THE NEUROBIOLOGY
OF ADHD AND LD:
UNDERSTANDING THE
BRAIN-BEHAVIOR
CONNECTION
by
Lance
Clawson,
M.D.,
F.A.A.C.A.P.
THOUGHTS ON THE SUBJECT
 The neurobiology of ADHD and LD are rapidly evolving fields.
 It’s clear that as we learn more, as with most neuropsychiatric
disorders, ADHD & LD are complex/multifactorial conditions,
with a single label, but a variety of overlapping, underlying
causes.
 Genetic variations explain the majority of these abnormalities,
but early pre and post natal insults can have profound ef fects
 SMGA babies, PKU, malnutrtion, CNS insult
 Interestingly, in some variations, the rearing environment can
strongly af fect the outcome as well (e.g. 9R vs. 10R DAT1
polymorphisms and conduct disorder)
 So, today will give you a view into this rapidly moving and
complex arena of research.
EXTERNAL ANATOMY (LANDMARKS) OF
THE HUMAN BRAIN
ADHD & LD: SEPARATE BUT OFTEN
OVERLAPPING SYNDROMES
 LD & ADHD Frequently co-occur
 Where ADHD leaves off and LD begins can be confounding
 Describes a large portion of our children, particularly
the most challenging
 Similar brain circuits may be involved
 E.g. WM deficits will affect both ADHD-like behaviors as
well as reading comprehension
 Can be challenging to tease apart behaviorally and
neurologically
 E.g. attention issue vs. auditory processing issue vs.
receptive language delay?
BRIEF REVIEW - ADHD: INATTENTION,
IMPULSIVIT Y, HYPERACTIVIT Y
Inattention
 Difficulty with attention relative to normal children of
the same age and gender
 Greatest difficulties in the areas of sustaining effort and
maintaining vigilance in response to a task.
 Most dramatic in situations requiring sustained attention to
dull, boring or repetitive tasks.
 For the ADHD child, most daily activities are indeed repetitive and boring!
 Difficulty with attention relative to normal children of
the same age and gender
 Tendency to focus on a more immediately reinforcing
activity, despite consequences associated with not attending
to the “required,” less reinforcing activity.
 HW vs. video games
 Attention is like water, it flows to the point of least
resistance
BRIEF REVIEW - ADHD: INATTENTION,
IMPULSIVIT Y, HYPERACTIVIT Y
 Impulsiveness or Behavioral Disinhibition
 A deficiency in inhibiting behavior in response to situational
demands
 Most commonly related to the inability to delay a response or defer
gratification or to inhibit dominant or pre -potent (preprogrammed)
responses
 Often respond quickly without waiting for instructions
 Often fail to consider negative consequences of their behavior,
leading to heedless/careless errors, and risk taking behavior
 Difficulty working towards long-term goals, preferring “shortcuts”,
avoiding tasks that require mental effort & seeking the most
immediate rewards
 This quality of dishibition/impulsivity is the most distinguishing
quality of ADHD children.
BRIEF REVIEW - ADHD: INATTENTION,
IMPULSIVIT Y, HYPERACTIVIT Y
Hyperactivity
 Excessive, developmentally inappropriate levels of
activity, whether motor or vocal.
 Restlessness, fidgeting, and general gross body
movements that are irrelevant to the task or
situation….purposeless movements.
 “On-the-go”, “driven by a motor”, “squirmy”, “hums or
makes odd noises” are often described
 Gross motor over-activity often wanes with increasing
age, but fidgeting and restlessness often remain
evident
GETTING TO THE CAUSES OF ADHD: THE
MACRO LEVEL
 Once again! ADHD arises from multiple causes
 All currently recognized causes fall in the realm of biology
(neurology & genetics)
 The various causes may compound one another in a
single individual
 Genetic/inheritance is the strongest factor in the majority
of cases
 Final common pathway for disorder appears to be
the fronto-striatal-cerebellar circuits in the brain
 The signalling deficits, genetically, appear to be due to a
number of gene variants that affect the sensitivity and
responsiveness of the brain to both dopamine and
norepinephrine (and perhaps others, such as acetylcholine)
A 3-D VIEW OF THE FRONTAL-STRIATALCEREBELLAR CIRCUIT
ADHD IS REAL: PET SCAN SHOWING 2DEOXYGLUCOSE UPTAKE AT REST
BASIC NEUROLOGICAL FACTS
REGARDING ADHD
 Voumetric Studies: Consistent finding of global
reductions in total brain volume (both white and gray
matter equally) (Valera et al 2007)
 Specifically, reductions in specific areas as consistently seen in
ADHD, namely the striatum (caudate nucleus and globus
pallidus), anterior + posterior cingulate cortices, and the
midline cerebellar vermis.
 Shaw (2007) has demonstrated significantly delayed neruonal
maturation. Less impaired parietal cortex thickness is related
to better long term outcomes
BASIC NEUROLOGICAL FACTS
REGARDING ADHD
 Functional Imaging: There are many inconsistent
results in this area… A 2006 review of all fMRI
studies at the time (Dickenson) showed consistent
patterns of “frontal hypoactivity (Ant Cingl Cortex,
DLPRC, inf. PFC, basal ganglia and thalamus)
 Typically scan during a Go/No-Go task, need to inhibit a
prepotent respond (e.g. Stroop test)
 The most general finding is hypoactivation in the ventralstriatal system during tasks that measure differential
response to rewards between ADHD and Control groups
A PEEK AT GENETIC VARIABILIT Y AND
COMPLEXIT Y
 ADHD is highly heritable (genetic factors explain 76%
of diagnoses, similar to eye color), but there is no
one gene that explains the entire condition.
 Instead, there appears to be a large variety of genetic
alterations that contribute to ADHD (Farone 2005).
 This makes sense, since any genetic change that interfers
with the functioning of the PFC-striatal-thalamiccerebellar circuit could lead to symptoms that are
diagnosed as ADHD.
 Candidate genes that have been studied include, for
example those that encode for the followign proteins:
DA receptors 4&5, DAT, NE synth enzyme, DA beta
hydroxylase, 5HT transporter, tand the 5HT1B
receptor,
A PEEK AT GENETIC VARIABILIT Y AND
COMPLEXIT Y
 Thus, the genetic variations or particular gene
combinations in certain crucial genes may
affect/predict the ‘flavor’ of the ADHD you might
display…
 By ‘flavor’ I mean the various combinations of how
inattentive, impulsive, hyperactive, and perhaps
executively impaired an individual with ADHD might
be.
 [genes are the store house of information in each cell of
the body, and when they are ‘transcribed’ eventually lead
to the production of proteins which carry out biologic
functions]
A PEEK AT GENETIC VARIABILIT Y AND
COMPLEXIT Y
 E.G. the DAT1 gene (DAT = dopamine transporter
which clears DA from the synapse once it is
released) comes in a number of different forms in
what we call ‘polymorphisms’.
 The 10R (10 repeat) allele is strongly associated
with a diagnosis of ADHD. Experimentally, the 10R
causes a 50% increase in the number of DAT binding
sites (VanNess 2005)
 Theoretically, when DA is released as part of signal
transduction, it’s effect is shorter lived/muted, as the
increased number of DAT binding sites suck all the DA back up
more quickly.
WHAT DOES IT LOOK LIKE?
NEUROTRANSMITTER PHYSIOLOGY
A PEEK AT GENETIC VARIABILIT Y AND
COMPLEXIT Y
 Other studies have shown DAT variants that ‘run
backwards’, flooding the synapse with DA based on a
‘leaky’ DAT, thereby reducing the clarity of the signal
(Blakey et al 2008).
 Methylphenidate and amphetamine both stop this ‘back
leaking’ of the DAT, as well as increase DA/NE release.
 The D4 and D5 receptor polymorphisms (D4/D5 are
mostly seen in the PFC and not the striatum to a
great degree like D1/D2) may be involved in the WM
deficits seen in many individuals with ADHD
(Goldman-Rakic 1999)
A PEEK AT GENETIC VARIABILIT Y AND
COMPLEXIT Y
 The 9R polymorphism, as well as the D4-7R allele
are associated with impulsivity, although not
associated with a diagnosis of ADHD (Forbes 2009) .
 Blakey and his colleagues (2009) have also
implicated a genetic abnormality in the NE
transporter in inattentive forms of ADHD
(atomoxetine affects the NE transporter) as well as
abnormalities in the choline transporter (choline is a
precursor to acetylcholine another crucial
neurotransmitter), and that this genetic variation
may be involved in the ‘combined’ forms of ADHD.
NEUROCHEMISTRY & TRANSMITTERS AT
THE NERVE SYNAPSES
A PEEK AT GENETIC VARIABILIT Y AND
COMPLEXIT Y
 Needless to say, what genetic variants any one
person carries will help shape the type of ADHD
impairments they display as well as what
medications that may respond to...
IF DA/NE SIGNALS ARE IMPAIRED, HOW
DOES THIS PLAY OUT BEHAVIORALLY?
 Dopamine (DA) is involved in reward and pleasure
circuits and therefore central to all learning, as it
tells the brain “keep going, keep exploring, keep
engaging, continue this behavior, this is good”
 Inattention may be due to limited ‘reinforcement’ of
DA neurons to previous experience (due to fuzzy,
muted signals), or a reduced efficiency of DA reward
circuits…
 So learning based on past rewards is weaker, esp. with
time delays (Frank et al 2007 & Lauman et al 2009).
 Thus, they tend to go for (prefer) the immediate reward
vs. waiting for the larger delayed reward (they can’t
manage delays in reinforcement and discount future
rewards if it requires waiting) (Sonuga-Barke et al 2008).
IF DA/NE SIGNALS ARE IMPAIRED, HOW
DOES THIS PLAY OUT BEHAVIORALLY?
 This is called a ‘partial reinforcement’ schedule… which
requires that one learn from past rewards, so they can
maintain attention and effort in anticipation of future
reward.
 Thus, individuals with ADHD do better under
continual reward systems vs. partial reward (Luman
et al 2005). Although large enough delayed reward
can be effective, as well as random reward schedules
 Reduced signal clarity in the reward systems of the
brain lead to impairments in the ability to sustain
attention to task and achieve a particular goal based
on ‘Internal’ motivations (ideas, beliefs, anticipated
future reward), and thus remain dependent on
external motivators.
DA BINDING IN THE CAUDATE NUCLEUS
IF DA/NE SIGNALS ARE IMPAIRED, HOW
DOES THIS PLAY OUT BEHAVIORALLY?
 Impaired integration of earlier reinforcers is another
feature based on impaired signal transduction.
 This refers to the ability to hold events in working
memory (both DA and NE dependent) long enough to
link/tie them to previous rewards received, so that a
more complex picture linking one’s behavior to
expected reward can be built up and utilized to
predict future reward scenarios (Tripp & Alsop 1999)
IMAGE OF LACK OF PFC (CINGULATE)
ACTIVIATION IN WM TASK (STROOP)
IF DA/NE SIGNALS ARE IMPAIRED, HOW
DOES THIS PLAY OUT BEHAVIORALLY?
 An additional wrinkle: Disinhibited behavior observed
in ADHD may be due to ‘impaired passive avoidance’.
 Meaning once the individual ‘locks on’ to a reward,
they have an impaired ability to inhibit this reward
seeking in spite of imminent punishment.
 Felt to be due to over activity of the meso-limbic DA
pathway (sympathetic system), overriding inhibitory
signals (of the parasympathetic system) (Patterson &
Neuman 1993).
RATE OF CEREBRAL MATURATION: ADHD
VS. NON-ADHD (2 TO 4 YR DELAY)
 Shaw 2007: delay in the growth cortical thickness in a
population of ADHD children vs. controls, particularly in the
PFC.
 Certain genetic variants of ADHD normalize cortical
thickness with age (about 1/3 according to Barkley by the
mid to late 20’s), and 2/3 remain with varying degrees of
impairment.
VOLUMETRIC COMPARISONS: ADHD VS.
NON-ADHD
 Sowell & Peterson 2004: Displays thinner cortical areas in
ADHD subjects vs controls in PFC and Temporal-Parietal lobes
YES FOLKS, IT IS REAL…
 Cunningham et al 2007: fMRI shows decreased parietal lobe
activity during mental rotation task.
 This dif ference is meant to show the level of distraction in the
ADHD children
LEARNING IMPAIRMENTS
 The majority of the research has been done with
Developmental Dyslexia/Reading impairments
 The bulk of findings point to a dif ficulty in
perceiving/processing phonemes/perceiving the phonemic
aspects of words as one reads.
Normal
Dyslexic
READING IMPAIRMENTS
 Dyslexia occurs in 5% to 12% of the populations
 It is familial, and inherited factors account for about 80% of
dyslexia overall
 There are a number of chromosomal regions implicated, most
recently chromosome 6, p21 -p22 region is felt to be the
location of the major genetic disturbance. A number of
candidate genes are still being investigated.
 These genetic abnormalities are felt to af fect ‘neuronal
migration’
LEARNING IMPAIRMENTS
 It appears that dyslexics do not utilize the ‘verbal associative’
areas of the brain (temporal -parietal region) in the way that
normal readers do (Shaywitz 1998). They can be trained to do
this, and the functional imaging shows actual changes in that
the posterior areas are recruited more when reading after
training.
LEARNING IMPAIRMENTS
 Gabrieli (2011) has recently identified that in both
child and adult dyslexics, even though they have
become proficient readers, continue to suffer from
impairments in ‘hearing’ spoken language accurately
(such as discerning the ‘P’ vs. ‘B’ sounds when
conversing), and have higher rates of ‘misspeaking’
 e.g.. An individual who is at a ball game is thirsty and states
“I’m thirsty, can we go to the confession stand?”
LEARNING IMPAIRMENTS
 Math Impairments are less well understood neurobiologically.
 Recent work shows that young children with difficulty
in relating the numerical symbol to an exact quantity
(such as the numeral ‘3’ representing 3 toys) later
develop math learning disabilities (they lack what
teachers refer to as “number sense”).
 Large ongoing study at Stanford using fMRI to study
the brains of math disabled and normal students.
Results are not yet complete.
ADHD: EFFECTS ON READING FLUENCY,
COMPREHENSION & LEARNING
 4 th grade, when children begin to read to learn vs.
learning to read. Children with ADHD begin to have
academic difficulty.
 Limited Working Memory in ADHD may impair
reading comprehension as kids with ADHD are more
susceptible to being overrun by details when reading
longer text - unable to “remember” main ideas.
 Children with ADHD often display slow processing
speed, which then may influence reading fluency,
thus slowing the pace and limiting the acquisition of
reading ‘automaticity’, which allows one to read with
limited effort and thus focus on the meaning of the
text.
ADHD: EFFECTS ON READING FLUENCY,
COMPREHENSION & LEARNING
 Impaired motor coordination and low motor endurance seen in
many ADHD children can also contribute to limited written
output and interference with new learning. They produce
written work more slowly, and with greater required ef fort.
They experience cognitive and physical fatigue when trying to
keep up with typical classroom demands, and may appear
distracted, and thus, less available for learning.
 Multitasking demands have been shown to impair learning in
ADHD individuals in that they response time and processing is
further slowed. A good example is note taking. The ef fort to
focus on the speaker, discern the meaning of the lecture and
simultaneously transcribe what is being said onto notes can
overwhelm many individuals with ADHD, and thus the common
accommodation of note taking assistance.
SO, WHAT SHOULD WE DO?
 Parents & Teachers are Shepards, Not Engineers
 Reduce Delays, Externalize Time
 Externalize Important Information
 Externalize Motivation
 Externalize Problem-Solving
 Use Immediate Feedback
 Increase Frequency of Consequences
 Increase Accountability to Others
 Use more salient and artificial rewards
SO, WHAT SHOULD WE DO?
 Change rewards periodically
 Touch more, talk less
 Act, Don’t Yak
 Keep your sense of humor
 Use rewards before punishments (4:1 ratio)
 Anticipate problems settings – Make a plan
 Keep a sense of priorities
 Maintain a disability perspective
 Practice Forgiveness (Child, Self, Others)
SO, WHAT SHOULD WE DO?
 Minimum 3X/week exercise for at least 45 min
 Improves mood, anxiety, sleep, attention and working memory
 Address sleep, ensure that it’s adequate and routinized
 Establish regular eating patterns, frequent smaller meals with
lower glycemic index (ensure adequate mix of protein in with
the carbohydrate and fat that they crave)
 Make sure that medications are on board when demands are
high (like during homework and chores at home).
 Enjoy them! It’s the only chance you’ve got!