Transcript Slide 1 - Massachusetts Institute of Technology

The Prefrontal Cortex: Brain Waves
and Cognition
Earl K. Miller
The Picower Institute for Learning and Memory and
Department of Brain and Cognitive Sciences,
Massachusetts Institute of Technology
www.ekmiller.org
Our Goal:
To understand the neural basis of higher cognition.
The prefrontal cortex (PFC)
Our Approach:
Multiple-electrode recording in trained monkeys.
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.
Working Memory – The “Sketchpad” of Conscious Thought
Working memory is
the ability to hold
and manipulate
information in mind.
It is central to
normal cognition
and closely linked to
a wide range of
cognitive abilities
such as attention,
planning, reasoning,
etc.
A Classic Test of Working Memory: Oculomotor Spatial Delayed
Response Task (Goldman-Rakic and colleagues)
Fixate until fixation cross disappears. Then look at the cued position
A Classic Test of Working Memory: Oculomotor Spatial Delayed
Response Task (Goldman-Rakic and colleagues)
Fixate until fixation cross disappears. Then look at the cued position
The Classic Approach to Studying Neurons: Measure
Average Level of Neural Activity of Individual Neurons
This neuron “remembers”
the upper left location. It is
more active when the
remembered cue was in the
upper left.
Holding a single thought or
memory in mind is a
fundamental, but relatively
simple, cognitive function.
From Funahashi and Goldman-Rakic (1989)
How Do You Hold and Order Multiple Items in Working Memory?
Task: Remember two objects and
their order of appearance
The classic
approach:
Information about
each object from
the average
activity of
individual PFC
neurons
Just examining
the activity of
individual
neurons does not
clearly distinguish
object order
Siegel, Warden, and Miller (2009) Proc. Nat. Acad. Sci.
So, How Do You Hold and Order Multiple Items in Working Memory?
A solution: Brain waves
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.
How Do You Hold and Order Multiple Items in Working Memory?
Task: Remember two objects and
their order of appearance
Hypothesis: Brain waves act as a “carrier signal” that helps
order multiple thoughts held in mind.
Siegel, Warden, and Miller (2009) Proc. Nat. Acad. Sci.
32 Hz Brain Waves During Memory Delays
Siegel, Warden, and Miller (2009) Proc. Nat. Acad. Sci.
Object Information in Activity of Individual Neurons by Brain Wave Phase
Information about which object is
held in memory from activity in
each brain wave phase bin.
Siegel, Warden, and Miller (2009) Proc. Nat. Acad. Sci.
Object Information in Activity of Individual Neurons by Brain Wave Phase
P = 0.0007
Objects were balanced by order
Siegel, Warden, and Miller (2009) Proc. Nat. Acad. Sci.
Object Information in Activity of Individual Neurons by Brain Wave Phase
P = 0.0007
Difference = 62 deg
P = 0.0002
P < 0.0001
Objects were balanced by order
Siegel, Warden, and Miller (2009) Proc. Nat. Acad. Sci.
Conclusions
During working memory, prefrontal activity shows 32 Hz brain waves.
Information about the different objects line up on different parts (phases) of
the brain waves according to their memorized order.
This may help order thought and keep multiple thoughts from interfering with
one another. A reduction in gamma band brain waves was recently seen in
schizophrenics.
32 Hz brain waves = spiketiming dependent plasticity?
This may also explain why short-term memory has a capacity
limitation.
Siegel, Warden, and Miller (2009) Proc. Nat. Acad. Sci.
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)
A Potential Application for Brain Waves: A
Cognitive Enhancer?
Cognitive capacity
(the width of one wave)
If we could (slightly) slow down the frequency, or increase the amplitude, of the
gamma band oscillations, we could, in theory, add an additional memory slot and
increase cognitive capacity.
This could increase the bandwidth of cognition and effectively increase general
intelligence.
www.ekmiller.org
Bottom-up vs top-down attention
Bottom-up (pop-out):
Stimuli-driven, reflexive
Other examples: fire alarms, looming objects
Top-down (search):
Goal-directed, knowledge-based,
volitional
Bottom-up (Reflexive) vs Top-down (Volitional) Attention
Bottom-up (pop-out)
Top-down (search)
indicates monkeys’
eye position
Buschman and Miller (2007) Science
Buschman and Miller (2009) Neuron
How Do We Search a Crowded Visual Scene?
Serial search:
A moving
“spotlight” of
attention
It is well known that
neurons in many brain
areas reflect the
ultimate focusing of
attention on a target
(e.g., Waldo).
However, neural
correlates of shifting
attention to search for
the target have not
been observed with
the classic singleelectrode approach.
Behavioral Reaction Times Suggest That Monkeys Use a
Clockwise Covert Serial Search Strategy
Example of behavioral reaction
time from one monkey during
one testing session.
This monkey tended to start
covert search at the lower right
location (4 o’clock) and then
searched clockwise.
Each monkey chose a different
starting point; both showed
evidence for clockwise covert
search.
Buschman and Miller (2009) Neuron
Serial Shifts of Covert Attention Were Synchronized to 25 Hz
Brain Waves in the Prefrontal Cortex
Target
Attention
Found target
Shifts of
attention every
40 ms
Neuron’s
receptive field
location
Upper
right
Lower
right
Lower
left
Upper
right
(target)
Brain Wave Frequency Was Correlated with Search Time
Correlation between brain wave frequency and time to
find the target
Target
Slower oscillations = slower shifts of attention =
more time required to search = longer reaction time
Buschman and Miller (2009) Neuron
Top-down (volitional) attention:
• Signals originate from prefrontal cortex
• Serial shifts of attention (every ~40 ms)
• 25 Hz brain waves may act as a ‘clock’ that
controls the shifts in attention.
Top-down
Bottom-up
Hypothesis: A reduction in beta-band oscillations
might explain why some people have trouble
shifting attention away from distracting things.
Buschman and Miller (2007) Science
Buschman and Miller (2009) Neuron
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
Puig, M.V. and Miller, E.K. (in preparation)
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
1
2
Drug
------------//----------3
4
Baseline
1
2
5
2
7
8
Drug
------------//----------3
4
5
Baseline
1
6
Washout
3
6
7
5
6
Block number
Puig, M.V. and Miller, E.K. (in preparation)
7
Session type #1
Washout
8
Drug
------------//----------4
9…
8
9…
Session type #2
Washout
9…
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
60
60
60
40
-60 -40 -20 0 20 40 60
40
-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
***
80
250
60
200
***
150
40
***
20
***
100
50
0
1
Baseline
Washout
2
Treatment
3
0
Effect on attention
Treatment
2
Effect on impulsivity
Saline
SCH
Puig, M.V. and Miller, E.K. (in preparation)
Baseline
1
Washout
3
Blocking D1R Receptors Causes Neuronal Avalanches: Super-synchronous activity
0.4
0.3
0.3
0.2
0.1
0.1
Amplitude (mV)
(mV)
Amplitude(mV)
Amplitude
0.2
0
-0.1
-0.2
-0.1
-0.2
-0.3
-0.3
-0.4
-0.4
-0.5
0
0
4
8
12
16
Time (min)
20
24
28
-0.5
0
2
4
6
8
10
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 %
Puig, M.V. and Miller, E.K. (in preparation)
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)
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.
Miller Lab
www.ekmiller.org
Oct 2009