• Basic premise for heritability and twin studies:
– Heritability: degree to which variability in a clinical
population can be accounted for by genes
– Monozygotic (identical) twins share 100% of genes
– dizygotic (fraternal) twins share 50% of genes
• Extent to which identical twins are more concordant (at
risk for ADHD) than fraternal twins.
– Monozygotic twins: 50-80% concordance
– Dizygotic twins: 33% concordance
Bradley & Golden, 2001
ADHD genetics: twin studies
• Faraone et al 2005:
– Estimated heritability of
ADHD based on pooled
results from 20 twin
studies.
– 76% mean heritability
estimate
ADHD genetics: molecular studies
1) Genome-wide linkage scans:
– Many DNA acid markers across the genome are
examined to determine whether any
chromosomal regions are shared more often
than expected among ADHD family members.
• 4 studies: some evidence of genomic region
linkage, but inconsistent across studies.
– 17p11 has been the one replicated risk locus
ADHD genetics: molecular studies
2) Candidate gene studies: Method of association to
determine whether biologically relevant genes
influence ADHD susceptibility.
– Case-control & family-based designs.
• Case-control: compare allele frequencies between ADHD pts & nonADHD controls. (ADHD allele > in ADHD pt)
• Family-based: compares alleles that parents transmit to ADHD
children with those they do not transmit. (ADHD allele more
common in transmitted versus nontransmitted alleles)
– Both designs can derive odds ratios (OR) or relative risk
(RR) statistics.
• OR or RR > 1.0 indicates allele increases ADHD risk
• OR or RR of 1.0 = no association; OR or RR <1.0 indicates decreased
ADHD risk.
ADHD genetics: molecular studies
• Candidate genes:
– Catecholiminergic genes (N=4)
• Dopamine-4 and dopamine-5 receptors (DRD4 & DRD5)
• Dopamine transporter (DAT1)
• Dopamine-b-hydoylase (DBH)
– SNAP-25 gene
– Serotonergic genes (N=2)
• Serotonin transporter (5-HTT)
• Serotonin1B-receptor (HTR1B)
Faraone et al 2005; Durston & Konrad, 2007
– Norepinephrine receptors (N=2)
• ADRA 2A
• ADRA 2C
Pennington et al 2009
ADHD genetics: summary
Gene
Study
Design
Pooled OR
95% CI
Dopamine D4 Receptor
(exon III VNTR, 7-repeat)
Family
1.16
1.03–1.31
Dopamine D4 Receptor
(exon III VNTR, 7-repeat)
Case–control 1.45
1.27–1.65
Dopamine D5 Receptor
(CA repeat, 148 bp)
Family
1.24a
1.12–1.38
Dopamine Transporter
(VNTR, 10-repeat)
Family
1.13
1.03–1.24
Dopamine b-Hydroxylase (Taql A)
Case–control 1.33
1.11–1.59
SNAP-25 (T1065G)
Family
1.19
1.03–1.38
Serotonin Transporter
(5-HTTLPR long)
Case–control 1.31
1.09–1.59
HTR1B (G861C)
Family
1.14–1.83
1.44
ADHD genetics: molecular studies
• Catecholiminergic genes
– Dopamine-4 (DRD4):
• Gene variance may be associated with post-synaptic receptor sensitivity
to dopamine.
• Both noradrenaline and dopamine are potent agonists of the D4
receptor.
• D4 is prevalent in frontal-subcortical networks.
• Research predominantly focused on tandem repeat polymorphism in
exon III of D4 given that one variant (the 7-repeat allele) produces a
blunted response to dopamine.
• ADHD association between 7-repeat allele and ADHD in case-control
and family studies (OR=1.9 and OR=1.4).
• Studies using symptom dimensions rather than categorical dx suggest
DRD4 is particularly relevant to symptoms of inattention.
ADHD genetics: molecular studies
Catecholiminergic genes
– Dopamine transporter (DAT1):
• gene variance may be associated with a dopamine transporter
abnormally inefficient at the reuptake process.
• Stimulant medications block the dopamine transporter as one
mechanism of action for achieving therapeutic effect.
• In mice, eliminating SLC6A3 gene function leads to
hyperactivity and inhibitory behavior; stimulants reduces
hyperactivity. Mice show extracellular dopamine, a doubling
of dopamine synthesis rate, and tyrosine hydroxylase in the
striatum.
• SPECT ADHD adult findings: DAT activity elevated by 70%
ADHD genetics: molecular studies
• Catecholiminergic genes
– Dopamine-5 (DRD5): little is known about
functional relevance of allelic variants.
• 148-bp allele found in family studies (OR=1.2) as well
as a strong effect in one study without parental ADHD
hx.
– Dopamine-b-hydoylase (DBH):
• involved in regulation of dopamine metabolism;
• enzyme responsible for converting dopamine to
noradrenaline.
ADHD genetics: molecular studies
– Serotonergic genes
• Serotonin1B-receptor (HTR1B):
– Mutation in HTR1B-gene which encosed the 5HT1B receptor
is thought to lead to an activity decrease in the enzyme
converting tryptophan (the precursor) into serotonin.
– Low serotonin activity has been associated with impulsivity,
aggression, and disinhibited behavior in animal and human
studies.
• Serotonin transporter (5-HTT):
– Polymorphisms in the serotonin transportor (5-HTT) may
similarly result in reduced transcription and lower transporter
protein levels.
ADHD genetics: molecular studies
• SNAP-25:
• Implications from mouse mutant strain coloboma.
• Mutations within the gene are thought to affect the functions of
synaptic vesicle fusion and neurotransmitter release.
• Noradrenergic receptors:
– ADRA2A:
• G allele associated with ADHD, ODD, and CD symptoms.
• 2 studies failed to show association between ADRA2A and
ADHD dx but one showed significant association of the G
allele with elevated attention and combined symptom scores.
ADHD: Future directions in genetics
• Endophenotypes:
– Phenotype more proximal to the biological etiology of a
clinical disorder than its symptoms and influenced by 1
or more of the same susceptibility genes as the
condition.
– Growing interest in molecular genetics for these
(including in ADHD).
• Candidate gene studies show inconsistent replication patterns,
with significant but not overwhelming odds ratios (OR=1.2-1.5
in ADHD).
• Genome scans so far have found largely non-overlapping
chromosomal regions for potentially harboring susceptibility
genes.
ADHD: Future directions in genetics
• Useful endophenotypes should:
– Co-occur with the condition of interest
– Be measured by tools with good psychometric
properties
– Show evidence of heritability
– Show familial-genetic overlap with disorder of
study. (should appear in unaffected family
members)
ADHD: Cognitive Neuroscience
Future directions:
• Combining neurobiological approaches
– functional imaging & electrophysiological methods
– Structural & functional imaging methods
– Imaging methods paired with neuropsychological
testing
– Combining genetics with above
– Better defining & delineating cognitive aspects of
function
ADHD: Cognitive Neuroscience
Future directions:
– Direct comparisons of neuropsychological theories
– Better defining & delineating cognitive aspects of
function