PARIS (FRONTLINE MEDICAL NEWS) – Neurofeedback based upon real-time functional magnetic resonance imaging resulted in long-term reduction in attention-deficit/hyperactivity disorder symptoms in adolescents in a randomized controlled proof-of-concept study, Katya Rubia, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.

The effect size of the improvement when measured at follow-up 11 months after completing the functional MRI-based neurofeedback (fMRI-NF) training exercises was moderate to large and comparable to that of psychostimulant medication in published placebo-controlled clinical trials. But the effects of the medications last only 24 hours after administration, and the drugs have side effects.

Thus, fMRI-NF offers several major advantages over drug therapy: “Learning brain self-regulation enhances neuroplasticity, and the effects are likely to be longer lasting than with external drug stimulation. Neurofeedback seems to have no side effects, and is preferred by parents and patients. And the long-term effects of stimulant medication on the developing brain are unknown,” said Dr. Rubia , professor of cognitive neuroscience and head of the section of developmental neurobiology and neuroimaging at the Institute of Psychiatry at King’s College London.

Neurofeedback is an operant conditioning procedure, which, through trial and error, teaches patients to self-regulate specific areas of the brain involved in psychopathology. EEG-based neurofeedback for ADHD has been extensively studied, with generally small to medium effect sizes being reported. Morever, patients need to be very highly motivated in order to succeed at EEG-NF: It takes 30-40 EEG-NF sessions, each an hour long, in order to learn targeted brain self-control in ADHD, whereas in Dr. Rubia’s study, patients learned to self-regulate brain activity in an average of eight fMRI sessions, each lasting 8.5 minutes, over the course of 2 weeks. The far speedier learning curve is probably tied to the superior specificity of spatial localization afforded by fMRI neurofeedback, according to the neuroscientist.

Also, fMRI-NF can reach certain key regions of the brain involved in ADHD that EEG-NF cannot, most notably the inferior frontal cortex (IFC) and basal ganglia, she added.

The target region in the proof-of-concept study was the right IFC, an area important for cognitive control, attention, and timing. Functional neuroimaging studies consistently have shown that the right IFC is underactive in ADHD, and that psychostimulant medications upregulate this area. A dysfunctional right IFC is an ADHD-specific abnormality not present in children with obessive-compulsive disorder ( JAMA Psychiatry. 2016 Aug 1;73[8]:815-25 ), conduct disorder, or autism.

“The IFC seems to be a very good functional biomarker for ADHD,” Dr. Rubia said.

The proof-of-concept study, published in Human Brain Mapping, included 31 boys with a DSM-5 diagnosis of ADHD, aged 12-17, who were randomized to fMRI-NF of the right IFC or, as a control condition, to fMRI-NF targeting the left parahippocampal gyrus. Two patients had the inattentive subtype of ADHD; the rest had the combined hyperactive/inattentive form. Parents and patients were blinded as to their study arm.

The fMRI-NF training teaches subjects to self-regulate the blood oxygen level–dependent response of target areas of the brain. So this program uses neuroimaging as a treatment. It is neuroimaging employed as neurotherapy. To make the training experience more attractive to young patients, it was presented as a computer game: By making progress in controlling their brain activity, patients could launch a rocket ship on the screen. With further progress, they could send the rocket through the atmosphere into space and eventually land it on another planet.

The primary study endpoint was change in the ADHD Rating Scale . The group that targeted self-upregulation of right IFC activity showed roughly a 20% improvement in scores, from a baseline mean total score of 36.7 to 30.2 immediately post treatment, further improving to a score of 26.7 at roughly 11 months of follow-up. Mean scores on the inattention subscale improved from 19.8 to 15.9 immediately post treatment and 15.3 at follow-up. Scores on the hyperactivity/impulsivity subscale went from 16.9 before treatment to 14.2 after treatment and 11.5 at follow-up.

There were no side effects of fMRI-NF in either study arm.

However, a degree of uncertainty exists regarding the clinical significance of the results, Dr. Rubia said. That’s because the control group showed a similar degree of improvement in ADHD symptoms immediately after learning to upregulate the left parahippocampal gyrus, although their scores did backslide modestly during 11 months of follow-up, while the IFC group continued to improve.

Dr. Rubia acknowledged that this raises the possibility that the observed improvement in clinical symptoms achieved through fMRI-NF could be attributable to a placebo effect. However, she said she believes this is unlikely for several reasons. For one, brain scans showed that targeting either the right IFC or the left parahippocampal gyrus not only resulted in upregulation of activity in those specific regions, but throughout the broader neural networks of which they are a part. The right IFC upregulators showed activation of a bilateral dorsolateral prefrontal cortex/IFC-insular-striato-cerebellar cognitive control network. In contrast, the boys who targeted the left parahippocampal gyrus experienced activation of associated posterior visual-spatial attention regions, which are relevant to ADHD. This made for a far from ideal control group.

Also, the amount of improvement in ADHD symptoms in the right IFC-targeted group correlated with the degree of activation of that region, indicative of a brain-behavior correlation that speaks against a nonspecific effect.

Because this was a small, unpowered pilot study and interest remains intense in potential nonpharmacologic treatments for ADHD, the U.K. Medical Research Council is funding Dr. Rubia and her colleagues for a new 100-patient study – including a sham fMRI-NF arm – in order to definitively address the possibility of a placebo effect. The study also will attempt to pin down the patient population most likely to benefit from fMRI-NF. “It’s possible that the inattentive subtype of ADHD will respond best. Neurofeedback is, after all, a form of attention training,” she noted.

While real-time fMRI-NF might sound prohibitively expensive for widespread use in clinical practice for a disorder as common as ADHD, which has an estimated prevalence of about 7%, it might actually stack up reasonably well in a cost-benefit analysis, compared with ongoing medication costs and side effects or with a year’s worth of weekly psychotherapy, according to Dr. Rubia.

In parallel with the ongoing sham-controlled fMRI-NF study, Dr. Rubia also is conducting a clinical trial of transcranial direct current stimulation of the right IFC in combination with cognitive training. The idea is to study the clinical impact of directly upregulating activity in this area of the brain, bypassing the added step of training patients to gain self-control over this dysregulated region. The early findings, she said, look promising.

The fMRI-NF study ( Hum Brain Mapp. 2017 Jun;38[6]:3190-209 ) was sponsored by the U.K. National Institute for Health Research and the Maudsley NHS Foundation Trust. Dr. Rubia reported receiving speakers honoraria from Lilly, Shire, and Medice.

Source: Rubia K et al. European College of Neuropsychopharmacology.


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