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)
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.
Why so many?
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
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)
Impaired maturation and/or function of the
prefrontal cortex
What is the neurobiological basis of ADHD?
Prefrontal Cortex Most highly evolved
brain region
Working Memory
(“Mental Sketch Pad”) Mental Representation
Foundation of abstract thought
The Prefrontal Cortex Regulates Attention, Behavior and Emotion
Arnsten (2010) Expert Rev Neurother 10: 1595-605; Arnsten et al Neuron 76:223-39
Ability to plan ahead and to have the
patience to wait for a larger reward
(impulse control)
Top-down control of attention, action
and emotion
Prefrontal Cortex
The Prefrontal Cortex Regulates Attention, Behavior and Emotion
Arnsten (2010) Expert Rev Neurother 10: 1595-605; Arnsten et al Neuron 76:223-39
Planning and organizing
High-order decision-making
Insight and judgment
Inhibition of inappropriate actions
Executive Functions:
Prefrontal Cortex
The Prefrontal Cortex Regulates Attention, Behavior and Emotion
Arnsten (2010) Expert Rev Neurother 10: 1595-605; Arnsten et al Neuron 76:223-39
Emotion
Action
Thought
Top-down regulation of:
Prefrontal Cortex
The Prefrontal Cortex Regulates Attention, Behavior and Emotion
Arnsten (2010) Expert Rev Neurother 10: 1595-605; Arnsten et al Neuron 76:223-39
Thought
sensory association
cortices
caudate
cerebellum via pons
sensory association
cortices, hippocampus
NE, DA, 5HT cell bodies
Top-down regulation of:
Prefrontal Cortex
Widespread Connections
Bottom-up attention: Stimulus salience (moving, bold, loud) e.g. video games
Top-down attention: Stimulus relevance e.g. studying for a test
Arnsten (2010) Expert Rev Neurother 10: 1595-605; Arnsten et al Neuron 76:223-39
Action
motor, premotor cortices
caudate, putamen,
subthalamic nuc.
cerebellum via pons
Top-down regulation of:
Prefrontal Cortex
Widespread Connections
Inhibition of inappropriate, impulsive actions
(especially right hemisphere)
Arnsten (2010) Expert Rev Neurother 10: 1595-605; Arnsten et al Neuron 76:223-39
Emotion
Action
hypothalamus
nuc. accumbens
Brainstem eg PAG
amygdala
NE, DA, 5HT cell bodies
Top-down regulation of:
Prefrontal Cortex
Widespread Connections
Inhibition of inappropriate emotions, e.g. aggression
Arnsten (2010) Expert Rev Neurother 10: 1595-605; Arnsten et al Neuron 76:223-39
In humans, the right hemisphere is specialized for inhibition, while the left hemisphere is the
“generative “ hemisphere
Left Generative Lesions: reduced initiative, depression
Right Inhibitory Lesions: impulsive, mania sociopathy
Lateralization
Action
The right, inferior PFC is especially important for inhibiting
inappropriate actions
Aron (2011) Biol Psych 69: e55-68
Normal Development: The Right inferior PFC grows larger between ages 4-20
The Prefrontal Cortex Develops Slowly Maturing Fully in the 20’s
Action
Right PFC bigger
Left PFC bigger
Shaw et al. (2009) Arch Gen Psych
Shaw et al. (2009) Arch Gen Psych
ADHD: Laterality unchanged (Right hemisphere does not enlarge)
Altered Maturation of PFC in ADHD
Action
Left PFC bigger
Left PFC bigger
Reduced Structure and Function of PFC in ADHD
(similar results with impaired attention)
Reduced PFC connectivity
Reduced PFC volume Makris et al, (2007)
Mostofsky et al, (2002)
Rubia et al, (2009) Am J Psychiatry 166:83-94
Reduced Right inferior dlPFC functional activity
Rubia et al, (2009) Am J Psychiatry 166:83-94
Disorder Specific Changes
(similar results with impaired attention)
Reduced Right inferior dlPFC functional activity
Reduced Right Orbital PFC functional activity in Conduct Disorder
Impaired regulation of emotion
Lead Poisoning Mimics ADHD
Lead poisoning is associated with reduced PFC gray matter, perhaps due to mimicking calcium and increasing intracellular stress signaling pathways in PFC neurons
Cecil et al, PLOS 2008
Mania Mimics ADHD
The right PFC is underactive during mania
Blumberg et al., (1999) Arch Gen Psych 156:1986-8.
Regulation of action
Regulation of emotion
Meta-cognition Insight
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 Cortex
Prefrontal Neuronal Network Connections
Prefrontal Cortical Networks
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 Cortex
Prefrontal Cortical Glutamate Synapses
glutamate
NMDA receptors dendrite
spine axon
Prefrontal Neuronal Network Connections
Ca2+
Prefrontal cortical pyramidal cell networks connect via glutamate NMDA receptor
synapses on spines
Wang et al (2013) Neuron 77:736-49
Prefrontal Cortex
Prefrontal Cortical Glutamate Synapses
dendrite
spine axon
Prefrontal Neuronal Network Connections
Ca2+
SIGNALS
“NOISE”
SIGNALS “NOISE”
Top-down control requires strong connections with neurons bringing in relevant information (“signals”), and weaker connections to those
with irrelevant information (“noise”) High network firing Low network firing
Arnsten et al (2012) Neuron 76:223-39
Prefrontal Cortex
Prefrontal Cortical Glutamate Synapses
dendrite
spine axon
Prefrontal Neuronal Network Connections Are Altered by the Arousal Systems
Our state of arousal markedly alters PFC connections and function
Alert
Fatigue Stress
Strong PFC function
Weak PFC function
Ca2+
Like Goldilocks, PFC has to have everything “just right”
SIGNALS
“NOISE”
Arnsten et al (2012) Neuron 76:223-39
Prefrontal Cortex K+
AC cAMP
Prefrontal Neuronal Network Connections Are Altered by the Arousal Systems
Fatigue
Ca2+-cAMP signaling weakens connectivity by opening K+ channels
K+
AC cAMP Ca2+
(saves energy, as recurrent excitation is energy intensive)
SIGNALS
“NOISE”
Arnsten et al (2012) Neuron 76:223-39
Prefrontal Cortex
norepinephrine
K+
α2A-AR
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
Ca2+-cAMP-K+ Signaling Weakens Connectivity
Prefrontal Neuronal Network Connections Are Altered by the Arousal Systems
Alert
AC cAMP Ca2+ K+
AC cAMP
SIGNALS
“NOISE”
Arnsten et al (2012) Neuron 76:223-39
Prefrontal Cortex
norepinephrine
K+
K+
AC cAMP
dopamine
α2A-AR
D1R
Ca2+-cAMP-K+ Signaling Weakens Connectivity
Prefrontal Neuronal Network Connections Are Altered by the Arousal Systems
Alert
AC cAMP Ca2+
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
SIGNALS
“NOISE”
Arnsten et al (2012) Neuron 76:223-39
signal
Prefrontal Cortex
Amygdala
Prefrontal Cortical Glutamate Synapses
norepinephrine
K+
K+
AC cAMP
noise α2A-AR
D1R
dopamine
Optimal Prefrontal Cortical Regulation of Attention, Behavior and Emotion
Striatum
Sensory Cortex
Alert
AC cAMP Ca2+
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
signal
Prefrontal Cortical Synapses Disconnect
K+
K+
AC cAMP
noise
Prefrontal Cortex
D1R β1-AR
D1R
α2A-AR
Uncontrollable Stress Takes PFC “Off-Line” and Switches Control to More Primitive Systems
dopamine
norepinephrine
AC cAMP Ca2+
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
signal
Prefrontal Cortical Synapses Disconnect
K+
K+
AC cAMP
noise
Amygdala
Prefrontal Cortex
D1R β1-AR
D1R
α2A-AR
Uncontrollable Stress Takes PFC “Off-Line” and Switches Control to More Primitive Systems
dopamine
norepinephrine Striatum
Sensory Cortex
AC cAMP Ca2+
High levels of catecholamines strengthen the activity of more primitive circuits
Stress Arnsten et al (2012) Neuron 76:223-39
signal
Prefrontal Cortical Synapses Disconnect
K+
K+
AC cAMP
noise
Amygdala
Prefrontal Cortex
D1R β1-AR
D1R
α2A-AR
Uncontrollable Stress Takes PFC “Off-Line” and Switches Control to More Primitive Systems
dopamine
Why stress can mimic ADHD
norepinephrine Striatum
Sensory Cortex
AC cAMP Ca2+
Stress Arnsten et al (2012) Neuron 76:223-39
NE
DA
TOO LITTLE
TOO LITTLE TOO MUCH (D1)
TOO MUCH (α1)
OPTIMAL (α2A)
OPTIMAL (D1) Dopamine
Norepinephrine
signal noise
signal noise
Arnsten (2011) Biol Psychiatry 69: 89-99
signal
Prefrontal Cortical Synapses Disconnect
K+
K+
AC cAMP
noise
Amygdala
Prefrontal Cortex
D1R β1-AR
D1R
α2A-AR
Chronic Stress: Architectural Changes
dopamine
norepinephrine Striatum
Sensory Cortex
AC cAMP Ca2+
Stress Chronic
signal
Prefrontal Cortical Synapses Atrophy
K+
K+
AC cAMP
noise
Amygdala
Prefrontal Cortex
D1R β1-AR
D1R
α2A-AR
Chronic stress leads to loss of PFC spines and function (reversible)
Striatum
Sensory Cortex
AC cAMP Ca2+
Control Chronic Stress
e.g. Radley et al (2006) Cereb Cortex 16:313-20; Hains et al (2009) PNAS 106:17957-62
Stress Chronic
Chronic Stress: Architectural Changes
Activated by lead poisoning
Prefrontal Cortical Synapses Disconnect
K+
Prefrontal Cortex
Lead Exacerbates Stress Signaling Pathways in PFC
AC cAMP PKC
Ca2+
Arnsten and Manji (2008) Future Neurology 3:125-31
Activated by lead poisoning
Prefrontal Cortical Synapses Disconnect
K+
Prefrontal Cortex
Lead Exacerbates Stress Signaling Pathways in PFC
AC cAMP PKC
Ca2+
May help to explain loss of PFC gray matter seen with lead poisoning
Arnsten and Manji (2008) Future Neurology 3:125-31
Altered in bipolar disorder
Prefrontal Cortical Synapses Disconnect
K+
Prefrontal Cortex
Bipolar Disorder Linked to Genetic Alterations that Exacerbate Stress Signaling Pathways in PFC
AC cAMP PKC
Ca2+
Arnsten and Manji (2008) Future Neurology 3:125-31
Prefrontal Cortical Synapses Disconnect
Prefrontal Cortex
Right PFC underactive during mania
Bipolar Disorder Linked to Genetic Alterations that Exacerbate Stress Signaling Pathways in PFC
Why bipolar disorder can mimic ADHD
Blumberg et al., (1999) Arch Gen Psych156:1986-8.
Regulation of action
Regulation of emotion
Meta-cognition Insight
Prefrontal Cortex
Relevance to ADHD Genetics and Medications
Prefrontal Cortex AC
K+
cAMP K+
AC cAMP
Prefrontal Cortex
Prefrontal Cortex
signal
Prefrontal Cortical Glutamate Synapses
norepinephrine
AC
K+
cAMP K+
AC cAMP
noise α2A-AR
D1R
dopamine NET DAT
Relevance to ADHD Genetics
Genes related to: • norepinephrine: DBH, ADRA2A, NET • 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
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
Nic-α4β2
A variety of genetic alterations can disrupt the precise modulation of PFC circuits needed for PFC function
Prefrontal Cortex
Prefrontal Cortex
signal
Prefrontal Cortical Glutamate Synapses
norepinephrine
AC
K+
cAMP K+
AC cAMP
noise α2A-AR
D1R
dopamine NET DAT
Transporters take up norepinephrine and dopamine
Relevance to ADHD Medications
Prefrontal Cortex
Stimulants block NE and DA transporters and increase catecholamines in PFC
Prefrontal Cortex
signal
Prefrontal Cortical Glutamate Synapses
norepinephrine
AC
K+
cAMP K+
AC cAMP
noise α2A-AR
D1R
dopamine NET DAT
Stimulants (methylphenidate, amphetamines)
signal
Prefrontal Cortex
Prefrontal Cortical Glutamate Synapses
norepinephrine
AC
K+
cAMP K+
AC cAMP
noise α2A-AR
D1R
dopamine NET DAT
Berridge et al, (2006) Biological Psychiatry 60: 1111-20.
Clinically-relevant (i.e. low) doses of methylphenidate preferentially
increase catecholamines in PFC
Stimulants (methylphenidate, amphetamines)
signal
Prefrontal Cortical Synapses Disconnect
AC
K+
cAMP
EXCESSIVE DOSE OF STIMULANT
K+
AC cAMP
noise
Prefrontal Cortex
D1R β1-AR
D1R
α2A-AR
• Excessive levels of catecholamines in PFC weakens PFC function
• Increased catecholamines in primitive circuits, e.g. striatum, strengthens habitual responding
dopamine
norepinephrine
Why excessive doses of stimulant can impede cognitive flexibility
NET DAT
Amygdala
Striatum
Sensory Cortex
Berridge and Devilbiss (2011) Biological Psychiatry 69:e101-11; Gamo et al. (2010) J Amer Acad Child Adol Psych 49:1011-23
Stimulants (methylphenidate, amphetamines)
signal
Prefrontal Cortex
Prefrontal Cortical Glutamate Synapses
norepinephrine
AC
K+
cAMP K+
AC cAMP
noise α2A-AR
D1R
dopamine
Atomoxetine
NET DAT
Atomoxetine selectively blocks norepinephrine transporters (NETs)
The NET takes up both NE and DA in PFC
Bymaster et al.(2002) Neuropsychopharm 27: 699-711
signal
Prefrontal Cortex
Prefrontal Cortical Glutamate Synapses
norepinephrine
AC
K+
cAMP K+
AC cAMP
noise α2A-AR
D1R
dopamine NET DAT
An optimal dose of atomoxetine is needed to enhance PFC physiology
Gamo et al. (2010) J Amer Acad Child Adol Psych 49:1011-23
NO DRUG TOO MUCH
OPTIMAL
signal noise
Atomoxetine
signal
Prefrontal Cortex
Prefrontal Cortical Glutamate Synapses
Guanfacine (Intuniv) Clonidine (Kapvay)
AC cAMP
α2A-AR
Guanfacine and Clonidine
α2A blockade
guanfacine α2A stimulation
signal noise
Guanfacine enhances PFC physiology
Wang et al (2007) Cell 129:397-410
Prefrontal Cortex
PFC functions improved by guanfacine in monkeys:
Guanfacine Strengthens PFC Function
• Improved working memory
• 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
Prefrontal Cortex
Guanfacine: Clinical Use
PFC disorders improved by guanfacine in patients:
• 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: 755-
68; 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:
• MERIT Award AG06036 • Conte Center P50MH068789 • Yale Stress Consortium: AA017536-U54RR024350 • Program Project AG030004
Prefrontal Cortex
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?