Jessica Hartstein Psyc 480 Oct. 29th, 2003 ADHD: Anatomic and neural differences in ADHD children vs. normal children Jessica Hartstein Psyc 480 Oct. 29th, 2003

Remember the people of ADHD Considered the inability to block out (inhibit) unimportant information and to focus only on relevant input Characterized by: Inattentiveness Hyperactivity Impulsivity Affects 3-5% of school-aged children

Current diagnosis and treatment Investigating: home/school life Diet of children (are they just overly-caffeinated?) Interviews with parents, teachers, and other close adults Noting behavior in noisy and unstructured environments Noting behavior with tasks requiring attention and analysis Treatment (in US) is most often medication Consider the implications of starting young children on permanent medication

Differential Patterns of Striatal Activation in Young Children with and without ADHD Sarah Durston et al 2003

Question número 1 Using fMRI are there neuronal functional differences between subjects with and without ADHD? Alt 1: No, children use the same parts of their brain for cognitive functioning regardless of whether they have ADHD or not. In analysis could treat two groups as one Alt 2: Yes, normal subjects would rely mostly on the caudate and globus pallidus, while ADHD subjects would have more activity in their cortex. With question: And what are those differences? Durston began with the 2nd alternative

Question número 2 Are there any behavioral differences between subjects with and without ADHD? Alt 1: No, subjects with ADHD and subjects without ADHD perform the same on tests Alt 2: Yes, normal subjects perform better and have less of an interference effect than do ADHD subjects Expected the 2nd

Methods 14 right-handed subjects used in fMRI, 24 used in behavioral task ADHD diagnosed in a structured interview ADHD subjects withheld from taking their stimulant medication the day of the fMRI Go/Nogo task, with Pokemon figures 1, 3, 5 intervening gos between nogos 500 ms stimulus duration and 3500 ms interstimulus interval In scanner for about 1 hour for functional and anatomical imaging (also Pokemon figures) 2 and 4 intervening gos also done, but just so that the subjects wouldn’t figure out the paradigm, the data wasn’t actually analyzed

Behavioral results ADHD subjects made significantly more errors on nogo trials than did normal subjects (79.1%accuracy vs. 90.4%accuracy) Differences on accuracy and RT on go trials didn’t reach significance Number of errors made on the nogo trials increased with number of preceding go trials in control children ADHD performance with 1 intervening go is similar to that of control group with 3-5 intervening gos Their conclusion doesn’t mention that ADHD did better at 5 than at 3 intervening. Potentially not significant….

Errors for the two groups on nogo task Note that ADHD children are always comparatively worse ADHD actually better at 5 intervening than 3, but choose to conclude: ADHD at 1 intervening similar to normal at 3-5 intervening

Neural results Divided data into four groups for further analysis Condition (go vs. nogo) Group by condition (ADHD vs. control and go vs. nogo) Condition for control children Condition for ADHD children

Go Trials vs. Nogo Trials MR signal increased for go trials (requiring motor task) compared to nogo trials in the left primary motor cortex Inhibition of action activated the right inferior parietal lobe and bilateral posterior cingulate gyrus and posterior hippocampus

Effects of group by condition Control group activated the left caudate nucleus (known for control) Children with ADHD activated regions of the cortex: right superior frontal gyrus, right middle frontal gryrus, right inferior parietal lobe, bilateral posterior cingulate gyrus, bilateral precuneus, right superior temporal gyrus, and the bilateral occipital cortex

Effects of condition (lumped together) In both the control subjects and the ADHD subjects the gos were treated distinctly from the nogos In fact, for both ADHD and normal subjects, the gos were treated rather similarly (activating the left primary motor cortex) Their behaviors diverge in the inhibition task Using right hand to announce GO Could specifically say what those differences are…but

Effect of preceding context Remember that in control subjects, we saw performance decline as the number of intervening gos between nogos increased. Scan analysis showed no such effect This means that the changes in activation occurred regardless of number of intervening go trials

Picture the difference Caudate Globus pallidus Increased activity for nogo to go trials Different Z coordinates of brain L (control): bottom—globus pallidus, above—caudate, part of the striatum R: ADHD—increased activation of right inferior parietal lobe and posterior cingulate gyrus

Last week’s model This model tried to explain four different disorders, while we are just dealing with one Could be a decent explanation for the different structures activated in subjects with and without ADHD Helps to explain potentially why so much of the cortex is activated in ADHD patients…the striatum doesn’t work quite right…when the striatum is less activated, it inhibits the GPi less, which activates the thalamus more which activates the frontal cortex more

Potential Errors Effects of treating medicated/non medicated ADHD patients as 1 group Sample size small Group averages used Select ages (development continues on past 10 years) Different groups of ADHD subjects (combined and inattentive types)

Previous studies Lou et al suggests that basal ganglia and prefrontal cortex may be hypoperfused in ADHD children (while others say they are different sizes)—not a credible study Found atypical frontostriatal function in children with ADHD and no activation of the basal ganglia (where control subjects activated)

Inferences ADHD subjects likely have a different trajectory in impulse control OR they exhibit less control earlier in development compared to normal subjects Normal children activated the basal ganglia much more than ADHD children (caudate is the doorway to the basal ganglia)

Inferences continued ADHD children rely on a more diffuse network of neural systems for cognitive control Parts of brain used may implicate involvement of working memory and a need for or reliance on vigilance to sustain visual attention

Diagnosis of ADHD What light does this study shed on our “how do you diagnose ADHD?” problem? While Durston doesn’t outright say anything about diagnosis, she stands firm in her neural differences findings…might this be credibility for using fMRI as opposed to methods mentioned earlier for ADHD diagnosis?

Brain Imaging of Attention Deficit/Hyperactivity Disorder Jay N. Giedd et al

Question hào má yī Across anatomical and neurological studies, are there brain regions we can pinpoint as being responsible for normal and ADHD behavior? Yes, across studies, the same regions continue to be found essential in the cognition (and inhibition during task) of children with ADHD and that other regions continue to be imperative for the cognition (and inhibition during task) of children without ADHD. No, we find similar anatomical and neurological results in ADHD and normal subjects No, we find differences in ADHD and normal subjects, but the findings cannot conclusively pinpoint any brain regions as being responsible for these differences

Functional Brain Imaging Studies Methylphenidate study 10 boys with ADHD and 6 controls, scanned with and without methylphenidate (even controls) while doing Go/Nogo tasks Striking difference in caudate and putamen (more known for relationship to Tourette’s syndrome) Both groups activated larger numbers of pixels in prefrontal cortex with drug than they did without drug Hadn’t been medicated for 36 hours pre-scanning and potentially the controls were going through withdrawl Caudate finding important because that was also found in the previous study

Stop Task 7 adolescent boys with ADHD and 9 controls Scanned while performing the Stop Task and a delay task that required synchronization of a motor response to an intermittently appearing visual stimulus Concluded that “the caudate…has been related to the response inhibition” Again, caudate importance

Limitations of fMRI studies While supportive of fMRI potential, Giedd highlights some limitations: Extremely sensitive equipment Bite-bar not ideal test-taking environment Verbal responses sometimes withheld for fear of movement Potential effects of medication—maybe none, but as of yet, we don’t know Also mentions limitations of other studies, such as PET and recognizes ease of single-photon computer emission tomography

Inconclusive studies summary Differences due to age and IQ Small samples ADHD associated with a subnormal activation of the prefrontal systems responsible for higher-order motor control

Anatomic studies Anatomic studies have been performed since the 70’s Lots of technological advances have been made since then, basically rendering old studies insufficient/incorrect compared to current studies Best studies will control statistically for differences among individuals in reference to brain sizes (because they vary), but most of studies to date have not done this

Fun with tables Few anatomical studies as it is, and the ones he gives us he’s really critical about anyway…here we have horribly-matched control groups, a dependant group with more than just ADHD wrong with them WHAT ARE THE IMPLICATIONS OF USING SIBLINGS?

Repeat offenders: Corpus callosum (fibers between R and L hemispheres) smaller in ADHD, caudate asymmetry reversal for ADHD, Globus Pallidus smaller in ADHD Giedd is more supportive of these studies than others, but he’s still critical of them

Important brain structures CORPUS CALLOSUM Largest interhemispheric commissure in the brain The myelinated fibers connecting the R and the L hemispheres Some discrepancies, but overall, they’ve found this to be smaller in ADHD subjects Even the rostrum, the most anterior portion of the corpus callosum, is smaller

Caudate Nucleus and Globus Pallidus Caudate thought to play important role in ADHD Abnormalities of caudate nucleus volume or asymmetry have been reported, although the studies differ as to what is abnormal asymmetry Inconsistency may be due to methodology Globus pallidus related to the basal ganglia and difficult to measure with fMRI Found to be significantly reduced in size in ADHD subjects, although the studies have differed as to which sides have the larger difference in ADHD vs. normal subjects

Conclusions to the review The studies suggest right frontal-striatal circuitry involvement in ADHD with a modulating influence from the cerebellum Right frontal-striatal circuitry has been shown to be involved in hyperactivity of primates in that there is interference with orbital and other projections passing to the caudate Other neuropyschological studies have found right-sided frontal striatal dysfunction in ADHD subjects They mentioned that the cerebellum volume is about 5% smaller in ADHD than in normal subjects, but I didn’t really see studies where they talked about the cerebellum, unless it was via other brain structures

To make things better Anatomic findings in ADHD are tentative, need replication of results and quantification of finer cerebral subdivisions Higher statistical power of studies (brain variation large) Investigate effects of medication on studies Giedd hints that functional imaging provides more credible results

Can we use this information for diagnosis? Giedd says: NO! Individual variation is too large, and studies are accurate with respect to large groups Children with no symptoms and an ADHD-like brain shouldn’t be considered to have ADHD Children with symptoms and no ADHD-like brain shouldn’t necessarily be considered to not have ADHD But, Dunstun might say: Yes! The neurological differences are so strong that ADHD can be defined by those differences If you have A, B, C (neurological characteristics)…you have ADHD. If you have X, Y, Z you don’t.

Why study this, then? We can hope to uncover the neuropathology of the disorder We can educate families and the public that it is a biological entity Some people think that it has to do with good parenting, TV watching, diet, etc. Help us classify subtypes of ADHD Can help guide treatment interventions