Transcript Annual Review of Neuroscience

Single-electrode
Recording
The primary tool for
investigation of brainbehavior relationships for
over 60 years
A useful tool for studying the
details of properties of individual
neurons. Ideal for an
understanding at the level of
individual neurons.
Measures electrical
activity of neurons near
electrode tip
Less appropriate for studying
networks and systems of
neurons.
Does not allow measurements
of the precise timing of
activity between neurons
that give insight into how
they communicate and
interact.
The result: a piecemeal
understanding of brain
function
The classic single-electrode
approach only allows
indirect inferences about
neural networks.
A More Global View of Brain Function: FMRI. However….
FMRI measures patterns of blood flow
to brain areas (the BOLD signal).
Result of neurons needing energy
(oxygen) when they fire electrical
impulses (“action potentials”).
The Good:
Provides a global view of which brain
areas are engaged by a cognitive function.
The Bad:
It takes five-six seconds for the BOLD
signal to build. A lot can happen in the
brain in 5-6 seconds.
Our approach: Multiple-electrode Recording in Monkeys
Performing Cognitive-demanding Tasks
Electrode arrays with 500
um spacing to investigate
microcircuitry
Electrode arrays in
different brain areas to
investigate large-scale
networks.
Allows direct measurements of the networks that underlie cognition.
Brain Waves Play a Central Role in Brain Function
Brain waves are rhythmic, coordinated oscillations
between neurons (1 – 100 Hz). They reflect how and
when networks of neurons communicate.
They allow local networks of neurons to synchronize
with one another and with distant networks. This
allows the brain to orchestrate billions of neurons to
produce elaborate behaviors.
The idea is that when neurons fire in synchrony with
one another, they are better able to communicate
than when they fire out of sync.
Mounting evidence that brain waves play a critical role in attention, working memory, memory
storage, recall, learning, sequencing, planning and more. Abnormal brain waves are
associated with neuropsychiatric disorders.
•Parkinson’s patients show increased beta band brain waves (which can be decreased by DA therapy)
•Schizophrenia patients show decreased gamma band brain waves.
•Guanfacine (ADHD treatment) increases brain wave (EEG) synchrony in rats.
•Methylphenidate (ADHD) increases theta brain waves in the hippocampus.
Our Approach:
Complex Behavioral Paradigms for Complex Cognition
1. We use monkeys. Primates have higher-level, and more flexible, cognition than
other animals.
2. The Miller Lab are experts at animal training and design the most sophisticated
behavioral paradigms in systems neurophysiology.
Learning of abstract categories and concepts
Rule learning
Multi-tasking
Decision-making
Task switching
Reversal learning
Sequence memory
Planning
Attention
Working Memory
“Cats vs dogs”
Small numbers
Functional Endpoints: Proposed Project
Our multiple electrodes and sophisticated behavioral paradigms can provide precise diagnostic
tools for assessing the effects of guanfacine (and other drugs) on the mechanisms of cognition.
1.
Our task: Enhancement of higher-order (prefrontal cortex-dependent) learning
Guanfacine does not improve simple learning (subcortical or posterior corticaldependent). It does improve many prefrontal cortex (PFC) dependent tasks, but its effects
on PFC-dependent learning are not known.
We will use a learning task (conditional visuomotor learning) that is highly PFC
dependent. Guanfacine, at the proper dose, should improve learning.
2.
Multiple-electrodes offer a powerful diagnostic for directly measuring the effects of
guanfacine on cognition.
Arnsten and colleagues have provided elegant evidence that guanfacine improves
communication in PFC microcircuits that underlie working memory (“delay”) activity. This
was indirectly inferred from the activity of single neurons as well as detailed anatomy.
Multiple electrodes allow direct examination of the functioning of microcircuits. This gets
directly at the network mechanisms underlying cognition and how they are improved by
drug therapy.
The Role of Dopamine (D1R) Receptors in the Prefrontal Cortex During Learning
Novel images
Monkeys learned by trial and error
to associate two novel visual cues
with either an eye movement to
the right or left
Cue
Delay
Target onset
40 %
Fixation
40 %
Familiar images
800 ms
10 %
10 %
500 ms
1000 ms
Response
Recording with Multiple Electrodes while Injecting a D1R Blocker
Location of the injections and grid configuration
Saline 3 µl
SCH 23390 (D1 antagonist) 30 µg in 3 µl
Infusion rate: 0.3 µl/min (3 µl in 10 minutes)
Injection schedules
Baseline
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Drug
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Baseline
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Block number
8
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Washout
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Session type #2
9…
Drug
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Session type #1
9…
Drug
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Baseline
1
7
Washout
9…
Washout
Session type #3
Blocking D1R Receptors Impairs New Learning But Not Long-Term Memory
Performance novel associations
80
100
Criterion
60
40
-60 -40 -20 0 20 40 60
100
60
90
85
80
75
70
40
-60 -40 -20 0 20 40 60
Baseline
Percent Correct
80
60
Chance
95
100
80
100
Washout
40
-60 -40 -20 0 20 40 60
SCH23390
100
Washout
100
80
80
80
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-60 -40 -20 0 20 40 60
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-60 -40 -20 0 20 40 60
Trial From Block Switch
40
-60 -40 -20 0 20 40 60
1
Baseline Saline
Washout
100
Percent correct
Percent Correct
100
Saline
Percent correct
Baseline
Performance familiar associations
95
90
ns
85
80
75
70
Baseline
SCH
1
Washout
Blocking D1Rs Decreases Attention and Increases Impulsivity
Fixation breaks per block
Early trials per block
100
300
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80
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60
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150
40
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100
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0
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Baseline
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Treatment
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Washout
0
Effect on attention
Baseline
1
Treatment
2
Effect on impulsivity
Saline
SCH
Washout
3
D1R blockade induces negative deflections on the LFPs
Injection
Neuronal avalanches are generated by super-synchronous activity
0.4
0.3
0.3
0.2
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0.1
Amplitude (mV)
(mV)
Amplitude(mV)
Amplitude
0.2
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-0.1
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Time (min)
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Time (sec)
Avalanches appeared in 47 of 68 electrodes (~70% of
9 sessions)
Duration
18 ± 5min (~10-30 min)
Frequency of deflections
0.44  0.03 Hz (0.2-0.6 Hz)
Amplitude of deflections is huge: in most cases over
500 mV
Performance
7 sessions with impairment: drops to 56 ± 15 %
Blocking D1R Receptors Causes a Broad-Band Increase in PFC Brain Waves
Task Interval:
Cue
Normalized spectrum
dB
spectrumdB
Normalized
Delay
Baseline
SCH
Abnormal brain waves
are a bad thing
Response
Brain wave frequency
Puig, M.V. and Miller, E.K. (in preparation)
Functional Endpoints: Other Projects
Multiple-electrode neurophysiology provides a direct and powerful measure of the cellular
basis for the network properties that underlie cognitive enhancements by guanfacine.
1. Improve functioning of orbital frontal cortex (OFC) networks
Reversal learning is highly dependent on the OFC. By adding the requirement to reverse
associations to our conditional visuomotor task, we can make it an OFC task. Guanfacine
should improve reversal learning and our multiple electrodes can directly measure the
network cellular basis for that improvement.
2.
Guanfacine as an intelligence enhancer
We know that guanfacine improves working memory (WM) for a single to-beremembered item and helps alleviate ADHD. Can it improve general intelligence?
The ability to hold a single item in WM does not correlate well with general intelligence
and single item WM is not impaired in many neuropsychiatric disorders.
By contrast, WM capacity (how many items you can hold in WM simultaneously)
correlates highly with intelligence measures and is reduced in virtually every
neuropsychiatric disorder and in aging. In other words, WM capacity may be a great
diagnostic of WM function.
Cognitive capacity: How many things can you hold in mind
simultaneously?
It is linked to normal cognition and intelligence:
Individual differences in capacity limits can
explain about 25-50% of the individual
differences in tests of intelligence
Capacity is highest in younger adults and
reduced in many neuropsychiatric disorders
Schizophrenia
Parkinson’s Disease
Cognitive capacity is the bandwidth of cognition. It may be directly related to
brain waves.
www.ekmiller.org
Vogel et al (2001); Gold et al (2003); Cowan et al (2006); Hackley et al (2009)
Functional Endpoints: Other Projects
Guanfacine as an intelligence enhancer
The Miller Lab used cutting edge multiple-electrode technology to that has yielded the first
neurophysiological insight in WM capacity limitations: gamma-band oscillations (brain waves)
in the prefrontal cortex.
Siegel, Warden, and Miller (2009) showed that PFC gamma-band brain waves provide
“memory slots” for holding multiple items in WM. WM capacity is due to a limited number of
slots per wave.
In theory (soon to be tested), we can increase WM capacity by slowing down the
brain wave frequency or increasing its amplitude. This could add 1-2 more memory
slots and effectively increase general intelligence.
CONCLUSIONS
Brain waves are central to brain function. They regulate communication between
neurons and there is mounting evidence that they play specific and important roles
in higher cognition. Abnormal brain waves are apparent in neuropsychiatric
disorders.
Multiple-electrodes offer a new tool for directly measuring the effects of potential
drug therapies on cognition. They allow direct examination of the functioning of
microcircuits and large-scale networks of neurons. This gets directly at the network
mechanisms underlying cognition.
The combination of cutting-edge multiple-electrode technology and
sophisticated behavioral paradigms in monkeys can provide a powerful
diagnostic of the cellular mechanisms that underlie cognitive
enhancements by potential drug therapies.
What the Miller Lab can offer Shire
1. Investigation of brain-pharmacology-neurophysiology relationships
using cutting-edge multiple-electrode recording techniques.
The Miller Lab has invented and pioneered the use of multiple electrodes in
behaving monkeys. This has yielded new and direct insight into the
communication within networks of neurons during high-level cognition. This
can provide a power diagnostic for assessing potential drug therapies.
2. Investigation of the highest levels of cognitive function using the
most sophisticated animal training in neuroscience.
Most neurophysiological studies of cognition use relatively basic tasks (“pay
attention here.” “hold one thing in mind”) The Miller Lab has taken monkey
training to a higher level than any other lab. We have taught monkeys to juggle
multiple things in memory, anticipate and imagine forthcoming events, make
cognitive decisions, to recognize abstract categories and concepts (“cat vs dog”,
“same vs different”, numbers 1-5). More complex behavioral methods are
needed to understand the pharmacology of truly intelligent behavior.
We can also apply this approach to a wide
range of cognitive functions
Category Learning
Fundamental to normal human
cognition because they imbue the
world with meaning.
They allow discarding detailed
information in favor of general
concepts.
Disrupted in neuropsychiatric
disorders such as autism,
schizophrenia, and learning
disorders.
Patients become mired in details
(they lose the forest in the trees).
Freedman, Riesenhuber, Poggio, and Miller (2001) Science
Freedman, Riesenhuber, Poggio, and Miller (2002) J. Neurophysiology
Freedman, Riesenhuber, Poggio, and Miller (2003) J. Neuroscience
Roy, Riesenhuber, Poggio, and Miller (submitted)
Cromer, Roy, Riesenhuber, Poggio, and Miller (in preparation)
Categories and
Concepts
For example, my concept of dogs
is inextricably linked to every dog
I've ever known. It's as if I have a
card catalog of dogs I have seen,
complete with pictures, which
continually grows as I add more
examples to my video library.
Temple Grandin, Ph.D.
Thinking in Pictures
Freedman, Riesenhuber, Poggio, and Miller (2001) Science
Freedman, Riesenhuber, Poggio, and Miller (2002) J. Neurophysiology
Freedman, Riesenhuber, Poggio, and Miller (2003) J. Neuroscience
Roy, Riesenhuber, Poggio, and Miller (submitted)
Cromer, Roy, Riesenhuber, Poggio, and Miller (in preparation)
“Cats” Versus “Dogs”
80% Cat
Morphs
60% Cat
Morphs
60% Dog
Morphs
80% Dog
Morphs
Prototypes
Prototypes
100% Dog
100% Cat
Category
boundary
50%
Learned categories: monkeys had no prior experience with cats and
dogs and could learn to categorize the stimuli after their
reassignment to arbitrary categories.
About 1/3 of Prefrontal Neurons Respond to Category
Membership not Physical Appearance
Activity to individual stimuli along the 9 morph
lines that crossed the category boundary
C2
C3
C1
“cats”
category boundary
Single neuron:
C1
C1
C1
C2
C2
C2
C3
C3
C3
D1
D2
D3
D1
D2
D3
D1
D2
D3
0
“dogs”
D1
D3
D2
Freedman, Riesenhuber, Poggio, and Miller (2001) Science
Freedman, Riesenhuber, Poggio, and Miller (2002) J. Neurophysiology
Freedman, Riesenhuber, Poggio, and Miller (2003) J. Neuroscience
0.5
Normalized firing rate
1.0
Theories of Prefrontal Cortex
Function
Prefrontal cortex: Slower,
reward-shaded, plasticity
Basal ganglia (striatum):
Fast, reward-gated,
plasticity
Slower learning of more elaborate,
generalized, less error-prone,
representations that include the regularties
across experiences.
Fast learning (“snapshots”) of the specific
experiences that predict reward. Error
prone.
Balance between advantages and disadvantages of slow and fast learning
A switch operator in a system of railroad tracks:
DA reward
The integrative anatomy of the PFC and BG allows rapid
acquisition of the logic of a goal-directed task. This is a
“roadmap” that specifies which pattern of “tracks” (neural
pathways) are needed to solve a given task.
BG loops
PFC
“Context”
Guest
At home
Phone
rings
This pattern is activated and
maintained in the PFC during task
performance, producing “top-down”
signals that bias the flow of activity in
the cortex along task-relevant
pathways.
Don’t answer
“Cue”
Active
Sensory
cortex
Motor
cortex
Answer
Goal-direction
Overcome habits
Flexibility
Inactive
Miller, E.K. (2000) Nature Reviews Neuroscience, 1:59-65
Miller, E.K. and Cohen, J.D. (2001) Annual Review of Neuroscience, 24:167-202
A switch operator in a system of railroad tracks:
The integrative anatomy of the PFC and BG allows rapid
acquisition of the logic of a goal-directed task. This is a
“roadmap” that specifies which pattern of “tracks” (neural
pathways) are needed to solve a given task.
PFC
“Context”
Guest
At home
Phone
rings
This pattern is activated and
maintained in the PFC during task
performance, producing feedback
signals that bias the flow of activity in
the cortex along task-relevant
pathways.
Don’t answer
“Cue”
Active
Sensory
cortex
Motor
cortex
Answer
Goal-direction
Overcome habits
Flexibility
Inactive
Miller, E.K. (2000) Nature Reviews Neuroscience, 1:59-65
Miller, E.K. and Cohen, J.D. (2001) Annual Review of Neuroscience, 24:167-202
A switch operator in a system of railroad tracks:
DA reward
The integrative anatomy of the PFC and BG allows rapid
acquisition of the logic of a goal-directed task. This is a
“roadmap” that specifies which pattern of “tracks” (neural
pathways) are needed to solve a given task.
BG loops
PFC
“Context”
Guest
At home
Phone
rings
This pattern is activated and
maintained in the PFC during task
performance, producing feedback
signals that bias the flow of activity in
the cortex along task-relevant
pathways.
Don’t answer
“Cue”
Active
Sensory
cortex
Motor
cortex
Answer
Goal-direction
Overcome habits
Flexibility
Inactive
Miller, E.K. (2000) Nature Reviews Neuroscience, 1:59-65
Miller, E.K. and Cohen, J.D. (2001) Annual Review of Neuroscience, 24:167-202