RANZCP Annual Congress, 14th May 2014, Perth WA
ADHD and Emotional Dysregulation: Some Current Topics
Wai Chen
PhD MPhil(Camb) BM DCH MRCP MRCPsych
Acknowledgement
Eric Taylor (DSM V), Philip Asherson, Anita Thapar, Steve Faraone, Richard Todd (DSM V), Andrew Merwood. Conflict of Interests
• Consultancy: national and international advisory boards for Shire on LDX and Guanfacine; advisory board for FlynPharma.
• Lecture fees from Shire, Lily, Jansen and FlynPharma.
• Research grant from Shire and NIMH.
• Conference attendance support from Shire, Jansen, FlynPharma.
Narrative Review:
Share some findings
Limitations of current diagnostic taxonomy
Think outside the box
Splitters’ vs ‘Lumpers’ vs ‘Diplomats’
Overview’
I. Emotion Regulation or Dysregulation (ED)
In the context of ADHD
II. Clinical Considerations of ED:
• Overview of 7 models of Emotion Regulation or Dysregulation (ED):
.
Emotions
• Emotion – ‘people’s valenced (positive or negative) reactions to events that they perceive as relevant to their ongoing concerns ….multiple components that include specific thoughts, feelings, physiological and behavioural responses (Koole 2011)
• Evolutionarily adaptive actions (survival and reproduction)
• Supra-spinal, ‘sub-cortical’ ‘reflexes’
• Fast (limbic) and slow (cortical) highways in ‘The Emotional Brain’ (JE LeDoux 1996) Emotional Dysregulation (Eisenberg & Fabes 1992, 1996):
Emotionality (E) (automatic arousal; intensity experienced; negativity; frustration intolerance; overwhelmed)
Emo Regulation (capacity to self-regulate)
• Low E predicts high social competence • high E with high Emo Reg no risk • high E with poor Emo Reg poor social functioning and behavioural problems
Dysregulation:
Failure of automatic or effortful control of immediate emotional reaction and behaviours which are not compatible with long term goals or advantages
(conflict with a temporal distant standard – DLPFC, ACC)
Why Important? Emotional lability (EL) Excessive emotional reactions , frequent mood changes: Irritability, volatility, hot temper1 Mood Emotional instability dysregulation
Affective lability
Emotional EL impulsivity
Deficient emotional self regulation 60-70% heritable2 1Skirrow et al (2009); 2van Beijsterveldt et al (2004)
•Demands must be met immediately, easily frustrated •Cries often and easily •Mood changes quickly •Temper outbursts Adult ADHD sample:
EL
• most strongly predicted by hyperactivity– impulsivity rather than subsyndromal comorbid symptoms.
• contributed independently to impairment in family life, life skills, self- concept, social problems and risks The Experience sampling method (ESM)
• Participant wears a watch which vibrates at varying intervals
• Then they fill out a questionnaire on the PDA
• Responses collected 8 times a day for a working week (mon-fri) Anger ratings for individuals with ADHD and healthy controls over the 5-day period (Skirrow & Asherson in press)
ADHD n=35
Controls Subjective N=44 rating of angry 100 75 50 25 0
(Matched for age, IQ and years in education) Impact of adult ADHD on criminality Proportion of Swedish adults with criminal convictions over a 4-year period (Jan 1, 2006 to Dec 31, 2009)
Lichtenstein P, et al. N Engl J Med 2012;367:2006–14. 15 ‘Emotional-Impulsivity’ (EI) or ‘Deficient Emotion Self Regulation’ (DESR)
(Barkley & Fischer 2010):
High rates of EI in ADHD cases persistent into adulthood (from a FU study of ADHD childhood cohort).
EI -after adjusting for Inatt & Ha/Imp - contributes to impairments in:
• occupational, • educational, • criminal, • driving, • financial, • social relationships.
16 Common mistaken diagnoses
Adults Bipolar disorder Personality disorder Anxiety and depression
Children Juvenile bipolar disorder Severe mood dysregulation Oppositional defiant disorder/conduct disorder Emotional disorders (anxiety/depression) Childhood ADHD: 5 fold increase risk of depression by age 18 (Chronis-Tuscano 2010).
Comorbid ADHD+ Depression cases are 3- fold increase in complete suicide than either alone(James 2004). Childhood ADHD: 5 fold increase risk of depression by age 18 (Chronis-Tuscano 2010).
Comorbid ADHD+ Depression cases are 3- fold increase in complete suicide than either alone(James 2004). Childhood ADHD: 5 fold increase risk of depression by age 18 (Chronis-Tuscano 2010).
Comorbid ADHD+ Depression cases are 3- fold increase in complete suicide than either alone(James 2004). Genetic Architecture: ADHD & Emotional Lability in Manchester twins Merwood & Chen, Thapar, Asherson et al. (JAACAP 2.2014)
• Sample: – 1920 twin pairs from Greater Manchester Twin Register – Mean age = 11.15 years (SD = 3.09, range = 5-18)
• Measures : IA – 18 IA & HI items – 4 EL items from Conner’s Abbreviated HI EL Parent Questionnaire (APQ)
1,920 twin pairs from Manchester Twin Registry (mean age=11.2 (SD 3.1): Phenotypic Correlations of HA. IA, EL
Summary
• IA & HI & EL = highly heritable and largely influenced by a single liability
• This suggests EL likely a significant component of ADHD at the genetic (aetiological) level – potentially ‘third dimension of ADHD’
• Univariate heritabilities (~70%) similar to previous research (van Beijsterveldt et al, 2004)
• Caveat: family study showed ‘ADHD+ED’ co- segregation as ‘familial subtype’ (Surman et al. 2011).
Developmental Model of ADHD (Halperin & Schultz (2006))
• ADHD is due to subcortical neural dysfunction
• These remains static throughout lifetime
• PFC circuitry is not linked to the cause of ADHD, but the RECOVERY
• Age related remission of ADHD (mirror PFC/EF maturity), compensating through ‘top down’ regulatory control
Developmental Model of ADHD (Halperin & Schultz (2006))
• ADHD is due to subcortical neural dysfunction
• These remains static throughout lifetime
• PFC circuitry is not linked to the cause of ADHD, but the RECOVERY
• Age related remission of ADHD (mirror PFC/EF maturity), compensating through ‘top down’ regulatory control
Neuroscience-based Parenting Training (NBPT)- Understanding Emotional Dysregulation with 7 Models (Wai Chen 2014)
1. 2-stage Model (Koole); 2. Process Model (Gross); 3. Neuroanatomical bottom-up and top-down model 4. Attachment Theory Model (Mikulincer & Shaver), Compassion-Focused Therapy Model (Paul Gilbert); 5. Stress and Peer Victimisation Model (McLaughlin et al.), Mediation to Depression Model (Seymour et al.), Social Psychology and Group Identity Model (Amy Cuddy); Neurobiology of abuse (Teicher) 6. SRS Depletion Model (Self-Regulatory Strength System) (Baumeister) 7. Dynamic Network Connectivity (DNC) (Arnsten)
I: Two-stage Model
(Koole 2009) Two-Stage Model of Emotional Reaction (Koole 2009)
Two-Stage Model of Emotional Reaction (Koole 2009)
Stage Stage 1 Stage 2 Trigger, stress, habit, arousal Appraisal, modulate arousal Entry gradient Exit gradient II. Process Model
Gross & Thompson (2007) Process Model of Emotion Regulation (Gross & Thompson 2007)
More Effective Upstream Progressively Less Effective Downstream III. Neuro-anatomical Model
Reactive Bottom-up Effortful Top-down lobes of brain.gif lobes of brain.gif Neuro-anatomy of the emotional brain:
‘Reactive’ Bottom-up System: Limbic, amygdala, ventral striatum, vmPFC, Insula, Orbitofrontal, Papez Circuit
‘Effortful’ Top-Down System: Cingulate, Inferior PFC, DLPFC via OFPFC
Bottom-up System:
The Limbic System
Amygdala Amygdala
Caudate Striatum nucleus
Lentiform nucleus Pallidum
Amygdala Amygdala: 3 gp of nuclei
Central nucleus Corticomedial nuclei
Basolateral nuclei Amygdala
EFFERENT OLFACTORY PATHWAY AFFERENTS (stria terminalis)
ISOCORTICAL AFFERENTS Papez Circuit: CG parahippo hippocampus amygdala fornix Mamillary body (to HPA, brain stem, ANS, visceral) Th back to Cortex
Cingulum bundle
Cingulate gyrus Anterior thalamus
Mamillothalamic Internal capsule tract
Mamillary body (hypothalamus)
Fimbria / fornix
Hippocampus Top-down System:
PCF:
Paralimbic : CgC
(1) Dorsal (DLPFC): cognitive; (2) Inferior PFC: Inhibition; (3) Ventral and Ventral Medial: emotional/motivation. DA/NE (dorsal) ------5HT (ventral) (Arnsten & Rubia 2012)
Cingulate Cortex (transitional zone between archicortex and isocortex)
Cingulate gyrus
Isthmus
Cingulate sulcus
OFC
Subgenual area Parahippocampal gyrus ACC
• Important in Error Detection • ‘Reality mismatches Expectation’ • Alerting Arousal
• Change ‘Reality’ • Change ‘Expectation’
• Dorsal ACC (cogntive) vs Rostral ACC (emotional)
Subdivisions of Ant-CC: •Dorsal (cognitive) •Rostral (affective/emotional) Paul MacLean
The ‘triune brain’ model (1964) Neuo-anatomy of the emotional brain:
Bottom-up System (‘automatic’): Top-Down System (‘effortful’):
Two-Stage Model of Emotional Reaction (Koole 2009)
Reactive Limbic Effortful OFC ACC (DLPCF) IV. Stress Model: Peer Victimization and other abuse
Brain Structural Changes during Sensitive Periods when Exposed to Sexual Abuse (Andersen et al. 2008) Brain Structural Changes during Sensitive Periods when Exposed to Sexual Abuse (Andersen et al. 2008)
- Brain Structural Changes during Sensitive Periods when Exposed to Sexual Abuse (Andersen et al. 2008) Source: Professor Martin Teicher • Blue indicates positive correlation
• Red indicates negative correlation Peer Verbal Bullying correlates with psychiatric symptoms and brain changes (Teicher et al. 2010) 707 young adults with no history of exposure to childhood sexual abuse, physical abuse, witnessing domestic violence, peer physical bullying, harsh corporal punishment, or significant parental verbal abuse; and 63 for neuorimaging. ED as a mechanism linking stress and Internalising Symptoms: Final Mediation Model of ED and Latent Variables predicting Internalising Disorder (all paths shown p<0.05, except broken lines; n=1,065, age 11-14) ( McLuaghlin, Hatzenbuehler & Hilt (2009)
ED increased IS over a 7 month period
Bullying increased ED over a 4 month period Stereotype Content Model (SCM) (Amy Cuddy 2008) In-group skills (Social Identity Theory, Tajfel 1974)
• Prosocial
• Identify commonality
• Introduction and association by in-group members V. Attachment Model
Adult Attachment & Affect Regulation (Mikulincer & Shaver 2008)
• Threats activate proximity and support seeking – especial from a sympathetic figure
• Internal attachment figure – supportive, soothing and available - reduce perceived threat, over-whelm, increase a sense of agency and coping impact ‘Appraisal’ & ‘Response’.
• Internal speech – ‘super-ego’, ‘adult’ in TA, relational and reputational self-concept
• Bidirectional: Child is affected by, but also evokes environment. Parents shape the child; but also react to child and to internal attachment objects (trans-generational transmission). ADHD parents.
• Oxytocin in father affect babies’ oxytocin (Feldman)
Trier Social Stress Test
Neural Bases of Threat Processing (LeDoux, 1994)
Neural Bases of Threat Processing (LeDoux, 1994)
Fright Fight Flight Freeze
Over- riding circuit
What’s other major threat to human beings? Social threat
New-SCARF
SCARF (David Nock 2010) Status Certainty Autonomy Relatedness Fairness
New-SCARF (Wai Chen) Novelty Types of Affect Systems (Compassion Focused Therapy CFT (Paul Gilbert)) o. Incentive/resource Affiliative focused focused Seeking and Soothing/safeness behaviour activating Opiates (?) Dopamine (?)
Threat-focused safety seeking
Activating/inhibiting Serotonin (?) Self-Critics & Shame (‘Abuse by ‘self’)
• Shame (core self), self-criticisms, ruminations (past), worries (future), frustrations (thwarted drives) intensify THREAT system.
• CBT challenges content (could increase threat).
• Drip-drip undermining; high Expressed Emotions. Criticisms by parents more distressing.
• Highly critical internal dialogues.
• Inability to self soothe.
• Shame. VI. Depletion Model: Self-Regulatory Strength (SRS)
(Bauer & Baumeister 2011)
SRS is a limited resource: Self-control resemble a muscle (Mauraven & Baumeister 2000, Baumeister et al. 2006) • SRS is limited
• Various acts/tasks draw on the same and limited resource
• Repeated demands expend and deplete leading to self-control failure
• Impairment and breakdown of self-control following continuous challenges without recovery breaks
• ED is after-effects of stress, self-control, dieting, ignoring distractions, suppression, mood regulation, effort demands, continuous performance, mental tasks, resisting temptations Boosting of SRS (Bauer & Baumeister 2011)
• Glucose level dropped after self-control exercise and restoring blood glucose boost SRS, i.e. a glucose drink • Positive mood induction • Laughter/pleasure: watching a comedy • Self-affirmation: being in touch with core values • 3-10 minutes of relaxation • Mindfulness training • Regular physical exercise • Practising self-control (SRS training) consistently
VII. Dynamic Network Connectivity (DNC)
(Arnsten) Dynamic Network Connectivity The cellular architecture for executive function and working memory has been recently mapped
Working memory as ‘mental sketch pad’ differs from ‘short term and long term memory’
Arnsten’s model for these functions, called Dynamic Network Connectivity (DNC) Model
Unstressed: Top-down control (connectivity) of subcortical structures: • Basal Ganglia (habits); • Hypothalamus (drives – hunger, sex, aggression); • Amygdala (emo/fear)
Stressed: PFC ‘swtiched off’ connectivity lost ‘Going to Hell in a Handbasket’, ‘Meltdown’, ‘Lost it’. Tonic vs Phasic DA Firing Tonic vs Phasic DA
Tonic – good esp in PFC
Phasic – little is good in Nu Acc = motivated and rewarded
Phasic – excessive in sub-cortical regions leads to addiction/anxiety/noise
‘Dynamic Network Connectivity’ (DNC) model involving Hyperpolarization-activated cyclic nucleotide-gated (HCN channels) (Arnsten, Wang, Paspalas 2012; Wang et al. 2007) Prefrontal Network Dynamic Network Connectivity (Arnsten, Nat Rev NeuroSc 2009) Balance between D1 and alpha 2A stimulation: Signal to Noise (Arnsten & Rubia 2012; Arnsten 2009).
Optimal: Moderate DA engagement of D1 increases cAMP, open HCN K+ channels.
NE engagement of alpha 2A receptors inhibit cAMP close HCN K+ channels
Under stress, high levels of cAMP open HCN channels,
When the Ca2+ waves invade the soma, Ca2+-activated K+ channels (SK channels) and reduce cell firing.
Balance between D1 and alpha 2A stimulation: Signal to Noise (Arnsten & Rubia 2012; Arnsten 2009).
Optimal: Moderate DA engagement of D1 increases cAMP, open HCN K+ channels.
NE engagement of alpha 2A receptors inhibit cAMP close HCN K+ channels
Under stress, High levels of cAMP open HCN channels
When the Ca2+ waves invade the soma, Ca2+-activated K+ channels (SK channels) open and reduce cell firing.
Dynamic Network Connectivity (Arnsten, Nat Rev NeuroSc 2009)
Dynamic Network Connectivity
Exposure to even mild, uncontrollable stress causes a rapid loss of PFC function.
Feedforward Ca2+-PKC and cAMP-PKA signaling rapidly opens K+ channels to disconnect dlPFC networks and reduce neuronal firing, i.e. Going To Hell In A Handbasket.
What do these all mean?
Biological (CUSHION)
Environment (SCAFFOLD)
Self-control (EFFORT)
JOSHUA
• Adopted child – multiple high risk factors, low SES adopted parents
• Crisis after crisis – exclusion by school (age 9); teachers scooped him out under-table & attacked.
JOSHUA
• Adopted child – multiple high risk factors, low SES adopted parents
• Crisis after crisis – exclusion by school (age 9); teachers scooped him out under-table & attacked.
• Diagnoses: ADHD + ASD + EL + SLD
• CUSHION: Medical (MPH/DEX) (+SSRI) (+AAP); parents find-dose titration
• SCAFFOLD: NBPT to parents/teachers (labelling, no mirroring)
JOSHUA
• Adopted child – multiple high risk factors, low SES adopted parents
• Crisis after crisis – exclusion by school (age 9); teachers scooped him out under-table & attacked.
• Diagnoses: ADHD + ASD + EL + SLD
• CUSHION: Medical (MPH/DEX) (+SSRI) (+AAP); parents find-dose titration
• SCAFFOLD: NBPT to parents/teachers (labelling, no mirroring)
• EFFORT: Child self-aware/applies efforts change of internal speech: ‘there are always solutions to most problems’ (age 14)
JOSHUA
• Adopted child – multiple high risk factors, low SES adopted parents
• Crisis after crisis – exclusion by school (age 9); teachers scooped him out under-table & attacked.
• Diagnoses: ADHD + ASD + EL + SLD
• CUSHION: Medical (MPH/DEX) (+SSRI) (+AAP); parents find-dose titration
• SCAFFOLD: NBPT to parents/teachers (labelling, no mirroring)
• EFFORT: Child self-aware/applies efforts change of internal speech: ‘there are always solutions to most problems’ (age 14) • Offered university place (age 17)
Happiness is not a destination. It is a method of life.
Burton Hills END
Thank you for your attention • EL were associated with altered amygdala–cortical intrinsic functional connectivity (iFC).
EL scores: • greater positive iFC between the amygdala and rostral anterior cingulate cortex I • Negatively associated with iFC between bilateral amygdala and posterior insula/superior temporal gyrus.
Latent Class Analysis: ADHD and Emotion Lability in the IMAGE (International Multicentre ADHD Genetic) Study sample
LC Latent Class Subtype
None or few LC1 symptom
LC2 Mild Inattentive
LC3 Talkative/Impulsive
LC4 Moderate Combined
Mild LC5 Hyperactive/Im pulsive
LC6 Severe Combined
LC7 Severe Inattentive
Severe Hyperactive/ LC8 Impulsive Emotional Lability problem (as rated by parents) is strongly associated with any subtype of ADHD Latent Classes. EL is associated with LC7 (S Inatt) only in the presence of ASD symptoms. LC8 (S Ha-Imp) not driven by ASD LC4 is as impaired as CT, IA and H/I LC subtypes of ADHD, but is diagnostically ‘homeless’ – replicating previous publications by his group Take home messages:
1. Any form of ‘ADHD’ is associated with EL
2. ‘CT + EL’ & ‘Ha/Imp + EL’ driven by Imp.
3. ‘Inatt + EL’ indexes the presence of ASD
4. LC4 is a ‘lost tribe’ in DSM-IV and DSM-V (6 or 6= disorder; but 3+3=no disorder) Bifactor Model of ADHD
Three studies confirming the bifactor model (Toplak et al. 2009; Martel & Nigg 2010)
Replicated in IMAGE sample – invariant across age and national groupings (Toplak et al 2012) ADHD and AU spectrum Disorders (van de Meer 2013): ADHD+(AU) highest EL; AU+(ADHD) high EL and highest Perfectionism
______ADHD and AU spectrum Disorders (van de Meer 2013): ADHD+(AU) highest EL; AU+(ADHD) high EL and highest Perfectionism
______In deep sleep, unconscious = the absence of acetylcholine stimulation of nic-α7R which is permissive for NMDA actions.
When awake, cholinergic stimulation of nic-α7R allows networks to connect.
Moderate levels of NE (in response to interesting events) stimulates α2A-AR, which strengthens preferred connections and promotes PFC cognitive abilities.
DA released to salient events, which gates out nonpreferred network inputs through stimulation of D1R optimal for tasks requiring precise focus. In contrast, high levels of norepinephrine and dopamine release during stress suppress neuronal firing and impair prefrontal function through a α1R and D1R, respectively.
Dynamic Network Connectivity Emotional Dysregulation (Lemerise & Arsenio 2011):
• Emotionality - increased (drive/motivation/communicative)
• Emo Regulation – decreased (within and in-between)
• Social Information Processing (encode cues (internal/external) interpret cues goals (pro-social, instrumental, homeostatic) response construction response decision/evaluation/outcome /cost-gain=self-efficacy)
SCM Emotional Lability problem (as rated by parents) is strongly associated with any subtype of ADHD Latent Classes. ADHD+EL Probands do not index higher ADHD recurrence in siblings ADHD+EL Probands do not index higher ADHD recurrence in siblings Partial ‘Breeding True’ of EL in LC6 (after accounting for the main effect of LC6) in Familial Risk Analysis (n probands=997 and siblings=1112)
– partially consistent with ‘Deficient Emotional Self-Regulation (DESR) as familial subtype’ Surman, Biederman, Spencer, Yorks, Miller Petty, Faraone June 2011 Am J Psych (n=83 probands and 128 siblings) Autism Spectrum Disorder Symptoms (as rated by parents) is strongly associated with ADHD LC4, 5, 6, & 7 EL is associated with LC7 (S Inatt) only in the presence of ASD symptoms. LC8 (S Ha-Imp) not driven by ASD LC4 is as impaired as CT, IA and H/I LC subtypes of ADHD, but is diagnostically ‘homeless’ – replicating previous publications by his group LC4 is as impaired as CT, IA and H/I LC subtypes of ADHD, but is diagnostically ‘homeless’ – replicating previous publications by his group
Acknowledgement and Tribute to late Professor Richard Todd (1951- 2008), past member of DSM-V workgroup: Seminal works on LCA of ADHD and training/support during the IMAGE LCA work Bifactor Model of ADHD
Bifactor Model of ADHD
• Two studies confirming the bifactor model (Toplak et al. 2009; Martel & Nigg 2010)
• Replicated in IMAGE sample – invariant across age and national groupings (Toplak,.. Chen et al. in press)
• External validation of Specific Factors:
Specific inattention Factor: associated with depression/withdrawal, slower cognitive task performance, introversion, agreeableness, and high reactive control; specific hyperactivity- impulsivity Factors: associated with rule-breaking/aggressive behavior, social problems, errors during set-shifting, extraversion, isagreeableness, and low reactive control. Prefrontal Network Prefrontal Network Prefrontal Network Mode of Action of Guanfacine Stress and maternal separation Rats exposed to stress decreased dentritic spine density in anterior cingulate gyrus and orbitofrontal cortext.
Prenatal exposure to stress hormone (animal studies) • increased adult Cortcotrophin-Releasing Hormone (CRH) in central nucleus of amygdala, key region in regulating fear and anxiety • Learning impairments (hippocampal changes) • Enhanced sensitivity to drugs of abuse • Increased anxiety- and depression-related behaviours (CRH changes in amygdala
Natural experiments in children – exposure to maternal separation and nursury care, effects of age (toddlers vs preschool aged) and duration)
• Rise in glucocorticoid levels by late afternoon. • Less supportive care increased the rise and increases more emotionally negative and disorangized behaviours.
• In poor care – EARLY, LONGER – increased risk of behaviour problems in later development
• Parent-child interaction also modulate HPA axis