The need for better long term outcomes -

personalised assessments, and treatments

ADHD

The Circadian Sleep-Wake cycle

N e u r o f e e d b a c k

Mark Ryan*, Trevor Brown* & Martijn Arns**n e u ro C a re A u s t r a l i a * and n e u r o C a r e M u n i c h **

Research Institute Brainclinics & Utrecht University, The Netherlands**

What we see is biased by what we believe/expect/predict to see

In this presentation the aim is to introduce some new beliefs/expectations about ADHD to enable seeing and treating it differently

Steps along the way to expanding attention and perception about inattention etc:

Efficacy & effectiveness of ADHD treatments

      short and long term outcomes

Sleep, ADHD and neurofeedback       

        the causal role of sleep disorders &        

      effective treatment with neurofeedback

Cognitive & Behavioural Treatments & Medications

An overview of efficacy

Sonuga-Barke et al. (2013)

Psychological & non-pharmacological treatments for ADHD: Proximal treatment Outcomes

The conditionality of treatment efficacy of medication Medication and behaviour therapy - MTA Trial

Short term condition - remission rates 25-68%

* 68% combined CBT + meds

          * 56% meds only

          * 25% CBT & community treatment arms (+meds) = TAU

initial large ES shrinks by 14 months

Longer term condition - further shrinking; initial benefit not sustained

* @ 3yrs, initial advantage of meds over behavioural therapy                  disappears  (Jensen et al., 2007)

* @ 8 yrs, no advantage of medication over other treatments (Molina et                      al.,2008; Swanson et al., 2018)

Medication does not improve outcomes in the longer term: ADHD patients continued to lag behind non-ADHD on            academic & mental health measures (Molina et al., 2008; Swanson et al.; 2017)

Wang et al. (2013)

Up-regulation of dopamine transporter availability with continued use of Ritalin (Wang et al., 2013)

Well known stimulant medications side effects include              : appetite and mood problems common (Cascade et al., 1010; McDonagh et al., 2017)

              : reduced adult height (Swanson et al., 2017)

Both stimulant and non-stimulant meds (atomoxetine) reduce electric power in sleep EEG & alter CLOCK gene expression             :             : disrupts entrainment & amplitude of the diurnal circadian rhythm             : resulting in prolongation SOL, increased nocturnal activity, reduced sleep duration and               quality with more WASO (Boonstra et al., 2007; Coogan et al; in press)

Medication treatment outcomes in ADHD: receptor up-regulation and sleep

PET - dopamine transporter

N e u r o f e e d b a c k

An overview of efficacy: a closer look

Neurofeedback & ADHD: Treatment OutcomesSHORT-TERM EFFECTS

RCTs, cf semi-active control groups, ‘standard neurofeedback protocols’

Large ES for inattention & impulsivity

Medium ES for hyperactivity

32-47% remission rate (Arns et al., 2009)

More recent RCTs - Duric et al., 2012; Meisel et al., 2013

Theta/Beta Neurofeedback as effective as methylphenidate in reducing all ADHD symptoms

BUT superior academic performance (2 RCTs @

30-40 Neurofeedback sessions; no evidence for nonstandard protocols (e.g. Z-Score & LORETA NFB (Coben et al., 2018)

LONG-TERM EFFECTS All NFB studies show benefits persist / further improvement (ES) in the follow-up period after course of

Neurofeedback cf, medication effects

confirmed in a recent systematic review & meta-analysis

(Van Doren et al., 2018)

Effectiveness of treatment: Beyond the RCT, how well does it actually work in

everyday clinical practice

Purely statistical evidence is never enough

Medications & neu ro feedback

A comparison of effectiveness in everyday clinical practice

MTA Medication

In open label trials and clinical practice, medication benefits much lower than the original MTA trial results

ISPOT-A ** - open label multi-centre trial, included Australian centres; MTA algorithm used as control (Arns et al., 2018; Elliott et al., 2017)

the MTA 56-68% remission rates drop to 31%

loss of effect of medicat ion over t ime

Neurofeedback

Large ES with a remission rate of 53% in the clinical setting, using QEEG informed ‘standard NFB protocols’ (Arns et al., 2012)

NFB (standard protocols) translates well into clinical practice with efficacy similar to multicomponent behaviour therapy arm of MTA and only marginally below MTA medication arms

Currently in the NeuroCare clinics across the world we are achieving a 55% remission rate, based on the very strict Swanson et al (2001) criteria#

**

Conclusion: standard neurofeedback protocols achieve

clinically relevant benefits and better long-term outcomes C l i n i c a l b e n e f i t o f M TA m e d i c a t i o n a r m s n o t a c h i e v e d i n c l i n i c a l p r a c t i c e (Arns et al., 2018; Elliott et al., 2017).

Medication does not achieve long term maintenance of remission of symptoms of ADHD (Molina et al.,2008; Swanson et al., 2017).

Standard Neurofeedback protocols (SMR, Theta/Beta & SCP) translate well into cl inical practice achieving an effectiveness similar/better relat ive to medication in MTA Trial (Arns et al., 2012; Arns et., 2018; Elliott et al., 2017).

Neurofeedback benefits persist beyond cessation of NFB, with further improvement in the follow up period (Van Doren et al., 2018)

NFB is both non invasive and safe - no significant NFB specific side effects reported in the literature (Strehl et al., 2017)

What is neurofeedback?

Evidence based neurofeedback is the operant training of EEG activity using ‘standard protocols’

Effective Neurofeedback requires adequate training of the therapist and

strict adherence to principles of operant learning* & adequate intensity and duration of

treatment

Standard neurofeedback protocols, are efficacious and specific in the treatment of ADHD(Level 5 evidence; Updated APA Guidelines - Arns, Heinrich and Strehl., 2016)

Not neurofeedback: ‘double sham’

(2017)

Neurofeedback - the importance of doing it correctly = standard protocols and operant learning principles

So, what about sleep? Sleep as a biomarker

Sleep disorders in ADHD lurking in plain sight

What has neurofeedback                got to do with it?

Common sleep problems in ADHDObstructive sleep apnoea - 20% prevalence (Silvestri et al., 2009)

Restless legs - 26% prevalence (Konofal et al, 2010; Silvestri et al, 2009)

Delayed onset circadian rhythm sleep disorder (sleep onset insomnia) ~ 80% prevalence and diurnal dysregulation of cortisol and melatonin (van der Heijden et al 2005: 2007: van Veen et al, 2010)

ADHD children deficient in sleep spindles (12-15Hz) (Saletin et al., 2017)

Gene-environment interactions

High prevalence (>40%) of evening chronotype - ‘night owl’ (Rybak et al., 2007) - more susceptible to sleep restriction due to poor sleep hygiene and social demands etc

Lower prevalence of ADHD in regions of higher solar intensity (Arns et al., 2013)

Sleep-Wake disturbances and ADHD 1. shorter sleep duration

Skimping on sleep - our dark deprived urban night time environment, social demands & lifestyle

self reported sleep duration declined > 1.5-2.0 hours/night in last 50 years (National Sleep Foundation in America poll, 2015)

children sleeping 75 minutes/night less than 100 years ago (Matricciani et al., 2012)

shorter sleep duration/sleep restriction in children & adolescents correlates with

reduced school performance impaired executive functioning, mood dysregulation, behavioural impulsivity and internalising and externalising  behaviour problems (Astil et al, 2012: meta-analysis N = 35936; van Dongen et al., 2003)

ADHD symptoms in both healthy (Axelsson et al., 2008; Belenky et al., 2003: van Dongen et al., 2004; Calhoun et al.,

2017; Gau et al., 2007; Kass et al., 2003) and ADHD groups (Mahajan et al., 2010; Arns &   Vollebregt., 2019; Becker et al., 2018)

Shorter sleep duration is causal of inattention in those with and without ADHD (Becket et l., 2018; Arns and Vollebregt., 2019)

Melatonin improves sleep onset but not cognitive performance and behaviours in short-medium term (Van der Heijden et al., 2007)

Early morning bright light improves mood and ADHD symptoms (Rybak et al, 2006)

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LED (blue) l ight exposure at night positively associated with the amount of sleep onset delay (> 20 minutes)

which in turn is negatively related to sleep duration which leads to worsening of attention blue l ight also penetrates the closed eyelids

Adolescent ratings - no reports of inattention; Teacher ratings - attention worse, more oppositional

Sleep restriction & ADHD: the causal role of blue light at night

Sleep-Wake disturbances and ADHD 2. disordered sleep breathing

Disordered breathing in sleep - OSA and snoring without obstruction

adenotonsillectomy substantially improves attention and ADHD behaviours (Huang et al, 2007; Swedky et al., 2016)

cpap use results in improved ADHD symptoms (Johnstone et al.,2001)

disturbed sleep breathing - snoring without OSA also disrupts sleep quality

and is associated with ADHD symptoms (Sedky et al., 2014) and particularly with hyperactivity/impulsivity in ADHD (Silvestri et al., 2009) and in the general population (Bonuck et al., 2012)

Disrupted sleep & ADHD: the role of disordered breathing

*Sleep apnoea an exclusion criteria

The inside-out of ADHD The circadian pathway model*

*Arns & Kenemens (2012)

ATTENTION DEFICIT / HYPERACTIVITY DISORDER

Hyperactive subtype Combined Subtype Inattentive Subtype

Unstable Vigilance Regulation (trait-like)

Sleep disordered breathing /Circadian Phase delay & restricted sleep duration

Vigilance Autostabilisation Syndrome(e.g. hyperactivity, sensation seeking,

talkativeness)

Cognitive Deficits(e.g. impaired sustained attention

NUMEROUS BRAIN AND BODY FUNCTIONS ARE RESTORED & REGULATED IN SLEEP – INSOMNIA AS A 24/7 DISORDER

Necessary for memory & learningDuring sleep we process memories and learning from the day - lack of sleep affects long-term and short-term memories and learning. Regulates emotions, steadies mood swings; we process emotional experiences in sleep; enabling us to cope and emotionally regulate better

Improves concentrationOur attention/concentration, motivation, energy and learning are reduced when we have not slept enough

Important to get good night’s sleep before and after any therapy!

Adequate sleep enhances and generalises learning (e.g.) fear response to stimulus addressed in therapy.

Lack of sleep reduces benefits of medications, psychotherapy, and of course neuromodulation therapies.

CRSD predicts non response to rTMS for OCD and is the major causal factor for most with ADHD

Restores, Repairs & Resetsmuscle recovery; BP reset; metabolic reset; hormone secretion; restores the immune system; drains beta amyloid from the brain

Improves social behaviour & occupational performance; Lack of sleep means we are less likely to correctly ‘read’ emotion and social cues/ feelings of others; less able to be empathic; less efficient and productive, make more errors

Improves behaviour & sporting performance; Lack of sleep results in irritability, impulsivity and disruptiveness; better sleep meansbetter sporting and other performances

30

For adequacy of awake state functioning Sleep is necessary for everything

W h i l e c a u s a l i t y i s n e v e r o n e t h i n g , b u t m a n y, s l e e p i s t h e m a j o r c a u s a l f a c t o r i n t h e

l a rg e s t s u b g ro u p w i t h A D H DNew DSM category? - “ADHD-SOM” - where sleep problems largely explain ADHD symptoms (Arns & Vollebregt, 2019)

sleep assessment and personalised treatment of sleep key to optimal outcome

Adolescents, sleep restriction & social demands: a particular concern           (aggravates the adolescent circadian phase delay and CRSD)

increased SWS intensity in which synaptic pruning occurs begins posteriorly & progresses frontally            (mirrors psychosocial development)

Disruption of this process resulting in abnormal synaptic & connectome development         associated with risk of SZO, depression

caffeine, alcohol, stimulant use, further disrupt sleep, attention, mood and other self-regulation, learning and synaptic pruning

Summary: Sleep, ADHD and neurofeedback

A D H D s y m p t o m s c a n b e c a u s e d b y s l e e p p r o b l e m s ; t r e a t i n g t h e s l e e p p r o b l e m s c a n r e m i t A D H D s y m p t o m s & b e h a v i o u r s [Arns et al., 2012; Arns and Kenemans., 2012; Duric et al., 2012; Meisel et al., 2013]

S t a n d a r d N e u r o f e e d b a c k p r o t o c o l s a r e e f f i c a c i o u s , e f f e c t i v e a n d s p e c i f i c i n t h e t r e a t m e n t o f A D H D ( L e v e l 5 e v i d e n c e ; Updated APA Guidelines - Arns, Heinrich and Strehl., 2016)

S M R N e u ro f e e d b a c k e f f e c t s a re m e d i a t e d

b y n o r m a l i s a t i o n o f s l e e p o n s e t l a t e n c y ( A r n s e t a l . , 2 0 1 4 )

the e f fects o f neuro feedback are susta ined a t fo l low up wi th fu r ther ga ins a f te r neuro feedback t reatment has s topped ( Va n D o re n e t a l . , 2 0 1 8 )

New DSM category proposed: “ADHD-SOM” where ADHD symptoms can be largely explained by sleep problems (Arns & Vollbregt., 2019; Bijlenga et al., 2018)

Poor sleep duration / efficiency Impaired daytime vigilance ADHD-like symptoms

Psychostimulant medictions

ADHD medications adversely impact

on the electrical quality of sleep and

also the molecular clocks regulating circadian rhythm and sleep-wake

regulation [Korman et al., 2018]

Benefits of medication not sustained

over the longer term and do not

improve long term outcomes [Jensen et

al., 2007; Molina et al., 2008; Swanson et

al., 2017]