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The Prefrontal Cortex: Brain Waves and Cognition Earl K. Miller The Picower Institute for Learning and Memory and Department of Brain and Cognitive Sciences,

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Presentation on theme: "The Prefrontal Cortex: Brain Waves and Cognition Earl K. Miller The Picower Institute for Learning and Memory and Department of Brain and Cognitive Sciences,"— Presentation transcript:

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

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

3 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 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 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. Working Memory – The “Sketchpad” of Conscious Thought

7 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)

8 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)

9 The Classic Approach to Studying Neurons: Measure Average Level of Neural Activity of Individual Neurons From Funahashi and Goldman-Rakic (1989) 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.

10 Siegel, Warden, and Miller (2009) Proc. Nat. Acad. Sci. How Do You Hold and Order Multiple Items in Working Memory? 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 Task: Remember two objects and their order of appearance

11 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. So, How Do You Hold and Order Multiple Items in Working Memory? A solution: Brain waves 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 Siegel, Warden, and Miller (2009) Proc. Nat. Acad. Sci. 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.

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

14 Information about which object is held in memory from activity in each brain wave phase bin. Object Information in Activity of Individual Neurons by Brain Wave Phase Siegel, Warden, and Miller (2009) Proc. Nat. Acad. Sci.

15 P = 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

16 P = P < Objects were balanced by order Difference = 62 deg P = Siegel, Warden, and Miller (2009) Proc. Nat. Acad. Sci. Object Information in Activity of Individual Neurons by Brain Wave Phase

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. This may also explain why short-term memory has a capacity limitation. Siegel, Warden, and Miller (2009) Proc. Nat. Acad. Sci. 32 Hz brain waves = spike- timing dependent plasticity?

18 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) Cognitive capacity is the bandwidth of cognition. It may be directly related to brain waves.

19 A Potential Application for Brain Waves: A Cognitive Enhancer? 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. Cognitive capacity (the width of one wave)

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

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

22 60 electrodes simultaneously implanted in the frontal cortex (PFC and FEF) and parietal cortex (LIP) An area with a shorter neural latency for a given signal is more likely to be its source. Where Do Top-down and Bottom-up Attention Signals Originate?

23 Bottom-up (reflexive) Top-down (volitional) When Does Each Brain Area First Find the Target? Bottom-up Top-down LIP > PFC > FEFPFC = FEF > LIP All P < 0.01 Visual array onset Buschman and Miller (2007) Science

24 How Do We Control Voluntary Shifts of Attention? Buschman and Miller (2007) Science Buschman and Miller (2009) Neuron indicates monkeys’ eye position

25 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.

26 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

27 FEF Population Activity during Search Preferred location Neuron’s preferred location Eye movement to target Clockwise covert search Neural Evidence for a Moving “Spotlight” of Attention Buschman and Miller (2009) Neuron

28 FEF Population Activity during Search Preferred location One position clockwise from the preferred direction Neuron’s preferred location Eye movement to target Clockwise covert search Buschman and Miller (2009) Neuron Neural Evidence for a Moving “Spotlight” of Attention

29 FEF Population Activity during Search Preferred location One position clockwise from the preferred direction Neuron’s preferred location Eye movement to target Clockwise covert search Buschman and Miller (2009) Neuron Neural Evidence for a Moving “Spotlight” of Attention

30 FEF Population Activity during Search Preferred location One position clockwise from the preferred direction Neuron’s preferred location Eye movement to target Clockwise covert search Two positions clockwise from the preferred direction Neural Evidence for a Moving “Spotlight” of Attention

31 FEF Population Activity during Search Preferred location One position clockwise from the preferred direction Neuron’s preferred location Eye movement to target Clockwise covert search Two positions clockwise from the preferred direction Neural Evidence for a Moving “Spotlight” of Attention

32 How Long Does It Take to Shift Attention? ~40 ms Behavioral testing: Adding more distractors increased behavioral reaction time by 40 ms per distractor Buschman and Miller (2009) Neuron

33 Baseline Shift of attention Buschman and Miller (2007) Science Visual Popout Stronger for top-down attention Stronger for bottom-up attention Hypothesis: Middle frequency (beta) band brain waves control when attention is shifted. 40 ms Visual search Normalized difference in coherence between frontal and parietal LFPs during search minus pop-out Middle Frequency (Beta) Band Brain Waves Appear During Visual Search

34 Serial Shifts of Covert Attention Were Synchronized to 25 Hz Brain Waves in the Prefrontal Cortex Neuron’s receptive field location Upper right Lower right Lower left Upper right (target) Shifts of attention every 40 ms Target AttentionFound target

35 Brain Wave Frequency Was Correlated with Search Time Target Slower oscillations = slower shifts of attention = more time required to search = longer reaction time Buschman and Miller (2009) Neuron Correlation between brain wave frequency and time to find the target

36 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 Buschman and Miller (2007) Science Buschman and Miller (2009) Neuron Hypothesis: A reduction in beta-band oscillations might explain why some people have trouble shifting attention away from distracting things.

37 Novel images Familiar images Fixation Cue DelayTarget onset 800 ms 500 ms1000 msResponse 40 % 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 Puig, M.V. and Miller, E.K. (in preparation)

38 … Injection schedules Block number Location of the injections and grid configuration Saline 3 µl SCH (D1 antagonist) 30 µg in 3 µl Infusion rate: 0.3 µl/min (3 µl in 10 minutes) BaselineDrugWashout // … BaselineDrugWashout // … BaselineDrugWashout // Session type #1 Session type #2 Session type #3 Recording with Multiple Electrodes while Injecting a D1R Blocker Puig, M.V. and Miller, E.K. (in preparation)

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

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

41 Blocking D1R Receptors Causes Neuronal Avalanches: Super-synchronous activity 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 ( Hz) Amplitude of deflections is huge: in most cases over 500  V Performance 7 sessions with impairment: drops to 56 ± 15 % Amplitude (  V) Puig, M.V. and Miller, E.K. (in preparation)

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

43 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

44 Miller Lab Oct 2009


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