The NeuroBiology of ADHD and LD: Understanding the Brain-Behavior Connection

1. The NeuroBiology of ADHD and LD: Understanding the Brain-Behavior Connection by Lance Clawson, M.D., F.A.A.C.A.P.

2. 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 effects • SMGA babies, PKU, malnutrtion, CNS insult • Interestingly, in some variations, the rearing environment can strongly affect 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.

3. External anatomy (landmarks) of the human brain

4. 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?

5. …brief review - ADHD: Inattention, impulsivity, hyperactivity • 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

6. brief review - ADHD: Inattention, impulsivity, hyperactivity • 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.

7. brief review - ADHD: Inattention, impulsivity, hyperactivity • 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

8. 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)

9. a 3-d view of the frontal-striatal-cerebellar circuit

10. ADHD is real: PET scan showing 2-deoxyglucose uptake at rest

11. 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 globuspallidus), 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

12. 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 ventral-striatal system during tasks that measure differential response to rewards between ADHD and Control groups

13. A peek at genetic variability and complexity • 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-thalamic-cerebellar 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,

14. A peek at genetic variability and complexity • 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]

15. A peek at genetic variability and complexity • 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.

16. What does it look like? neurotransmitter physiology

17. A peek at genetic variability and complexity • 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)

18. A peek at genetic variability and complexity • 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.

19. Neurochemistry & transmitters at the nerve synapses

20. A peek at genetic variability and complexity • 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...

21. 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).

22. 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.

23. DA Binding in the caudate nucleus

24. 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 DAand 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)

25. Image of lack of pfc(cingulate) activiation in wm task (stroop)

26. 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).

27. 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.

28. Volumetric comparisons: adhd vs. non-adhd • Sowell & Peterson 2004: Displays thinner cortical areas in ADHD subjects vs controls in PFC and Temporal-Parietal lobes

29. Yes folks, it is real… • Cunningham et al 2007: fMRI shows decreased parietal lobe activity during mental rotation task. • This difference is meant to show the level of distraction in the ADHD children

30. Learning impairments • The majority of the research has been done with Developmental Dyslexia/Reading impairments • The bulk of findings point to a difficulty in perceiving/processing phonemes/perceiving the phonemic aspects of words as one reads. Normal Dyslexic

31. 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 affect ‘neuronal migration’

32. 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.

33. 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?”

34. Learning impairments • Math Impairments are less well understood neuro-biologically. • 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.

35. ADHD: Effects on reading fluency, comprehension & Learning • 4th 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.

36. 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 effort. 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 effort 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.

37. 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

38. 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)

39. 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!