Martijn Arns, PhD Research Institute Brainclinics, Nijmegen

neuroCare Group, Munich

Dept. Experimental Psychology, Utrecht University, The Netherlands

Twitter : @Brainclinics @neuroclinicswww.neurocademy.com

UNDERSTANDING ADHD

NIMH-MTA STUDY (MOLINA ET AL., 2009)

•NIMH Collaborative Multisite Multimodal Treatment Study of Children with ADHD.

•N=579 children•Random assignment to:

• 14 mo. Medication management

• Multicomponent behavior therapy

• Combined

• Usual Comm. Care

•8 years FU

Wang et al. (2013)

PET: Dopamine transporter

IS THIS NEUROFEEDBACK?

NecomimiMattel Mindflex

SmartBrain TechnologiesEmotiv

THIS IS NEUROFEEDBACK!

Skinner’s Pigeons

IMPORTANT CONDITIONING PRINCIPLES

• For optimal learning:• Speed of reinforcement: Filter settings• Type of reinforcement: Neutral and specific; discrete vs.

Continous reward; NOT complicated games (treatment vs. Entertainment), also see PRS example next slide.

• Shaping of learning: Manual procedure, knowledge of EEG signal, no auto-tresholding• http://www.youtube.com/watch?v=TtfQlkGwE2U • Auto-tresholding: learning target a ‘moving target’• example of ‘screaming child’

Ritalin çè

Ritalin è

•

Sonuga-Barke, E. J., Brandeis, D., Cortese, S., Daley, D., Ferrin, M., Holtmann, M., . . . European ADHD Guidelines Group. (2013). Nonpharmacological interventions for ADHD: Systematic review and meta-analyses of randomized controlled trials of dietary and psychological treatments. The American Journal of

Psychiatry, 170(3), 275-89. doi:10.1176/appi.ajp.2012.12070991

Steiner et al. NF vs. WL? NF vs. CT!• Based on Sonuga-Barke et al. definition• NF and CT decreased medication by 30%!

Lansbergen study: Apples & Oranges (learning?; ‘different network’)

Parent ratings: ES=0.58 (95% CI=0.12–0.94; Z=3.52; p=0.0004),

Teacher ratings: ES=0.39 (95% CI=0.07–0.70; Z=2.39; p=0.02) Arns, M., & Strehl, U. (2013). Evidence for efficacy of neurofeedback in ADHD? The American

Journal of Psychiatry, 170(7), 799. doi:10.1176/appi.ajp.2013.13030293

Inattention Hyperactivity

Inattention Hyperactivity

HETEROGENEITY IN NEUROFEEDBACK OUTCOMES?

• Implementation

• Differences in neurofeedback protocols: Apples and oranges? Not all neurofeedback=neurofeedback.

• Well investigated in ADHD with consistent outcomes:

SCP (@Cz), SMR (@C3, Cz or C4) and TBR (@Fz or Cz).

• Learning theory?

• Percentage of reinforcement?

Not effective:

• Nall et al. (1973): Alpha enhancement neurofeedback

• Arnold et al. (2013) & deBeus & Kaiser (2011): Training of ‘NASA patented’ engagement index: Theta, Alpha, SMR & Beta with PlayStation feedback (entertainment?)

• Lansbergen et al. (2010) / van Dongen-Boomsma (2013): ‘QEEG based’ protocols incl. SMR @ F3-F4, two-channel set-up?

HETEROGENEITY IN NEUROFEEDBACK OUTCOMES?

• Implementation

• Differences in neurofeedback protocols: Apples and oranges? Not all neurofeedback=neurofeedback.

• Well investigated in ADHD: SCP (@Cz), SMR (@C3, Cz or C4) and TBR (@Fz or Cz).

• Learning theory? Entertainment vs. Neurofeedback

EVIDENCE: SUMMARY• Two independent multi-center studies (N>100), NF>CT and effects sustained after 6 mo.

(Steiner et al., 2014; Gevensleben et al. 2009)

• Two independent RCT’s comparing NF with medication, medication not superior to NF (Duric et al., 2012; Meisel et al., 2013)

• Three meta-analyses demonstrating similar effects (Arns et al., 2009; Sonuga-Barke et al., 2013; Arns & Strehl, 2013; Miccoulaud-Franchi et al. 2014)

• UPDATED AAPB GUIDELINES: Arns, Heinrich & Strehl (In Press)

Level 5: Efficacious and Specific (APA guidelines): SCP, TBR and SMR neurofeedback

• Difference in opinions mainly explained by a) using APA guidelines vs. b) rating as a drug.

UNDERSTANDING ADHD

Eyes Closed

Eyes Open

PROGRESSION OF EEG FROM WAKING TO SLEEP

PROGRESSION OF EEG FROM WAKING TO SLEEP

Based on Hegerl et al. (2010; 2012)

EEG VIGILANCE REGULATION IN ADHD

DEPRESSION: RIGID VIGILANCE REGULATION

Hegerl et al. (2011)

EEG VIGILANCE REGULATION IN ADHD

Arns, Gunkelman, Breteler & Spronk

FRONTAL THETA

12008214: EO; 13 yrs.

EEG VIGILANCE DYSREGULATION IN ADHD

• ADHD-subgroup characterized by lower EEG Vigilance (frontal alpha and frontal theta), symptoms understood from Vigilance model

• Responders to stimulant medication (Arns et al., 2008; Suffin & Emory, 1995) and Neurofeedback (Monastra et al., 2002; Gevensleben et al., 2009; Arns et al., 2012)

• Non-responders to antidepressants and rTMS (Arns et al., 2009; 2012; Prichep et al., 1993; Losiffescu et al., 2009; Knott et al. 1996; 2000)? Replicate in iSPOT?

• These sub-groups do respond to stimulant medication in Depression (Suffin & Emory, 1995; DeBattista et al., 2010) and Manic Depression (Bschor et al., 2001; Hegerl et al., 2010; Schoenknecht et al., 2010)

• Underlying etiology of this sub-group?

SLEEP DURATION AND SLEEP RESTRICTIONHEALTHY CHILDREN

• Sleep duration associated with school performance+, executive function+ and internalizing- and externalizing- behavior (Astill, van der Heijden, van Ijzendoorn & van Someren, 2012:

Meta-analysis: N=35.936 children)

• Sleep duration for children decreased across the last 100 years (Matricciani, Olds & Petkov, 2012; Meta-analysis N=690.747

children) and shorter sleep duration associated with obesity (Magee & Hale, 2012)

• Historically increased TBR often reported in ADHD (impaired vigilance reg.)

• TBR not reliable as a diagnostic marker• Increased TBR across 10 years for healthy

control groups• Further supporting decreased sleep

duration?

• Homeostatic process is responsible for the rise of sleep propensity during waking and its dissipation during sleep

• Circadian process is basically independent of prior sleep and waking (day-night)

TWO-PROCESS MODEL OF SLEEP REGULATION

• Hypersomnia: Not enough sleep pressure, rigid vigilance regulation: Difficulty falling asleep• Delayed circadian phase: Difficulty falling asleep: Labile vigilance regulation.

• Sleep restriction in healthy children results in impaired attention (Fallone et al., 2001; 2005; Sadeh et al.,

2003; Beebe et al., 2008) and increased Theta (Beebe et al., 2010; Process S)

• ‘Recovery’ of sleep restriction takes more days than actual sleep restriction!

• Sleep restriction as an explanation for increased incidence of ADHD and increased obesity rates?

SLEEP DURATION AND SLEEP RESTRICTIONHEALTHY CHILDREN

ADHD AND SLEEPMany sleep problems affecting sleep duration and sleep efficiency are more prevalent in ADHD:

• 20% prevalence of sleep breathing disorders/sleep apneu (Silvestri et al., 2009)• 26% restless legs syndrome (RLS: Konofal et al., 2010; Silvestri et al., 2009)• 70-80% sleep onset insomnia (SOI) characterized by delayed circadian phase (van der Heijden et al., 2005; 2007;

van Veen et al., 2010).

Treat these as ‘Sleep Phenotypes of ADHD’? (Miano, Parisi & Villa, 2012)• Treatment of sleep apnea (adenotonsillectomy) resulted in substantial improvement on attention and ‘ADHD

behavior’ (Huang et al., 2007).• Treatment of restless legs syndrome by LDOPA improved sleep and dramatic improvements in ‘ADHD behavior’

(Walters et al., 2000). Patients were unresponsive to Stimulants.• Chronobiological treatments for SOI in ADHD: LT Melatonin (Hoebert et al., 2009) and early morning bright

light (Rybak et al., 2006)• Neurofeedback?

From: Marcel Smits: www.melatoninecheck.nl

Weekdays

2013

/ Sleep Problems

VIGILANCE REGULATION AND SLEEP IN ADHD

SMR, TBR AND SCP NEUROFEEDBACK

• All TB NF studies have also included the SMR band in their beta band (e.g. 12-21 Hz).• Except Bakhshayesh et al. (2012)

• All protocols at Central locations (= same network)

SMR, TBR AND SCP NEUROFEEDBACK

• All TB NF studies have also included the SMR band in their beta band (e.g. 12-21 Hz).• Except Bakhshayesh et al. (2012)

• All protocols at Central locations (= same network)

Arns et al. (2009): Table 1

SMR (12-15 Hz) Neurofeedback

(during waking!):

• Longer epochs of undisturbed sleep• Increased SS density (still present >1 mo. post-training)

NEUROFEEDBACK AND SLEEP

• SMR (12-15 Hz) Neurofeedback (wake):• Increased number of sleep spindles

(Sterman et al., 1970; Hoedlmoser et al., 2008) • Decreased sleep latency, increased

total sleep time and sleep efficiency (Cortoos et al., 2010; Hoedlmoser et al., 2008; Sterman et al., 1970; Sterman & Friar, 1972; Schabus et al., 2013)

Hoedlmoser et al. (2008: 10 sessions!)

Cortoos et al. (2010); TST +44 min.

SLEEP-SPINDLE GENERATION

• SMR Neurofeedback = training sleep spindle circuitry directly (frequency & location)

• SMR neurofeedback in ADHD has specific effects and mediates neurofeedback outcome

Pre-treatment25 sessions of neurofeedback

Start NeurofeedbackHoliday &

Medication adjustment Christmas Holiday2 separate baselines

SOI (>30 min.): 57% ADHD and 18% controls

• SMR group (N=27):

• Theta inhibit: N=8

• SMR @ C4: N=12

• SMR @ C3: N=13

• No differences nor interactions with laterality!

• Cortical slow waves (< 1Hz) trigger sleep spindles (Amzica & Steriade, 1997; Marshall et al., 2006)

• SCP: Training this cortical ‘slow wave’ circuitry

• SCP, SMR (=TBR) impact on sleep spindle circuitry!• Shared mechanism between different types of

Neurofeedback

SLEEP-SPINDLE GENERATION

• Cortical slow oscillations

• Reticular-Thalamocortical-cortical sleep spindle network (12-15 Hz)

NETWORKS INVOLVED IN ADHD-SLEEP

CIRCADIAN REGULATION OF SLEEP SPINDLES

• Circadian modulation of sleep spindles and melatonin results in increased sleep spindle density (Dijk et al., 1995)

• Shared mechanism between melatonin and neurofeedback?

R2=59%

ADHD Prevalence (Children): CDC data

• Percentage ‘Low Birth Weight’ (LBW) and ‘Infant Mortality’ (IM): r2=18-22%

• Controlled for: latitude, SES, LBW, IM: r2: 34-41% (p<.001) explained variance

• Further corrections: Altitude; Medicaid coverage; male:female ratio; multi-raciality; ethnicity: No change.

• Similar prevalence data available for ASD (n=14), MDD (n=44), but no significant association with SI (p>0.913)

• A ‘protective effect’ of high solar intensity for diagnosis ADHD

5 10 153

4

5

6

7

ADHD Prevalence (in %: CDC, 2003)

Sola

r In

tens

ity (k

Wh/

m2/

day,

NRE

L)

5 10 153

4

5

6

7

ADHD Prevalence (in %: CDC, 2007)

Sola

r In

tens

ity (k

Wh/

m2/

day,

NRE

L)

2003 Prevalence: r2=36%, p<0.006

2007 Prevalence: r2=37%, p<0.0002

ADHD Prevalence (Adults): Fayyad et al. (2007)

• r2: 57% (p=.018) explained variance

• No association with altitude or latitude

• A ‘protective effect’ of high solar intensity for diagnosis ADHD

r2=57%, p=0.018

Protective effect of high SI, except for: Scandinavia and UK

Reduced sleep also for whole world, except…Scandinavia, Australia and UK

Hoffmann et al. (2013)

Protective effect of high SI, except for: Scandinavia and UK

Genetically protected? E.g SAD (Axelsson et al. (2002)

Possible protective role for DRD4-7R and other genes (Kim et al. 2010)? • DRD4 in retina: Phototransduction • Pineal DRD4 under circadian control • Dopamine - Circadian link!

BLUE LIGHT AND SCN

From Reppert & Weaver, 2002

• Melanopsin ➔ SCN: Non-image forming light detection: Only sensitive to blue spectrum (Reppert & Weaver, 2002; and ultraviolet: van Oosterhout et al. 2012)

LIGHT AND ADHD?• Not explained by Vitamin-D (Arns, van der Heijden, Arnold &

Kenemans, In Press)

• Evening use of iPADs, mobile phones, PC’s • Delayed sleep onset (Custers et al., 2012; van den Bulck et al.,

2004)• Shorter sleep duration (van den Bulck et al., 2004)• Melatonin suppression (Wood et al., 2012; Cajochen et al., 2011)

• LED and CFL lamps have a peak in the blue light spectrum (Incandescent lamps prohibited in EU!)

• Prevention: Install skylights in schools?From: Marcel Smits: www.melatoninecheck.nl

LIGHT AND ADHD?• Not explained by Vitamin-D (Arns, van der Heijden, Arnold &

Kenemans, In Press)

• Evening use of iPADs, mobile phones, PC’s • Delayed sleep onset (Custers et al., 2012; van den Bulck et al.,

2004)• Shorter sleep duration (van den Bulck et al., 2004)• Melatonin suppression (Wood et al., 2012; Cajochen et al., 2011)

• LED and CFL lamps have a peak in the blue light spectrum (Incandescent lamps prohibited in EU!)

• Prevention: Install skylights in schools?From: Marcel Smits: www.melatoninecheck.nl

• 25-30 min later school start -> 29-45 min longer sleep (Owens et al., 2010; Burgers et al., 2014)

• Multicenter study including 9.000 high-school students (Wahlstrom et al., 2014)

• school time shiften from 7.35 to 8.55. AM, 70% reduction in car crashes!

• Overall improvements on mood, alertness etc.

SLEEP EXTENSION?

CHARLES A. CZEISLER (2013)

…It is time to reassess the early assurances of Thomas Edison that using electric light “is in no way harmful to health, nor does it affect the soundness of sleep…

Czeisler, C. A. (2013). Perspective: Casting light on sleep deficiency. Nature, 497(7450), S13. doi:10.1038/497S13a

SUMMARIZING…• Based on APA criteria, specific neurofeedback protocols in ADHD are efficacious and specific: SCP,

TBR and SMR.• Some protocols are not efficacious: Alpha enhancement, engagement index and bi-frontal SMR NF• Neurofeedback has long term effects, tendency for further improvement• When evaluating neurofeedback focus on: Entertainment vs. neurofeedback • ADHD symptoms can be caused by sleep-problems, and treating sleep problems improves ADHD

behavior• Children today sleep less, have more Theta (drowsiness) and today higher rates of ADHD• Probably caused by evening use of modern media (iPads, laptops, mobile phones ) and modern

lighting (LED, CFL) in genetically susceptible individuals• Prevention: Decreased evening blue-light exposure and increase daytime sunlight exposure.

• Examples: Freeware F.lux, or install Skylight systems at schools.

SUGGESTIONS• Incorporate sleep questionnaires in practice and research:

• PSQI: Pittsburg Sleep Quality Inventory• HSDQ: Holland Sleep Disorders Questionnaire• Consider Actigraphy (e.g. Condor)• Quantify SOI or no-SOI

‘difficulty getting to sleep at a desired bedtime and/or sleep onset latency (time from bedtime to sleep start) of more than 30 minutes for at least 4 nights a week, existing for at least 6 months, and leading to impairment in several areas (Van veen et al., 2010)’Adults: Later than 23.30 hrs. Children: sleep onset later than 20.30 hrs. in children aged 6 years and for older children 15 minutes later per year until age 12 years.

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