The Neurobiology of ADHD and Related Disorders webinars/The Neurobiology of ADHD and … · Reduced...

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)

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?




http://www.cdc.gov

Common co-morbid diagnoses: Oppositional Defiant Disorder or Conduct Disorder (inappropriate aggression) Tourette’s Syndrome (tics)




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




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




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



Planning and organizing

High-order decision-making

Insight and judgment

Inhibition of inappropriate actions

Executive Functions:

Prefrontal Cortex



Emotion

Action

Thought

Top-down regulation of:

Prefrontal Cortex



Thought

sensory association

cortices

caudate

cerebellum via pons

sensory association

cortices, hippocampus

NE, DA, 5HT cell bodies


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


Action

motor, premotor cortices

caudate, putamen,

subthalamic nuc.

cerebellum via pons


Prefrontal Cortex


Inhibition of inappropriate, impulsive actions

(especially right hemisphere)


Emotion

Action

hypothalamus

nuc. accumbens

Brainstem eg PAG

amygdala

NE, DA, 5HT cell bodies


Prefrontal Cortex


Inhibition of inappropriate emotions, e.g. aggression


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


Ca2+

Prefrontal cortical pyramidal cell networks connect via glutamate NMDA receptor

synapses on spines

Wang et al (2013) Neuron 77:736-49

Prefrontal Cortex


dendrite

spine axon


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


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”


Prefrontal Cortex K+

AC cAMP


Fatigue

Ca2+-cAMP signaling weakens connectivity by opening K+ channels

K+

AC cAMP Ca2+

(saves energy, as recurrent excitation is energy intensive)

SIGNALS

“NOISE”


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


Alert

AC cAMP Ca2+ K+

AC cAMP

SIGNALS

“NOISE”


Prefrontal Cortex

norepinephrine

K+

K+

AC cAMP

dopamine

α2A-AR

D1R

Ca2+-cAMP-K+ Signaling Weakens Connectivity


Alert

AC cAMP Ca2+



SIGNALS

“NOISE”


signal

Prefrontal Cortex

Amygdala


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+




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


K+

K+

AC cAMP

noise

Amygdala

Prefrontal Cortex

D1R β1-AR

D1R

α2A-AR


dopamine

norepinephrine Striatum

Sensory Cortex

AC cAMP Ca2+

High levels of catecholamines strengthen the activity of more primitive circuits


signal


K+

K+

AC cAMP

noise

Amygdala

Prefrontal Cortex

D1R β1-AR

D1R

α2A-AR


dopamine

Why stress can mimic ADHD


Sensory Cortex

AC cAMP Ca2+


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


K+

K+

AC cAMP

noise

Amygdala

Prefrontal Cortex

D1R β1-AR

D1R

α2A-AR

Chronic Stress: Architectural Changes

dopamine


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


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


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


Altered in bipolar disorder


K+

Prefrontal Cortex

Bipolar Disorder Linked to Genetic Alterations that Exacerbate Stress Signaling Pathways in PFC

AC cAMP PKC

Ca2+



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


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


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


norepinephrine

AC

K+

cAMP K+

AC cAMP

noise α2A-AR

D1R

dopamine NET DAT

Stimulants (methylphenidate, amphetamines)

signal

Prefrontal Cortex


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


signal


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


signal

Prefrontal Cortex


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


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


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

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