CORTICAL SELF-ORGANIZATION AND PERCEPTUAL LEARNING Mike Kilgard University of Texas at Dallas

Pioneering experiments by Hubel and Wiesel, Merzenich, Weinberger, Greenough, and many others have shown that cortical circuits are highly adaptive. Neural plasticity is likely involved in perceptual learning, development, and recovery from brain injury. Cochlea Cortex Tone Frequency Action Potentials

Time  Frequency  15 Word Speech Stream >10 45 possibilities

Techniques used to study how complex sounds alter cortical processing Environmental Nucleus Basalis Behavioral Enrichment Stimulation Training

20±10 vs. 75±20 μV 81±19 vs. 37±20 μV Red Group EnrichedBlue Enriched 22 rats total Journal of Neurophysiology, 2004

High-density Microelectrode Mapping

40% increase in response strength –1.4 vs. 1.0 spikes per noise burst (p< ) 10% decrease in frequency bandwidth –2.0 vs. 2.2 octaves at 40dB above threshold (p< 0.05) 3 dB decrease in threshold –17.2 vs. 20 dB (p< 0.001) Decrease in best rate by 1.1 Hz in enriched rats –7.8 vs. 6.7 Hz (p< 0.001) Enrichment effects persist under general anesthesia n = 16 rats, 820 A1 sites Journal of Neurophysiology, 2004

Enriched housing alters temporal processing

200 ms Interstimulus Interval Enrichment Increases Paired Pulse Depression

Enrichment increases response strength and paired pulse depression in awake and anesthetized rats

Nucleus basalis stimulation causes stimulus specific plasticity. NB stimulation paired with a sound 300 times per day for 25 days. Pairing occurred in awake unrestrained adult rats. Stimulation efficacy monitored with EEG. Stimulation evoked no behavioral response.

Nucleus basalis stimulation paired with sensory experience can alter: Cortical Topography Maximum Following Rate Receptive Field Size Response Strength Synchronization Spectrotemporal Selectivity

Best Frequency Science, 1998 NB

Tone Frequency - kHz Frequency-Specific Map Plasticity N = 20 rats; 1,060 A1 sites

Naïve Control 1 Day Post 10 Day Post 20 Day Post All Groups Percent of Cortex Responding to 21 kHz at 40 dB * = p< 0.05 ** = p< 0.01 * * * ** Tone Frequency (kHz)

Reduced response to low frequency tones, p <0.001 Decreased bandwidth of high frequency neurons –2.8 vs. 3.8 octaves, p< (30 dB above threshold) Plasticity in Posterior Auditory Field N = 12 rats; 396 PAF sites

How does experience alter temporal processing?

Response of Neurons at a Single Site to Repeated Tones Group Average

Nature Neuroscience, 1998 N = 15 rats, 720 sites

Journal of Neurophysiology, 2001 N = 13 rats, 687 sites Temporal Plasticity is Influenced by Carrier Frequency

Stimulus Paired with NB Activation Determines Degree and Direction of Receptive Field Plasticity Frequency Bandwidth Plasticity N = 52 rats; 2,616 sites

Frequency Bandwidth is Shaped by Spatial and Temporal Stimulus Features Modulation Rate (pps) Tone Probability 15% 50 % 100% Journal of Neurophysiology, 2001 Spatial Variability Leads to Smaller RF’s Temporal Modulation Leads to Larger RF’s

How do cortical networks learn to represent more complex sounds? FM sweeps Frequency 160ms Experimental Brain Research, 2004

Frequency Time NB Stim. FM Sweep paired with NB stimulation (8 to 4 kHz in 160 ms) No map expansion No preference for downward vs. upward FM sweeps Decreased threshold by 3 dB and latency by 2 ms, and increased RF size by 0.2 octaves only in the region of the frequency map activated by sweep (p<0.01)

Frequency Time NB Stim. FM Sweeps paired with NB stimulation Five downward sweeps of one octave in 160 ms No significant plasticity

Frequency Time NB Stim. Does acoustic context influence plasticity? Five downward sweeps of one octave in 160 ms plus unpaired upward (160 ms) and downward (40 or 640 ms) sweeps Decreased threshold by 5 dB and latency by 2 ms, and increased RF size by 0.2 octaves all across map (p<0.01) No preference for downward vs. upward FM sweeps

Spectrotemporal Sequence 100ms20ms High Tone (12 kHz) Low Tone (5 kHz) Noise Burst Time  Frequency 

Paired w/ NB stimulation 100ms20ms High Tone (12 kHz) Low Tone (5 kHz) Noise Burst Unpaired background sounds }

Context-Dependent Facilitation 100ms20ms High Tone (12 kHz) Low Tone (5 kHz) Noise Burst Number of Spikes ms +50%

58% of sites respond with more spikes to the noise when preceded by the high and low tones, compared to 35% in naïve animals. (p< 0.01) Context-Dependent Facilitation 100ms20ms Low Tone (5 kHz) Noise Burst High Tone (12 kHz) N = 13 rats, 261 sites Proceedings of the National Academy of Sciences, 2002

25% of sites respond with more spikes to the low tone when preceded by the high tone, compared to 5% of sites in naïve animals. (p< 0.005) Context-Dependent Facilitation Low Tone (5 kHz) 100ms20ms High Tone (12 kHz) Low Tone (5 kHz) Noise Burst N = 13 rats, 261 sites Proceedings of the National Academy of Sciences, 2002

10% of sites respond with more spikes to the high tone when preceded by the low tone, compared to 13% of sites in naïve animals. Context-Dependent Facilitation 100ms20ms Noise Burst High Tone (12 kHz) High Tone (12 kHz) N = 13 rats, 261 sites Proceedings of the National Academy of Sciences, 2002 Low Tone (5 kHz)

Time  Frequency  How do cortical networks learn to represent speech sounds?

Sash

‘SASH’ Group - Spectrotemporal discharge patterns of A1 neurons to ‘sash’ vocalization (n= 5 rats) kHz

Sash

35 %  %  5.3 (p<0.0005) Tone Frequency (kHz)

Sensory experience can alter: Cortical Topography Maximum Following Rate Receptive Field Size Response Strength Synchronization Spectrotemporal Selectivity

How does discrimination of complex sounds alter auditory cortex? Two months of training on one of six Go-No go tasks Anesthetized high density microelectrode mapping

100ms 20ms High Tone (12 kHz) Low Tone (5 kHz) Noise Burst CS+ CS-’s Task Schematic

Experimental group # Rats # A1 Sites A) Naïve Controls7329 B) Sound Exposure Controls4263 C) Frequency Discrimination8444 D) HLN Detection Task4251 E) HLN vs. H L, or N Discrimination4253 F) HLN vs. HHH, LLL, NNN Discrimination4189 G) HLN vs. NNN, LLL, HHH Discrimination7433 H) HLN vs. NLH Reverse Discrimination5329 Totals432,491 Summary of Operant Training Experiments

HLN Detection Frequency Discrimination HLN vs. HHH, LLL, NNN HLN vs. H, L, N HLN vs. NNN, LLL, HHH HLN vs. Reverse Group #

Possible results: Greater response to CS+ Map expansion HLN order preference Temporal plasticity Receptive field plasticity

Possible results: Greater response to CS+ Map expansion HLN order preference Temporal plasticity Receptive field plasticity

Naïve Control Exposure Control Detection Frequency Triplet (high first) Sequence Element Triplet (noise first) Reverse order Naïve Control Exposure Control Detection Frequency Triplet (high first) Sequence Element Triplet (noise first) Reverse order Peak Latency (msec) Bandwidth at 40dB above threshold (octaves) Onset Latency to second noise Suppression Index

F (2, 32) =14.2, MSE = 0.01, p < Exposure Control Detection Frequency Triplet (high first) Sequence Element Triplet (noise first) Reverse order

Nucleus Basalis Stimulation versus Natural Learning

Behavioral Relevance Neural Activity - Internal Representation External World -Sensory Input Neural Plasticity - Learning and Memory

CONCLUSIONS 1) Response strength, topography, receptive field size, maximum following rate, and spectrotemporal sensitivity are influenced by acoustic experience associated with neuromodulator release. 2) Map plasticity can endure at least 20 days. 3) Both primary and non-primary fields are plastic, but do not necessarily express the same changes. 4) Background (CS-) sounds powerfully shape the expression of cortical plasticity.

CONCLUSIONS, continued 5) Plastic changes induced using simple sounds are also evoked by exposure to complex sounds. 6) Operant training does not induce the same cortical plasticity as NB stimulation. 7) Cortical refinement is an inverted U-shaped function of task difficulty. 8) Plasticity is shaped by sensory experience, attention, and neuromodulator release.

Enrichment A1 Experiments - Navzer Engineer Enrichment Evoked Potentials - Cherie Percaccio FM Experiments - Raluca Moucha Speech Experiments - Pritesh Pandya PAF Experiments - Amanda Puckett Time Course Experiments - Rafael Carrasco Operant Training Experiments - Navzer Engineer Crystal Novitski Acknowledgements: and

Behavioral Relevance Neural Activity - Internal Representation External World -Sensory Input Neural Plasticity - Learning and Memory

Behavioral Relevance Neural Activity - Internal Representation External World -Sensory Input Neural Plasticity - Learning and Memory Plasticity Rules - Educated Guess Behavioral Change

Neuron 1 Inputs to Neuron A Neuron 2 Receptive Field Overlap Neuron ANeuron B Inputs to Neuron B Spike synchronization and RF overlap are correlated. Brosch and Schreiner, 1999

Number of Synchronous Events Interval (msec) Cross-correlation: TC 0 25C1.MAT x TC 0 25C2.MAT Cross-correlation Shift Predictor Correlation strength = correlation peak in normalized cross-correlation histogram Correlation width = width at half height of correlation peak 250 um separation

After RF increase and Map Expansion: ~85% shared inputs After Sharper Frequency Tuning: ~25% shared inputs Predicted effects of cortical plasticity on spike synchronization Before plasticity: ~50% shared inputs Before Plasticity: ~50% shared inputs Increased Correlation Decreased Correlation

Experience-Dependent Changes in Cortical Synchronization Map expansion increased synchronization –15pps 9kHz tone trains  50% increase in cross-correlation height (p<0.0001)  17% decrease in cross-correlation width (p<0.01) Bandwidth narrowing reduced synchronization –Two different tone frequencies  50% decrease in cross-correlation height (p<0.0001)  22% increase in cross-correlation width (p<0.001) Intermediate stimuli caused no change in synchronization –15pps tone trains with several different carrier frequencies  No change in cross-correlation height or width N = 34 rats; 1,395 sites; 556 pairs

Experience-Dependent Changes in Cortical Synchronization (con’t) Enrichment also sharpened synchronization  25% increase in cross-correlation height (p<0.01)  20% decrease in cross-correlation width (p<0.01) N = 8 rats; 397 sites; 159 pairs

Time  Frequency  Example Speech Stream

* * * = p< 0.05 ** = p< 0.01 *** = p< 0.001

** *** * ** ***

Percent of Cortical Field Responding to 60 dB Tones Tone Frequency 2 kHz4 kHz8 kHz16 kHz PAF Control 87 ± 3 91 ± 281 ± 666 ± 7 19k w/NB 52 ± 6  70 ± 3  86 ± 274 ± 6 A1 Control42 ± 438 ± 343 ± 340 ± 3 19k w/NB32 ± 635 ± 248 ± 5 54 ± 5   Decrease in Response significant to p<0.001  Increase in Response significant to p<0.01

Enriched Housing Standard Housing

12 rats per group Plasticity Index 1X 2X Enriched  Standard  NB Lesion Enriched  NB Lesion Standard  Sham Enriched  Sham Standard  Exercise  Social  Auditory Exposure 

METHODS Stimulating Electrode Location from Bregma: 3.3 mm Lateral 2.3 mm Posterior 7.0 mm Ventral Location of reference points used to record EEG activity prior, during and after each stimulation. This information was used to confirm the efficacy of NB activation

NUCLEUS BASALIS ACTIVATION EEG Desynchronization Caused by NB Stimulation EEG VOLTAGE (mV) TIME (msec) The stimulation currents levels ( μAmps) were individually established to be the minimum necessary to briefly desyncronize the EEG during slow wave sleep. The stimulation consisted of a train of twenty biphasic pulses (100 Hz, 0.1 msec pulse width) 19 kHz 50dB 250 msec duration

Behavioral Relevance Neural Activity - Internal Representation External World -Sensory Input Neural Plasticity - Learning and Memory Plasticity Rules - Educated Guess Behavioral Change

Amphetamine, haloperidol, and experience interact to affect rate of recovery after motor cortex injury Feeney, Gonzalez, Law, Science Aug 27;217(4562): Beam Scoring 7 = traversed normally with <2 slips 6 = traversed using affected limbs to aid >50% of the steps 5 = traversed using affected limbs to aid <50% of the steps 4 = traversed and placed affected hind paw on horizontal surface at least once 3 = traversed dragging affected hind limb 2 = unable to traverse but placed hind limb on horizontal surface at least once 1 = unable to traverse and unable to place hind limb on horizontal surface

Amphetamine paired with physical therapy accelerates motor recovery after stroke. Walker-Batson D, Smith P, Curtis S, Unwin H, Greenlee R Stroke Dec;26(12):

25% of sites respond with more spikes to the low tone when preceded by the high tone, compared to 5% of sites in naïve animals. (p< 0.005) 10% of sites respond with more spikes to the high tone when preceded by the low tone, compared to 13% of sites in naïve animals. 58% of sites respond with more spikes to the noise when preceded by the high and low tones, compared to 35% in naïve animals. (p< 0.01) Context-Dependent Facilitation - Group Data N = 13 rats, 261 sites Proceedings of the National Academy of Sciences, ms20ms High Tone (12 kHz) Low Tone (5 kHz) Noise Burst

Simple to Complex Sounds Primary Auditory Cortex is strongly influenced by acoustic experience –Enrichment – LTP & PPD –NB map plasticity Frequency specificity Time course PAF vs. A1 –Temporal plasticity Faster or slower –Complex sounds and CS- (or distractors) FM and twitter Combination sensitivity Speech –Summary What about natural learning? –Edeline, Weinberger, Recanzone, Wang, Merzenich, Fritz, Shamma, and others… –Neurons respond better (more strongly and/or synchronously) to CS+ vs. CS- 2 exceptions visual cortex and frequency discrimination in cats Need to test with more tasks and more subjects –We expected forms of plasticity seen in above summary –Despite clear learning, we see no evidence of selective response to CS+ over CS-. –Instead we see inverted-U function relating task difficulty and plasticity Neuromodulators and experience RULE Extra xcorr Hopkins 2005 Outline