The Neurobiology of ADHD and Related Disorders
Amy F.T. Arnsten, Ph.D. Professor of Neurobiology Yale University School of Medicine
[email protected] Disclosure: AFTA and Yale University receive royalties from Shire Pharmaceuticals from the sale of IntunivTM (extended release guanfacine) for the treatment of ADHD and related disorders.
Attention Deficit Hyperactivity Disorder• Impaired regulation of attention, hyperactivity, impulsivity; often continues into adulthood • ~7.2% of school-aged children in the U.S. (4.1 million children) had a current ADHD diagnosis in 2007 (http://www.cdc.gov)
Attention Deficit Hyperactivity Disorder• Impaired regulation of attention, hyperactivity, impulsivity; often continues into adulthood • ~7.2% of school-aged children in the U.S. (4.1 million children) had a current ADHD diagnosis in 2007 (http://www.cdc.gov)
Why so many? Better awareness and diagnosis, but also: • Increasing demands for “top-down” self-control and organization needed to succeed in the Information Age. • Many schools are unable to give children extra help or resources without an official diagnosis.
Attention Deficit Hyperactivity Disorder• Impaired regulation of attention, hyperactivity, impulsivity; often continues into adulthood • ~7.2% of school-aged children in the U.S. (4.1 million children) had a current ADHD diagnosis in 2007 (http://www.cdc.gov) Common co-morbid diagnoses: Oppositional Defiant Disorder or Conduct Disorder (inappropriate aggression) Tourette’s Syndrome (tics)
Attention Deficit Hyperactivity Disorder• Impaired regulation of attention, hyperactivity, impulsivity; often continues into adulthood • ~7.2% of school-aged children in the U.S. (4.1 million children) had a current ADHD diagnosis in 2007 (http://www.cdc.gov) Common co-morbid diagnoses: Oppositional Defiant Disorder or Conduct Disorder (inappropriate aggression) Tourette’s Syndrome (tics) Disorders with symptoms that can look like ADHD: Stress or Post-traumatic stress disorder- e.g. from a family going through a divorce, or more gravely, from child abuse or witnessing traumatic events Bipolar disorder (mania) Lead poisoning
Attention Deficit Hyperactivity Disorder• Impaired regulation of attention, hyperactivity, impulsivity; often continues into adulthood • ~7.2% of school-aged children in the U.S. (4.1 million children) had a current ADHD diagnosis in 2007 (http://www.cdc.gov) Common co-morbid diagnoses: Oppositional Defiant Disorder or Conduct Disorder (inappropriate aggression) Tourette’s Syndrome (tics) Disorders with symptoms that can look like ADHD: Stress or Post-traumatic stress disorder- e.g. from a family going through a divorce, or more gravely, from child abuse or witnessing traumatic events Bipolar disorder (mania) Lead poisoning ADHD is a biological disorder: It is highly heritable, similar to eye color- (e.g. alterations in genes related to brain development and neuromodulation) The brains of patients with ADHD show replicable differences Gizer et al (2009) Human Genet 126:51-90; Caylak (2012) Am J Med Genet Part B 159B: 613-27
What is the neurobiological basis of ADHD?
Impaired maturation and/or function of the prefrontal cortex
The Prefrontal Cortex Regulates Attention, Behavior and Emotion
Prefrontal Cortex Most highly evolved brain region Mental Representation (“Mental Sketch Pad”) Foundation of abstract thought Working Memory
Arnsten (2010) Expert Rev Neurother 10: 1595-605; Arnsten et al Neuron 76:223-39
The Prefrontal Cortex Regulates Attention, Behavior and Emotion
Prefrontal Cortex Top-down control of attention, action and emotion Ability to plan ahead and to have the patience to wait for a larger reward (impulse control)
Arnsten (2010) Expert Rev Neurother 10: 1595-605; Arnsten et al Neuron 76:223-39
The Prefrontal Cortex Regulates Attention, Behavior and Emotion
Prefrontal Cortex Executive Functions: Planning and organizing High-order decision-making Insight and judgment Inhibition of inappropriate actions
Arnsten (2010) Expert Rev Neurother 10: 1595-605; Arnsten et al Neuron 76:223-39
The Prefrontal Cortex Regulates Attention, Behavior and Emotion
Prefrontal Cortex Top-down regulation of:
Thought Action Emotion
Arnsten (2010) Expert Rev Neurother 10: 1595-605; Arnsten et al Neuron 76:223-39
Widespread Connections
Prefrontal Cortex Top-down regulation of:
sensory association cortices caudate
Bottom-up attention: Stimulus salience (moving, bold, loud) e.g. video games
sensory association cortices, hippocampus
cerebellum via pons
NE, DA, 5HT cell bodies
Arnsten (2010) Expert Rev Neurother 10: 1595-605; Arnsten et al Neuron 76:223-39
Thought Top-down attention: Stimulus relevance e.g. studying for a test
Widespread Connections
motor, premotor cortices
Prefrontal Cortex Top-down regulation of:
caudate, putamen, subthalamic nuc.
Action Inhibition of inappropriate, impulsive actions (especially right hemisphere)
cerebellum via pons
Arnsten (2010) Expert Rev Neurother 10: 1595-605; Arnsten et al Neuron 76:223-39
Widespread Connections
Prefrontal Cortex Top-down regulation of:
nuc. accumbens
Inhibition of inappropriate emotions, e.g. aggression
Action
Emotion
hypothalamus amygdala
Brainstem eg PAG NE, DA, 5HT cell bodies Arnsten (2010) Expert Rev Neurother 10: 1595-605; Arnsten et al Neuron 76:223-39
Lateralization
Left Generative Lesions: reduced initiative, depression
Right
Action
Inhibitory Lesions: impulsive, mania sociopathy
The right, inferior PFC is especially important for inhibiting inappropriate actions
In humans, the right hemisphere is specialized for inhibition, while the left hemisphere is the “generative “ hemisphere
Aron (2011) Biol Psych 69: e55-68
The Prefrontal Cortex Develops Slowly Maturing Fully in the 20’s Left PFC bigger
Normal Development: The Right inferior PFC grows larger between ages 4-20
Action
Right PFC bigger Shaw et al. (2009) Arch Gen Psych
Altered Maturation of PFC in ADHD
Left PFC bigger
ADHD: Laterality unchanged (Right hemisphere does not enlarge)
Action
Left PFC bigger
Shaw et al. (2009) Arch Gen Psych
Reduced Structure and Function of PFC in ADHD Reduced Right inferior dlPFC functional activity
(similar results with impaired attention) Rubia et al, (2009) Am J Psychiatry 166:83-94
Reduced PFC connectivity
Mostofsky et al, (2002)
Reduced PFC volume Makris et al, (2007)
Disorder Specific Changes Reduced Right inferior dlPFC functional activity
(similar results with impaired attention) Rubia et al, (2009) Am J Psychiatry 166:83-94
Reduced Right Orbital PFC functional activity in Conduct Disorder
Impaired regulation of emotion
Lead Poisoning Mimics ADHD
Cecil et al, PLOS 2008
Lead poisoning is associated with reduced PFC gray matter, perhaps due to mimicking calcium and increasing intracellular stress signaling pathways in PFC neurons
Mania Mimics ADHD
Regulation of action Meta-cognition Insight
Regulation of emotion
The right PFC is underactive during mania
Blumberg et al., (1999) Arch Gen Psych 156:1986-8.
Prefrontal Cortex
Understanding the neurobiology of the prefrontal cortex provides clues to what may cause these disorders, as well as how to rationally treat symptoms of prefrontal cortical dysfunction
Prefrontal Neuronal Network Connections
Prefrontal Cortical Networks
Prefrontal Cortex
Top-down goals are represented by recurrent excitation in pyramidal cell networks in prefrontal cortex: The pioneering work of Patricia Goldman-Rakic
Goldman-Rakic (1995) Neuron 14:477-85
Prefrontal Neuronal Network Connections
Prefrontal Cortical Glutamate Synapses
glutamate
Prefrontal Cortex
axon
Ca2+
spine dendrite
NMDA receptors
Prefrontal cortical pyramidal cell networks connect via glutamate NMDA receptor synapses on spines
Wang et al (2013) Neuron 77:736-49
Prefrontal Neuronal Network Connections
Prefrontal Cortical Glutamate Synapses
SIGNALS
Prefrontal Cortex
axon
Ca2+
spine
“NOISE” dendrite
Top-down control requires strong connections with neurons bringing in relevant information (“signals”), and weaker connections to those with irrelevant information (“noise”)
Arnsten et al (2012) Neuron 76:223-39
SIGNALS
“NOISE”
High network firing
Low network firing
Prefrontal Neuronal Network Connections Are Altered by the Arousal Systems
Prefrontal Cortical Glutamate Synapses
SIGNALS
Prefrontal Cortex
axon
Ca2+
spine
“NOISE” dendrite
Our state of arousal markedly alters PFC connections and function Strong PFC function
Alert
Like Goldilocks, PFC has to have everything “just right”
Arnsten et al (2012) Neuron 76:223-39
Weak PFC function
Fatigue
Stress
Prefrontal Neuronal Network Connections Are Altered by the Arousal Systems
K+
SIGNALS
Prefrontal Cortex
Ca2+
AC
cAMP
K+
“NOISE”
cAMP
Ca2+-cAMP signaling weakens connectivity by opening K+ channels (saves energy, as recurrent excitation is energy intensive)
Fatigue Arnsten et al (2012) Neuron 76:223-39
AC
Prefrontal Neuronal Network Connections Are Altered by the Arousal Systems
Ca2+-cAMP-K+ Signaling Weakens Connectivity
K+
SIGNALS
Prefrontal Cortex
Ca2+
AC
cAMP
K+
“NOISE” α2A-AR cAMP
norepinephrine
Moderate levels of norepinephrine (NE) release engage high affinity α2A-AR NE α2A-ARs inhibit Ca2+-cAMP-K+ signaling and strengthens signals DA D1R increases Ca2+-cAMP-K+ signaling and decreases noise
Arnsten et al (2012) Neuron 76:223-39
Alert
AC
Prefrontal Neuronal Network Connections Are Altered by the Arousal Systems
Ca2+-cAMP-K+ Signaling Weakens Connectivity
K+
SIGNALS
Prefrontal Cortex
Ca2+
AC
cAMP
K+
“NOISE” α2A-AR cAMP
norepinephrine
AC
D1R dopamine
Moderate levels of norepinephrine (NE) release engage high affinity α2A-AR NE α2A-ARs inhibit Ca2+-cAMP-K+ signaling and strengthens signals DA D1R increases Ca2+-cAMP-K+ signaling and decreases noise
Arnsten et al (2012) Neuron 76:223-39
Alert
Optimal Prefrontal Cortical Regulation of Attention, Behavior and Emotion
Prefrontal Cortical Glutamate Synapses
K+
signal
Prefrontal Cortex
Sensory Cortex
Ca2+
AC
cAMP
K+ noise
α2A-AR
Striatum
cAMP
norepinephrine
AC
D1R dopamine
Amygdala
Moderate levels of norepinephrine (NE) release engage high affinity α2A-AR NE α2A-ARs inhibit Ca2+-cAMP-K+ signaling and strengthens signals DA D1R increases Ca2+-cAMP-K+ signaling and decreases noise
Arnsten et al (2012) Neuron 76:223-39
Alert
Uncontrollable Stress Takes PFC “Off-Line” and Switches Control to More Primitive Systems
Prefrontal Cortical Synapses Disconnect K+ signal
Prefrontal Cortex
Ca2+
AC
α2A-AR
cAMP
K+ noise
D1R β1-AR cAMP
norepinephrine
AC
D1R
dopamine
High levels of NE release engage lower affinity α1-AR and β1-AR which increase Ca2+-cAMP-K+ signaling and reduce firing High levels of DA D1R also increase Ca2+-cAMP-K+ signaling and decrease all network firing
Stress Arnsten et al (2012) Neuron 76:223-39
Uncontrollable Stress Takes PFC “Off-Line” and Switches Control to More Primitive Systems
Prefrontal Cortical Synapses Disconnect K+ signal
Prefrontal Cortex
Sensory Cortex
Ca2+
α2A-AR
Striatum
AC
cAMP
K+ noise
D1R β1-AR cAMP
norepinephrine Amygdala
AC
D1R
dopamine
High levels of catecholamines strengthen the activity of more primitive circuits
Stress Arnsten et al (2012) Neuron 76:223-39
Uncontrollable Stress Takes PFC “Off-Line” and Switches Control to More Primitive Systems
Prefrontal Cortical Synapses Disconnect K+ signal
Prefrontal Cortex
Sensory Cortex
Ca2+
α2A-AR
Striatum
AC
cAMP
K+ noise
D1R β1-AR cAMP
norepinephrine Amygdala
AC
D1R
dopamine
Why stress can mimic ADHD
Stress Arnsten et al (2012) Neuron 76:223-39
Norepinephrine
OPTIMAL (α2A)
TOO MUCH (α1)
TOO LITTLE
signal
noise NE
Dopamine
OPTIMAL (D1)
TOO MUCH (D1)
TOO LITTLE
signal
noise DA
Arnsten (2011) Biol Psychiatry 69: 89-99
Chronic Stress: Architectural Changes
Prefrontal Cortical Synapses Disconnect K+ signal
Prefrontal Cortex
Sensory Cortex
Ca2+
α2A-AR
Striatum
AC
cAMP
K+ noise
D1R β1-AR cAMP
norepinephrine Amygdala
AC
D1R
dopamine
Chronic Stress
Chronic Stress: Architectural Changes
Prefrontal Cortical Synapses Atrophy K+ signal
Prefrontal Cortex
Sensory Cortex
Ca2+
α2A-AR
Striatum
AC
cAMP
K+ noise
D1R β1-AR cAMP
AC
D1R
Amygdala
Control
Chronic Stress
Chronic stress leads to loss of PFC spines and function (reversible)
e.g. Radley et al (2006) Cereb Cortex 16:313-20; Hains et al (2009) PNAS 106:17957-62
Chronic Stress
Lead Exacerbates Stress Signaling Pathways in PFC
Prefrontal Cortical Synapses Disconnect
Activated by lead poisoning Prefrontal Cortex
Arnsten and Manji (2008) Future Neurology 3:125-31
Ca2+
PKC AC
K+
cAMP
Lead Exacerbates Stress Signaling Pathways in PFC
Prefrontal Cortical Synapses Disconnect
Activated by lead poisoning Prefrontal Cortex
Ca2+
PKC AC
May help to explain loss of PFC gray matter seen with lead poisoning
Arnsten and Manji (2008) Future Neurology 3:125-31
K+
cAMP
Bipolar Disorder Linked to Genetic Alterations that Exacerbate Stress Signaling Pathways in PFC
Prefrontal Cortical Synapses Disconnect
Altered in bipolar disorder Prefrontal Cortex
Arnsten and Manji (2008) Future Neurology 3:125-31
Ca2+
PKC AC
K+
cAMP
Bipolar Disorder Linked to Genetic Alterations that Exacerbate Stress Signaling Pathways in PFC
Prefrontal Cortical Right PFC underactive during mania Synapses Disconnect
Prefrontal Cortex Regulation of action Meta-cognition Insight Regulation of emotion
Why bipolar disorder can mimic ADHD
Blumberg et al., (1999) Arch Gen Psych156:1986-8.
Relevance to ADHD Genetics and Medications
K+
Prefrontal Cortex
AC
cAMP
K+
cAMP
AC
Relevance to ADHD Genetics
Prefrontal Cortical Glutamate Synapses K+
signal
Genes related to: Prefrontal • norepinephrine: DBH, ADRA2A, NET Cortex • Dopamine: DAT1, DRD5 • Both catecholamines: DRD4, COMT, MAOA • cholinergic: CHRNA4 • serotonergic: 5-HTT, HTR1B, HTR2A • Synaptic transmission (vesicle release): SNAP25 • CNS development and plasticity: BDNF
AC
cAMP
K+ noise
α2A-AR cAMP
norepinephrine Nic-α4β2 NET
D1R DAT
dopamine
A variety of genetic alterations can disrupt the precise modulation of PFC circuits needed for PFC function
Kim et al (2008) Ann N Y Acad Sci. 1129:256-60; Gizer et al (2009) Human Genet 126:51-90; Caylak (2012) Am J Med Genet Part B 159B: 613-27
AC
Relevance to ADHD Medications
Prefrontal Cortical Glutamate Synapses K+
signal
Prefrontal Cortex
AC
cAMP
K+ noise
α2A-AR cAMP
norepinephrine
AC
D1R NET
DAT
dopamine
Transporters take up norepinephrine and dopamine
Stimulants (methylphenidate, amphetamines)
Prefrontal Cortical Glutamate Synapses K+
signal
Prefrontal Cortex
AC
cAMP
K+ noise
α2A-AR cAMP
norepinephrine
AC
D1R NET
DAT
dopamine
Stimulants block NE and DA transporters and increase catecholamines in PFC
Stimulants (methylphenidate, amphetamines)
Prefrontal Cortical Glutamate Synapses
K+
signal
Prefrontal Cortex
AC
cAMP
K+ noise
α2A-AR
norepinephrine
cAMP
AC
D1R NET
Clinically-relevant (i.e. low) doses of methylphenidate preferentially increase catecholamines in PFC
Berridge et al, (2006) Biological Psychiatry 60: 1111-20.
dopamine
DAT
Stimulants (methylphenidate, amphetamines)
Prefrontal Cortical Synapses Disconnect K+ signal
Prefrontal Cortex
Sensory Cortex
α2A-AR
Striatum
cAMP
AC
K+ noise
D1R β1-AR cAMP
norepinephrine NET
Amygdala
AC
D1R DAT
dopamine
EXCESSIVE DOSE OF STIMULANT Why excessive doses of stimulant can impede cognitive flexibility
• Excessive levels of catecholamines in PFC weakens PFC function • Increased catecholamines in primitive circuits, e.g. striatum, strengthens habitual responding
Berridge and Devilbiss (2011) Biological Psychiatry 69:e101-11; Gamo et al. (2010) J Amer Acad Child Adol Psych 49:1011-23
Atomoxetine
Prefrontal Cortical Glutamate Synapses
K+
signal
Prefrontal Cortex
AC
cAMP
K+ noise
α2A-AR
norepinephrine
cAMP
AC
D1R NET
Atomoxetine selectively blocks norepinephrine transporters (NETs) The NET takes up both NE and DA in PFC
Bymaster et al.(2002) Neuropsychopharm 27: 699-711
dopamine
DAT
Atomoxetine
Prefrontal Cortical Glutamate Synapses
K+
signal
Prefrontal Cortex
AC
cAMP
K+ noise
α2A-AR
norepinephrine
cAMP
AC
D1R NET
dopamine
OPTIMAL An optimal dose of atomoxetine is needed to enhance PFC physiology
TOO MUCH
NO DRUG
Gamo et al. (2010) J Amer Acad Child Adol Psych 49:1011-23
signal
noise
DAT
Guanfacine and Clonidine
Prefrontal Cortical Glutamate Synapses
signal
Prefrontal Cortex
AC
cAMP
α2A-AR
Guanfacine (Intuniv) Clonidine (Kapvay)
guanfacine α2A stimulation Guanfacine enhances PFC physiology α2A blockade
Wang et al (2007) Cell 129:397-410
signal
noise
Guanfacine Strengthens PFC Function
PFC functions improved by guanfacine in monkeys: • Improved working memory Prefrontal Cortex
• Reduced distractibility • Improved Impulse control (ability to wait for a larger reward) • Improved regulation of emotional response (reversal of emotional habit)
Arnsten et al (1988) J. Neurosci 8:4287-98; Arnsten and Contant (1992) Psychopharm 108:159-69; Rama et al (1996) PBB 54:1-7; Steere et al (1997) Behav Neurosci 111:1-9; O’Neill et al (2000) Life Sci 67:877-85; Arnsten (2010) Expert Rev Neurother 10: 1595-605; Kim et al (2012) Psychopharm 219:363-75
Guanfacine: Clinical Use
PFC disorders improved by guanfacine in patients:
Prefrontal Cortex
• ADHD • Tourette’s (tics) • ODD (inappropriate aggression) • PTSD/emotional trauma in children • Behavioral disinhibition in autism • Mild traumatic brain injury • Stroke/encephalitis in association cortex • Substance abuse • Emergence delirium
e.g. Biederman et al (2008) Pediatrics 121:e73-84; Sallee et al (2009) J Am Acad Child Adol Psych 48:155-65; Scahill et al (2001) Amer J Psychiatry 158:1067-74; Scahill et al (2006) J Child Adoles Psychopharm 16:589-98;Connor et al (2010) CNS Drugs 24: 75568; McAllister et al (2011) Int J Psychophysio 82: 107-14; Singh-Curry et al (2011) J Neurol Neurosurg Psychiatry 82: 688-90; Fox et al (2012) J Psychopharm 26: 958-72; Connor et al (2013) J Child Adoles Psychopharm , in press.
Prefrontal Cortex
Understanding the neurobiology of the prefrontal cortex has helped guide new treatments for cognitive disorders
Funding Support: • • • •
Prefrontal Cortex
MERIT Award AG06036 Conte Center P50MH068789 Yale Stress Consortium: AA017536-U54RR024350 Program Project AG030004
If you are interested, recent reviews: Overall review on prefrontal cortex: Arnsten et al, Neuron 76: 223-39, 2012 Stress effects on prefrontal cortex: Arnsten Nat. Rev. Neurosci 10: 410-22, 2009 Arnsten et al, Scientific American, April 2012 ADHD and its treatment: Arnsten (2010) Expert Rev Neurother 10: 1595-605 Arnsten (2011) Biol Psychiatry 69: 89-99
QUESTIONS?
