Neurophysiological Markers of Pediatric Irritability and Its Response to Intervention

There has been an increasing focus on the adverse impacts of irritability, defined as
increased tendency towards anger.In children, irritability manifests as a persistently
negative mood and frequent temper outbursts. Severe, persistent irritability has been
conceptualized as Disruptive Mood Dysregulation Disorder (DMDD) with 3% of children meeting
criteria for it. Most youth with DMDD have Attention Deficit Hyperactivity Disorder (ADHD)
but only a subset of patients with ADHD exhibit impairing irritability. Even in children not
meeting full DMDD criteria, irritability causes a range of impairments and is a risk factor
for depression, suicide and substance use. Irritability has been identified as
transdiagnostic entity meriting investigation as a target for personalized intervention.
Irritability levels are only minimally correlated with severity of ADHD symptoms or
impairments in executive functioning, suggesting that irritability is distinct and not simply
a manifestation of severe ADHD. Presently, the first line treatment for irritability in
children with ADHD is to optimize the dose of the CNS stimulant. However, there is great
heterogeneity in response, with some children experiencing complete remission of their
irritability and others experience worsening irritability. Increased irritability is one of
the most common reasons why parents stop these medications. It is unknown what drives this
heterogeneity in response as no reliable treatment markers have been identified. The
unpredictability of CNS stimulants has led to the increasing use of atypical antipsychotics
for the off label treatment of ADHD. While effective, these medications are associated with
concerning side effects.

In order to identify markers of treatment response, it is necessary to delineate the causal
pathways underlying irritability. However, the mechanisms driving irritability are largely
unknown. Two areas theorized to contribute to irritability are impairments in learning from
experience (instrumental learning) and sensitivity to reward and loss. There are objective,
reliable methods for measuring these domains in children through the use of event related
potentials (ERPs), synchronous neural activity derived from the electroencephalogram (EEG) in
response to a stimulus. Reward positivity (RewP) is an ERP occurring in response to feedback
on task performance that can be broken down to separately analyze response to gain (delta
frequency) and loss (theta frequency). No prior work has examined these components of RewP
with irritability but others have found unique associations of each with depression. As
irritability is an established risk factor for depression, it is reasonable to surmise that
RewP may predict irritability as well. Error related negativity (ERN) reflects the
preconscious detection of potential conflict, serving as an early warning signal for errors
and a first step to adapting behavior in response to achieve a desired goal (e.g.,
instrumental learning.) A subset of children with ADHD exhibit a suppressed ERN on cognitive
tasks, and ERN amplitude is associated with task performance. When suppressed, CNS stimulants
normalize ERN, which is correlated with improved task performance. We theorize that
abnormalities in RewP to reward and loss on a monetary guessing task will predict the
severity of irritability, while ERN amplitude on a response inhibition task will predict the
degree of improvement in irritability after dose optimization of CNS stimulants. These
associations will be assessed in 47 children with ADHD and elevated levels of irritability
using daily parent ratings gathered before and after optimization of CNS stimulant. To
address the great variability in a child's daily behavior, we will use the recommended
collection format of ecological momentary assessment (EMA) to gather multiple daily ratings
of irritability. Lastly, there is a longstanding concern that CNS stimulants may lead to
rebound irritability late in the day as their effects fade. It is unclear if this simply
represents a return to the premedication baseline that parents perceive as more severe after
observing improved behavior earlier in the day or a true worsening in irritability.
Therefore, we will use EMA to compare changes in irritability during medicated times of day
versus unmedicated times, theorizing that greater daytime improvement will be associated with
parents rating worse evening behavior.

Aim1: Examine the capacity of lab measurements of reward sensitivity to predict irritability
in ADHD children H1: After controlling for relevant covariates, gain-related delta and
loss-related theta activity in the EEG during a reward-guessing task will each correlate with
levels of the child's irritability.

H2:Children with elevated levels of both loss related theta &gain-related delta will exhibit
the greatest irritability.

Aim2: Examine the capacity of ERN amplitude during a response inhibition task done in the
unmedicated state to predict the capacity of CNS stimulants to reduce irritability in
children with ADHD.

H1: Smaller baseline ERN will predict greater improvement in irritability with optimization
of stimulant dose.

Aim3: Examine the phenomena of rebound irritability with wear-off of the therapeutic effect
of CNS stimulants.

H1: Greater reductions in irritability when the CNS stimulant is active will be associated
with parents reporting increasing irritability after the stimulant has worn off.

Inclusion Criteria: 1. Ages 5-12: CNS stimulant medications are commonly used and well
studies in this age range (Mixed amphetamine salt has been approved for children age 3 +
and methylphenidate has been used in FDA funded studies on preschool children; American
Pediatric Association guidelines are also recommend for the preschool children) and these
are the age ranges where children are most likely to present for treatment of irritability.

2. Meets diagnostic criteria for any presentation type of ADHD. ADHD status will be
assessed on the NIMH Computerized Diagnostic Interview Schedule for Children (C-DISC).54
The C-DISC will also be used to assess psychiatric comorbidity, with diagnoses confirmed by
an MD/PhD prior to eligibility decisions. Symptom severity for ADHD, irritability and
Oppositional Defiant Disorder (ODD) will be assessed using the Disruptive Behavior
Disorders (DBD) Parent Rating Scale which is similar to the Vanderbilt, rating symptoms on
a 0-3 likert.24 In accordance with previous studies of irritability in ADHD, the DBD
irritability score (range 0-9) will be the primary outcome, with a moderate level of
irritability (≥5) required for entry.12 DMDD status will be assessed using Schedule for
Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version
(KSADS-PL) but DMDD will not be required for entry as subthreshold levels of irritability
produce significant impairment.7 3. Sex: male or female 4. Fluent in written and spoken
English.

Exclusion Criteria:

1. Age <5 years of age or >12 years of age.

2. Children with significant visual or hearing deficits or sensitivity to loud noises as
test performance requires intact hearing and vision.

3. Children with a latex allergy as the sensors used in electrophysiology assessments
have a latex component.

4. Serious neurological conditions that impacts cognition, such as an active seizure
disorder

5. Current psychotropics other than FDA approved ADHD medications, as medication will be
withheld on testing days. Unlike most other psychotropic medications, CNS stimulants
can be withheld for brief periods and acutely restarted with no safety risks and
lengthy titration process. Numerous ADHD studies have safely withdrawn these
medications or substituted inert placebo for testing or clinical observation. Children
taking an approved nonstimulant for ADHD plus a CNS Stimulant medication will be
allowed to participate and will just have their CNS stimulant dose withheld on testing
days.

6. Prominent traits of autism spectrum disorder (Social Communication Questionnaire Score
>15), marked developmental delay or psychiatric conditions requiring urgent treatment
(mania, psychoses, suicidal ideation).

7. Parent or child not fluent in English