Measures electrical activity of neurons near electrode tip Single- electrode Recording The primary tool for investigation of brain-behavior 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. 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 classic single- electrode approach only allows indirect The result: a piecemeal understanding of brain function
28
Embed
Measures electrical activity of neurons near electrode tip
Single-electrode Recording The primary tool for investigation of brain-behavior 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. - PowerPoint PPT Presentation
Welcome message from author
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Measures electrical activity of neurons near electrode tip
Single-electrodeRecording
The primary tool for investigation of brain-
behavior 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.
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 classic single-electrode approach only allows indirect inferences about neural networks.
The result: a piecemeal understanding of brain function
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 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.
Brain Waves Play a Central Role in Brain Function
•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.
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) learningGuanfacine does not improve simple learning (subcortical or posterior cortical-dependent). 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.
Novel images
Familiar images
Fixation
Cue Delay Target onset
800 ms
500 ms 1000 ms Response
40 %
40 %
10 %
10 %
The Role of Dopamine (D1R) Receptors in the Prefrontal Cortex During Learning
Monkeys learned by trial and error to associate two novel visual cues with either an eye movement to the right or left
D1R blockade induces negative deflections on the LFPs
Injection
Neuronal avalanches are generated by super-synchronous activity
0 4 8 12 16 20 24 28-0.5
-0.4
-0.3
-0.2
-0.1
0
0.1
0.2
0.3
0.4
Am
plitu
de (m
V)
Time (min)0 2 4 6 8 10
-0.5
-0.4
-0.3
-0.2
-0.1
0
0.1
0.2
0.3
Am
plitu
de (m
V)
Time (sec)
Avalanches appeared in 47 of 68 electrodes (~70% of 9 sessions)
Duration 18 ± 5min (~10-30 min)
Frequency of deflections0.44 ± 0.03 Hz (0.2-0.6 Hz)
Amplitude of deflections is huge: in most cases over 500 mV
Performance7 sessions with impairment: drops to 56 ± 15 %
Ampl
itude
(mV)
Blocking D1R Receptors Causes a Broad-Band Increase in PFC Brain Waves
Cue
Delay
Response
Nor
mal
ized
spe
ctru
m d
B
BaselineSCH
Task Interval:
Brain wave frequency
Nor
mal
ized
spe
ctru
m d
BAbnormal brain waves are a bad thing
Puig, M.V. and Miller, E.K. (in preparation)
Functional Endpoints: Other Projects
1. Improve functioning of orbital frontal cortex (OFC) networksReversal 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 enhancerWe know that guanfacine improves working memory (WM) for a single to-be-remembered 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.
Multiple-electrode neurophysiology provides a direct and powerful measure of the cellular basis for the network properties that underlie cognitive enhancements by guanfacine.
Cognitive capacity: How many things can you hold in mind simultaneously?
Individual differences in capacity limits can explain about 25-50% of the individual
differences in tests of intelligence
It is linked to normal cognition and intelligence:
Capacity is highest in younger adults and reduced in many neuropsychiatric disorders
Schizophrenia
Parkinson’s Disease
Vogel et al (2001); Gold et al (2003); Cowan et al (2006); Hackley et al (2009)www.ekmiller.org
Cognitive capacity is the bandwidth of cognition. It may be directly related to brain waves.
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.
Functional Endpoints: Other Projects
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.
CONCLUSIONS
What the Miller Lab can offer Shire1. 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
Freedman, Riesenhuber, Poggio, and Miller (2001) ScienceFreedman, Riesenhuber, Poggio, and Miller (2002) J. NeurophysiologyFreedman, Riesenhuber, Poggio, and Miller (2003) J. NeuroscienceRoy, Riesenhuber, Poggio, and Miller (submitted)Cromer, Roy, Riesenhuber, Poggio, and Miller (in preparation)
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) ScienceFreedman, Riesenhuber, Poggio, and Miller (2002) J. NeurophysiologyFreedman, Riesenhuber, Poggio, and Miller (2003) J. NeuroscienceRoy, Riesenhuber, Poggio, and Miller (submitted)Cromer, Roy, Riesenhuber, Poggio, and Miller (in preparation)
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
Categories and Concepts
Category boundary
50%
Prototypes100% Cat
80% Cat Morphs
60% Cat Morphs
60% Dog Morphs 80% Dog
Morphs
Prototypes 100% Dog
“Cats” Versus “Dogs”
Learned categories: monkeys had no prior experience with cats and dogs and could learn to categorize the stimuli after their reassignment to arbitrary categories.
“cats”
“dogs”
category boundary
C1
C2
C3
D2
D3D1
Activity to individual stimuli along the 9 morph lines that crossed the category boundary
Single neuron:
0 0.5 1.0
Normalized firing rate
C1C1C1C2C2C2
C3C3
C3
D1D2D3D1D2D3
D2D3
D1
About 1/3 of Prefrontal Neurons Respond to Category Membership not Physical Appearance
Freedman, Riesenhuber, Poggio, and Miller (2001) ScienceFreedman, Riesenhuber, Poggio, and Miller (2002) J. NeurophysiologyFreedman, Riesenhuber, Poggio, and Miller (2003) J. Neuroscience
Balance between advantages and disadvantages of slow and fast learning
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.
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.
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.
Goal-directionOvercome habits
Flexibility
Miller, E.K. (2000) Nature Reviews Neuroscience, 1:59-65Miller, E.K. and Cohen, J.D. (2001) Annual Review of Neuroscience, 24:167-202
Miller, E.K. and Cohen, J.D. (2001) Annual Review of Neuroscience, 24:167-202
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.
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.
Miller, E.K. and Cohen, J.D. (2001) Annual Review of Neuroscience, 24:167-202
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.
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.