Abstract
Background
Attention-deficit/hyperactivity disorder is characterized by neurobiological heterogeneity,
possibly explaining why not all patients benefit from a given treatment. As a means
to select the right treatment (stratification), biomarkers may aid in personalizing
treatment prescription, thereby increasing remission rates.
Methods
The biomarker in this study was developed in a heterogeneous clinical sample (N = 4249) and first applied to two large transfer datasets, a priori stratifying young
males (<18 years) with a higher individual alpha peak frequency (iAPF) to methylphenidate
(N = 336) and those with a lower iAPF to multimodal neurofeedback complemented with
sleep coaching (N = 136). Blinded, out-of-sample validations were conducted in two independent samples.
In addition, the association between iAPF and response to guanfacine and atomoxetine
was explored.
Results
Retrospective stratification in the transfer datasets resulted in a predicted gain
in normalized remission of 17% to 30%. Blinded out-of-sample validations for methylphenidate
(n = 41) and multimodal neurofeedback (n = 71) corroborated these findings, yielding a predicted gain in stratified normalized
remission of 36% and 29%, respectively.
Conclusions
This study introduces a clinically interpretable and actionable biomarker based on
the iAPF assessed during resting-state electroencephalography. Our findings suggest
that acknowledging neurobiological heterogeneity can inform stratification of patients
to their individual best treatment and enhance remission rates.
Keywords
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References
- A review of heterogeneity in attention deficit/hyperactivity disorder (ADHD).Front Hum Neurosci. 2019; 13: 42
- Attention-deficit/hyperactivity disorder: A current overview.Dtsch Arztebl Int. 2017; 114: 149-159
- Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: A systematic review and network meta-analysis.Lancet Psychiatry. 2018; 5: 727-738
- The MTA at 8 years: Prospective follow-up of children treated for combined-type ADHD in a multisite study.J Am Acad Child Adolesc Psychiatry. 2009; 48: 484-500
- Treatment efficacy and clinical effectiveness of EEG neurofeedback as a personalized and multimodal treatment in ADHD: A critical review.Neuropsychiatr Dis Treat. 2021; 17: 637-648
- Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework.Clin Pharmacol Ther. 2001; 69: 89-95
- Personalized medicine: Review and perspectives of promising baseline EEG biomarkers in major depressive disorder and attention deficit hyperactivity disorder.Neuropsychobiology. 2015; 72: 229-240
- Stratified psychiatry: Tomorrow’s precision psychiatry?.Eur Neuropsychopharmacol. 2022; 55: 14-19
- EEG abnormalities are associated with poorer depressive symptom outcomes with escitalopram and venlafaxine-XR, but not sertraline: Results from the multicenter randomized iSPOT-D study.Clin EEG Neurosci. 2017; 48: 33-40
- EEG alpha asymmetry as a gender-specific predictor of outcome to acute treatment with different antidepressant medications in the randomized iSPOT-D study.Clin Neurophysiol. 2016; 127: 509-519
- EEG biomarkers in major depressive disorder: Discriminative power and prediction of treatment response.Int Rev Psychiatry. 2013; 25: 604-618
- An electroencephalographic signature predicts antidepressant response in major depression.Nat Biotechnol. 2020; 38: 439-447
- Individual alpha frequency proximity associated with repetitive transcranial magnetic stimulation outcome: An independent replication study from the ICON-DB consortium.Clin Neurophysiol. 2021; 132: 643-649
- EEG connectivity between the subgenual anterior cingulate and prefrontal cortices in response to antidepressant medication.Eur Neuropsychopharmacol. 2017; 27: 301-312
- Utility of event-related potentials in predicting antidepressant treatment response: An iSPOT-D report.Eur Neuropsychopharmacol. 2015; 25: 1981-1990
- Electroencephalographic biomarkers as predictors of methylphenidate response in attention-deficit/hyperactivity disorder.Eur Neuropsychopharmacol. 2018; 28: 881-891
- The new international neuroblastoma response criteria.Pediatr Radiol. 2019; 49: 1433-1440
- Treatment stratification of patients with metastatic castration-resistant prostate cancer by machine learning.iScience. 2020; 23: 100804
- Treatment and biology of pediatric acute lymphoblastic leukemia.Pediatr Int. 2018; 60: 4-12
- EEG biomarker informed prescription of antidepressants in MDD: A feasibility trial.Eur Neuropsychopharmacol. 2021; 44: 14-22
- Standardization and personalized medicine using quantitative EEG in clinical settings.Clin EEG Neurosci. 2021; 52: 82-89
- Spontaneous alpha peak frequency predicts working memory performance across the age span.Int J Psychophysiol. 2004; 53: 1-9
- Making brains run faster: Are they becoming smarter?.Span J Psychol. 2016; 19: E88
- Brain potentials in children and adults.Science. 1936; 84: 354
- The electroencephalogram during normal infancy and childhood: II. The nature of the growth of the alpha waves.Pedagog Seminary J Genet Psychol. 1938; 53: 455-469
- EEG-based personalized medicine in ADHD: Individual alpha peak frequency as an endophenotype associated with nonresponse.J Neurother. 2012; 16: 123-141
- EEG alpha and theta oscillations reflect cognitive and memory performance: A review and analysis.Brain Res Brain Res Rev. 1999; 29: 169-195
- Individual alpha peak frequency is related to latent factors of general cognitive abilities.Neuroimage. 2013; 79: 10-18
- EEG spectral profile to stage Alzheimer’s disease.Clin Neurophysiol. 1999; 110: 1831-1837
- Decreased peak alpha frequency and impaired visual evoked potentials in first episode psychosis.Neuroimage Clin. 2019; 22: 101693
- Reduction in alpha peak frequency and coherence on quantitative electroencephalography in patients with schizophrenia.J Korean Med Sci. 2018; 33: e179
- On the efficiency of individualized theta/beta ratio neurofeedback combined with forehead EMG training in ADHD children.Front Hum Neurosci. 2018; 12: 3
- EEG phenotypes predict treatment outcome to stimulants in children with ADHD.J Integr Neurosci. 2008; 7: 421-438
- Interrelation between changes in the EEG and psychopathology under pharmacotherapy for endogenous depression. A contribution to the predictor question.Pharmacopsychiatry. 1984; 17: 178-183
- A multicenter effectiveness trial of QEEG-informed neurofeedback in ADHD: Replication and treatment prediction.Neuroimage Clin. 2020; 28: 102399
- Double-blind placebo-controlled randomized clinical trial of neurofeedback for attention-deficit/hyperactivity disorder with 13 month follow-up.J Am Acad Child Adolesc Psychiatry. 2021; 60: 841-855
- Neurofeedback for attention-deficit/hyperactivity disorder: Meta-analysis of clinical and neuropsychological outcomes from randomized controlled trials.J Am Acad Child Adolesc Psychiatry. 2016; 55: 444-455
- Sustained effects of neurofeedback in ADHD: A systematic review and meta-analysis.Eur Child Adolesc Psychiatr. 2019; 28: 293-305
- Which reference should we use for EEG and ERP practice?.Brain Topogr. 2019; 32: 530-549
- Remission versus response as the goal of therapy in ADHD: A new standard for the field?.Clin Ther. 2006; 28: 1892-1908
- Clinical relevance of the primary findings of the MTA: Success rates based on severity of ADHD and ODD symptoms at the end of treatment.J Am Acad Child Adolesc Psychiatry. 2001; 40: 168-179
- Sex differences in adolescent ADHD: Findings from concurrent EEG and EDA.Clin Neurophysiol. 2005; 116: 1455-1463
- The two decades brainclinics research archive for insights in neurophysiology (TD-BRAIN) database.Sci Data. 2022; 9: 333
- Effects of D-methylphenidate, guanfacine, and their combination on electroencephalogram resting state spectral power in attention-deficit/hyperactivity disorder.J Am Acad Child Adolesc Psychiatry. 2016; 55: 674-682.e1
- Response inhibition and emotional cognition improved by atomoxetine in children and adolescents with ADHD: The ACTION randomized controlled trial.J Psychiatr Res. 2018; 102: 57-64
- Matplotlib: A 2D graphics environment.Comput Sci Eng. 2007; 9: 90-95
- SciPy 1.0: Fundamental algorithms for scientific computing in Python [published correction appears in Nat Methods 2020; 17:352].Nat Methods. 2020; 17: 261-272
- Array programming with NumPy.Nature. 2020; 585: 357-362
Team T Pandas Development (2020): pandas-dev/pandas, version V1.0.3: Zenodo. Available at https://doi.org/10.5281/zenodo.3715232. Accessed January 13, 2021.
- Combined stimulant and guanfacine administration in attention-deficit/hyperactivity disorder: A controlled, comparative study.J Am Acad Child Adolesc Psychiatry. 2016; 55: 657-666.e1
- Combined frontal and parietal P300 amplitudes indicate compensated cognitive processing across the lifespan.Front Aging Neurosci. 2014; 6: 294
- Neurofeedback and attention-deficit/hyperactivity-disorder (ADHD) in children: Rating the evidence and proposed guidelines.Appl Psychophysiol Biofeedback. 2020; 45: 39-48
- Is autonomic nervous system function atypical in attention deficit hyperactivity disorder (ADHD)? A systematic review of the evidence.Neurosci Biobehav Rev. 2020; 108: 182-206
- Emotion regulation via the autonomic nervous system in children with attention-deficit/hyperactivity disorder (ADHD) [published correction appears in J Abnorm Child Psychol 2018; 46:655–657].J Abnorm Child Psychol. 2011; 39: 841-852
- Identification of biotypes in attention-deficit/hyperactivity disorder, a report from a randomized, controlled trial.Pers Med Psychiatry. 2017; 3: 8-17
- Emotion regulation via the autonomic nervous system in children with attention-deficit/hyperactivity disorder (ADHD): Replication and extension.J Abnorm Child Psychol. 2020; 48: 361-373
- Pain assessment by continuous EEG: Association between subjective perception of tonic pain and peak frequency of alpha oscillations during stimulation and at rest.Brain Res. 2010; 1344: 77-86
- Electroencephalographic slowing and reduced reactivity in neuropathic pain following spinal cord injury.Spinal Cord. 2008; 46: 118-123
- Increased EEG power and slowed dominant frequency in patients with neurogenic pain.Brain. 2006; 129: 55-64
- EEG findings in burnout patients.J Neuropsychiatry Clin Neurosci. 2010; 22: 208-217
- Peak high-frequency HRV and peak alpha frequency higher in PTSD.Appl Psychophysiol Biofeedback. 2013; 38: 57-69
- Methylphenidate: Its pharmacology and uses.Mayo Clin Proc. 2000; 75: 711-721
- Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: A potential mechanism for efficacy in attention deficit/hyperactivity disorder.Neuropsychopharmacology. 2002; 27: 699-711
- The role of guanfacine as a therapeutic agent to address stress-related pathophysiology in cocaine-dependent individuals.Adv Pharmacol. 2014; 69: 217-265
- Facilitation of spindle-burst sleep by conditioning of electroencephalographic activity while awake.Science. 1970; 167: 1146-1148
- Differential effects of theta/beta and SMR neurofeedback in ADHD on sleep onset latency.Front Hum Neurosci. 2014; 8: 1019
- Neurofeedback in ADHD and insomnia: Vigilance stabilization through sleep spindles and circadian networks.Neurosci Biobehav Rev. 2014; 44: 183-194
- Sleep disorders and daytime sleepiness in children with attention-deficit/hyperactive disorder.Sleep. 2004; 27: 261-266
- Relationship of autonomic nervous system activity to daytime sleepiness and prior sleep.Sleep. 1989; 12: 239-245
- Family structure and the gender gap in ADHD.Rev Econ Household. 2020; 18: 1101-1129
- The relationship between individual alpha peak frequency and clinical outcome with repetitive transcranial magnetic stimulation (rTMS) treatment of major depressive disorder (MDD).Brain Stimul. 2019; 12: 1572-1578
Article info
Publication history
Published online: February 28, 2022
Accepted:
February 18,
2022
Received in revised form:
February 11,
2022
Received:
October 27,
2021
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