Brain 'Go and Stop' Response May Hone ADHD Diagnosis in Kids

Wendy Wolfson

July 19, 2019

Differing brain activity, such as motor cortex inhibition and modulation, in attention deficit hyperactivity disorder (ADHD) could provide a more precise diagnosis of the condition, new research suggests.

In a case control study, the ability to start and delay a task in a racecar game was significantly different in children with ADHD than in typically developing children.

When children with ADHD are deciding to act or not act, the brain's electric excitability differs in two ways, said study investigator Donald Gilbert, MD, PhD, director of the Tourette’s Syndrome and Movement Disorder Clinics and the Transcranial Magnetic Stimulation Laboratory, Cincinnati Children's Hospital Medical Center, Ohio.

"[First], there's a very important braking system that they do not engage and secondly their overall ramping up with the brain's physiology to meet the challenge of the task is diminished," said Gilbert, who is also an associate professor of child neurology.

The findings were published online July 17 in Neurology.

Motor Cortex in ADHD

ADHD affects an estimated 7.5% to 10% of US children. Because there are no biomarkers, doctors diagnose the condition by asking parents and teachers a series of questions about the child's behavior.

ADHD is treated by medication and/or behavior therapy, which work to varying degrees depending on the individual. However, as reported by Medscape Medical News, a brain stimulation device to treat the disorder was also recently approved by the US Food and Drug Administration.

The researchers conducted an earlier study showing a relationship between motor cortex inhibition and ADHD.

The current study included 131 right-handed children (65% boys) between the ages of 8 and 12 years who were diagnosed with ADHD (n = 66) or acted as typical-developing controls (n = 65). All were instructed to start and stop a car traveling across a computer screen.

Transcranial magnetic stimulation (TMS) pulses were administered at 150 ms prior to the target "go action" and after the dynamic "stop cue" to evoke motor responses.

The researchers measured motor evoked potentials (MEP) and short interval cortical inhibition (SICI), considered one of the brain's "braking systems" and associated with γ-aminobutyric acid–mediated inhibition within the primary motor cortex.

The study's overall goal was to understand what happens in the motor physiology of kids with ADHD during the behavioral activities linked to clinical impairments, the investigators note.

The primary outcome was to develop measurements of brain activity and to determine how SICI differs between action selection and suppression.

As a secondary outcome, the researchers wanted to determine whether brain activation during response inhibition differed in the two groups of children.

Stop and Go

Children were screened for the study using various scales, including the ADHD Rating Scale IV, the Conners' Parent Rating Scale (Revised or Third Edition), and the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Aged Children, a clinical assessment by a board-certified pediatric neurologist, and the Hollingshead Parent History Questionnaire.

Short-acting medications were discontinued the day before and the day of testing; long-acting medications were barred.

Researchers measured the children's "resting" brain activity in the motor cortex, the area of the brain that controls voluntary movement, using a non-invasive TMS system to stimulate nerve cells in the brain.

Both groups of children were seated in comfortable chairs and asked to play a game involving a racecar moving across a screen. In reality, it was a modified Slater-Hammel task stop-signal reaction time paradigm that measured their response inhibition.

Participants started each trial by pushing his or her index finger on a game controller button, causing a racecar to rev its engine and travel down a track on the screen. The car drove as long as the button was pushed.

The goal was to get the car as close as possible to an indicated mark on the screen without passing it. But in 25% of the trials, the car stopped spontaneously. The child was instructed to keep his or her finger pushed down until he or she saw the stop cue of a checkered flag. Successful stopping meant not lifting their fingers at the mark.

TMS pulses were administered to the children's brains at varying intervals to stimulate the motor cortex for MEP and SICI.

The researchers were able to generate electrical activity in muscles and to then measure the difference in children's responses as they reacted to prompts to "engage" and "brake" the car on the screen via an electrode on their index finger.

Differences Detected

When stimulated by TMS pulses, the children with ADHD showed reduced SICI during both the response selection "go" and response inhibition "stop" compared with controls.

The "go" responses were significantly slower (P = .001) and more variable (P = .002) in those with ADHD than in the control group.

They also showed a strong association between severity of symptoms and task-related up-modulation (TRUM) of the motor cortex.

Diminished TRUM was associated with significantly more severe ADHD symptoms and slower reaction times to stop signals.

Compared with the control group, the ADHD group also showed different motor cortex physiology, reduced SICI across different behavioral states, and less task related up-modulation from the state of rest to selecting an action.

Children with ADHD showed less M1 SICI at rest (P = .02) and during go (P = .03) and stop trials (P = .02).

At rest, these children had a baseline inhibition level of 43% (95% confidence interval [CI], 0.51 - 0.63) compared with 54% (95% CI, 0.41 - 0.53) for controls. M1 SICI was also reduced by 19% in the ADHD cohort (P = .028).

Response-inhibition performance was comparable between the two groups.

Treatment Implications?

Resting M1 excitability was significantly increased during response inhibition-task engagement (P < .0001). This task up-modulation was less robust across and within groups. The children with more severe ADHD scores showed diminished TRUM and slower stop-signal reaction times.

Compared with the control group, they had 40% less inhibitory signaling to the finger during driving and 45% less inhibitory signaling during stopping.

Finally, the overall brain engagement was 10% lower in kids with ADHD, which correlated strongly with the severity of ADHD symptoms.

The investigators suggest that the M1 physiology indicates dysfunction in prefrontal or subcortical regions that are responsible for impairing inattention, hyperactivity, and impulsivity.

They summarize that children with ADHD showed differences in their motor cortex physiology, deficient SICI, and less task up-modulation from rest to selecting action, which mapped with the degree of severity of ADHD.

However, Gilbert noted that more research is necessary.

"If you came to me with your child worried about ADHD, I would ask you 18 questions," he said.

"That's how ADHD is diagnosed, there's no test. And so we really would like to find biological measurements that would allow us to understand different ways that the brain can be affected and produce ADHD symptoms," Gilbert said. "Ultimately, if we could understand that better, we can treat it better."

Overlapping Cohorts

Commenting on the findings for Medscape Medical News, Sandra Loo, PhD, professor in-residence, Division of Child Psychiatry and the Center for Neurobehavioral Genetics Brain Research Institute at UCLA, commended the investigators for including a large sample of kids.

In addition, the study "does indicate that there is some role of this motor cortex region in ADHD," said Loo, who was not involved with the research.

She noted that SICI is "a certain kind of measurement of electrical activity in the brain along this motor region that we know is biologically pretty well defined. And they do find there are group differences."

"One of the goals of finding a biomarker is, in theory, you want to find a marker that's going to differentiate ADHD and control," Loo said.

However, "when you have overlapping distributions like that, it's hard to say that it's going to work. And this is not the kind of analysis that you would do for a biomarker," she added.

"There's the same amount of variability across all kids, whether or not you have a diagnosis of ADHD. And so there's really what I call a 'population level variability' in brain function and cognitive functions," Loo said.

Still, she noted that the area is "a candidate" for further study.

"I think it needs to be broadened in terms of the way they're thinking about it; obviously, it's not just ADHD. They're really only sampling one area of the brain — and we know that the brain works in networks," Loo concluded.

The study was funded by R01 MH095014 and R01 MH085328. Gilbert has received honoraria and/or travel support from the Tourette Association of America/Centers for Disease Control and Prevention, the American Academy of Pediatrics, and the Child Neurology Society; compensation for expert testimony for the US National Vaccine Injury Compensation Program, through the Department of Health & Human Services; research support from the NIH (NIMH, NINDS); funding for work as a clinical trial site investigator from Ecopipam Pharmaceuticals and EryDel; and book royalties from Elsevier and Wolters Kluwer. Loo has disclosed no relevant financial relationships.

Neurology. Published online July 17, 2019. Abstract

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