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The Prefrontal Cortex: Brain Waves and Cognition Earl K. Miller

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.

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The Prefrontal Cortex: Brain Waves and Cognition Earl K. Miller

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  1. 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

  2. Our Goal: To understand the neural basis of higher cognition. The prefrontal cortex (PFC) Our Approach: Multiple-electrode recording in trained monkeys.

  3. 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. 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 classic single-electrode approach only allows indirect inferences about neural networks. The result: a piecemeal understanding of brain function

  4. 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.

  5. 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.

  6. 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.

  7. 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

  8. 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

  9. 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)

  10. How Do You Hold and Order Multiple Items in Working Memory? Task: Remember two objects and their order of appearance Just examining the activity of individual neurons does not clearly distinguish object order The classic approach:Information about each object from the average activity of individual PFC neurons Siegel, Warden, and Miller (2009) Proc. Nat. Acad. Sci.

  11. 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.

  12. 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.

  13. 32 Hz Brain Waves During Memory Delays Siegel, Warden, and Miller (2009) Proc. Nat. Acad. Sci.

  14. 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.

  15. 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.

  16. 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.

  17. 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 = spike-timing dependent plasticity? This may also explain why short-term memory has a capacity limitation. Siegel, Warden, and Miller (2009) Proc. Nat. Acad. Sci.

  18. Cognitive capacity: How many things can you hold in mind simultaneously? Capacity is highest in younger adults and reduced in many neuropsychiatric disorders Schizophrenia Parkinson’s Disease 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 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)

  19. 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

  20. Top-down (search): Goal-directed, knowledge-based, volitional Bottom-up (pop-out): Stimuli-driven, reflexive Bottom-up vs top-down attention Other examples: fire alarms, looming objects

  21. Bottom-up (Reflexive) vsTop-down (Volitional) Attention Bottom-up (pop-out) Top-down (search) indicates monkeys’ eye position Buschman and Miller (2007) Science Buschman and Miller (2009) Neuron

  22. 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 single-electrode approach.

  23. 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

  24. 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 Upperright Lowerright Lowerleft Upperright(target)

  25. 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

  26. 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

  27. Novel images Delay Target onset Cue 40 % Fixation 40 % Familiar images 800 ms 10 % 10 % 500 ms 1000 ms Response 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 Puig, M.V. and Miller, E.K. (in preparation)

  28. 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 Drug Washout ------------//----------- Session type #1 1 2 3 4 5 6 7 8 9 … Baseline Drug Washout ------------//----------- Session type #2 1 2 3 4 5 6 7 8 9 … Baseline Drug Washout ------------//----------- Session type #3 1 2 3 4 5 6 7 8 9 … Block number Puig, M.V. and Miller, E.K. (in preparation)

  29. Blocking D1R Receptors Impairs New Learning But Not Long-Term Memory Performance novel associations Baseline Saline Washout Criterion Performance familiar associations Chance Percent correct Percent correct Baseline SCH23390 Washout ns Baseline SCH Washout Baseline Saline Washout

  30. Blocking D1Rs Decreases Attention and Increases Impulsivity Fixation breaks per block Early trials per block *** *** *** *** Baseline Treatment Washout Baseline Treatment Washout Effect on attention Effect on impulsivity Saline SCH Puig, M.V. and Miller, E.K. (in preparation)

  31. Blocking D1R Receptors Causes Neuronal Avalanches: Super-synchronous activity Amplitude (mV) 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)

  32. Blocking D1R Receptors Causes a Broad-Band Increase in PFC Brain Waves Task Interval: Cue Abnormal brain waves are a bad thing Delay Normalized spectrum dB Normalized spectrum dB Response Baseline SCH Brain wave frequency Puig, M.V. and Miller, E.K. (in preparation)

  33. 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.

  34. Miller Lab Oct 2009 www.ekmiller.org

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