Auditory Notations

Remember

• Ketamine -NMDA / Non-NMDA antagonist
• Pentobarbitol - GABA_A Agonist
• MK-801 - NMDA antagonist
  

Moore, B: An Introduction to the Psychology of Hearing (1989, book)

• Basilar Membrane Motion - Pressure difference between the Scala Vest. and Tympani cause the Basilar Membrane to move up and down.
  • For lower frequency tone, BM will move up and down until maximum displacement at a certain point then taper off quickly.
  • There is also a phenomena of vibration in that at ALL audible frequencies, any part of the BM that is moving will vibrate at the frequency of the input.

                This is for sinusoidal pure tones. 

• Harmonic tones are represented well in the lower harmonics and begin to overlap and interfere with each other at higher frequencies. When this occurs, there is a general temporal envelope of fluctuation which coincides with the temporal pattern of the stimulus. So, the 2-5 harmonics may be discernible while the higher harmonics appear as a complex wave with period of the fundamental. 
• For complex tones in short bursts, an envelope wave will travel down the BM and excite BM at frequency of tuning for that location in a damping manner.
• Olivary complex has large influence over outer hair cells (efferent pathways) which likely tune BM and adjust for intensity. 
• Auditory Nerve Fiber Representation - Similar response to BM motion with tuning curves as noted elsewhere in auditory system
  • Delgutte displays an excitation pattern across AN fibers that strangely has a strong sub-peak around 3kHz (p35). This indicates a higher "on-frequency" at 3kHz
  • Phase locking is shown in that for pure tones a given nerve fiber will fire in integer intervals of the period. May not fire at every period of integer or smoothly.
    • Phase locking has an upper limit of about 5kHz (due to initiation of nerve impulse times)T
  • Two tone suppression is seen when a tone at CF is combined with a tone off-CF. As the second tone is shifted away from CF(just outside of the tuning curve), the response stops increasing the firing rate of the neuron and begins to suppress it. Moving the tone further away eliminates any effect of the second tone on the first (see: Robles).
    • Suppression in phase locking is also seen where one tone wins out and the response is phased locked only to it. This is typically when the two tones overlap each other in the tuning curve.
  • Higher harmonics will excite different regions of the BM and AN but a portion of the neural responses will be phase locked to the missing fundamental (Javel 1980).
  • For clicks presented the response mimics the BM. There will be a damped oscillation response (Large response...Smaller...smaller) of a period equal the the reciprocal of the CF at that BM region. Rarefaction clicks produce shortest onset latency whereas condensation clicks are longer. Periods are same except troughs and peaks are switched.
• Representation of Intensity - Hypothesized that the firing rate of neurons do this. If at CF that neuron is saturated then neurons on either side may not be and they can help code for the intensity. With white noise this is still possible due to the higher saturation levels of very high and very low tuned neurons (BM mechanics cause this). Both higher and lower frequency areas will code for this.
  • It is possible that this is not the whole picture. Phase locking of neurons not centered on tone may code for intensity....The more distance from the BF you get phase-locked responses, the more intense the sound is (tone intensity vs. noise background). This would be limited to the 4-5kHz phase locking cutoff. This phenomena may also code for the different intensities of a complex sound.
  • Phase locking cannot help in high freq. but a small number of unsaturated neurons on the sides can. Also note that there may be both High-level and Low-level saturating neurons in any location along the BM.
  • Speculations have been made that we only use a small number of neurons (~100) around the stimulus to code for intensity. This is backed up by our poor intensity discrimination ability. Perhaps we filter some of the neurons out early and use only what is left in higher centers for intensity.
  • For two complex sounds containing the same amount of energy, wider-band sounds will seem louder.
• Relative phase between multiple waveforms may only be discernible or important when the waveforms are very close to each other (inside critical band).

Robles and Ruggero - Mechanics of the Mammalian Cochlea (2001, review)

• Ossicular Movement - Pressure waved received by the ear are transmitted to the cochlea by the ossicles. As the ossicles are directed inward onto the Oval Window (scala vestibuli) a pressure wave in the cochlear fluid is induced. An inward movement of the stapes produces a downward response from the Basilar Membrane.
• Basilar Mambrane - BM movement is the exciter of the inner hair cells which send most or all of the spatial and temporal sound information to the brain. The amount of movement or attenuation of further movement may be mediated by the outer hair cells via higher order feedback control.
  • Responses to Pure Tones
    • Basal Locations - At low levels, responses (sensitivity) seem to grow linearly at CF with increasing intensity. There may also be a linear relationship at very high intensities perhaps associated with cochlear damage. Linear response is also seen when the stimulus is sufficiently far from the CF. When at or near CF there is considerable compression in the response magnitude compared to stimulus level (mid-high stimulus intensity). Sensitivity drops off dramatically past CF.
      • Tuning and isointensity functions show steepest slopes near CF and broader (less steep) tuning for lower frequencies. When gains are normalized to ossicle motion, an exponential type increase in gain is seen approaching CF from lower frequencies. As the tone goes above BF, a sharp drop off is seen. This is not so at more apical sites.
      • Phase of BM motion begins to fall off sharply as tone approaches CF from lower f and continues to drop sharply to a maximum within a few kHz higher than CF. This may not hold for the very highest CF's (30+kHz).
      • Second harmonics may be generated as a distortion component (3.5%) and decreases with increasing stimulus. DC current has not been observed.
    • Apical Locations - Conflicting reports. Many showing compressive non-linearities similar to basal sites below CF, yet the decrease is much less severe post CF. One report actually shows increased response magnitude (expansive) vs. freq just past CF.
      • Gains here are far different than at basal sites. Here there is seen a parabolic representation rising to CF from below and then decreasing similarly post CF.
      • Phase relationship to middle ear motion is also different from basal sites. Instead of sharp drop, we see a continually increasing phase lag from low to high freq. There is no abrupt or notable change in phase slope near CF.
      • Second harmonic magnitude can be as high as 50% for tone freq lower than CF.
  • Responses to broadband Clicks
    • Basal - Transient oscillations with frequency at CF of BM location. Frequency begins lower and ramps up to CF within a few hundred microseconds.
    • Apical - Similar to basal, latency of 1-1.5ms.
  • Traveling Waves (Pressure Waves) - Slower than sound waves that travel along the BM (the mechanism of travel is obscure, but it is generally agreed that these are the cause of neural excitation).
    • Increasing phase lag from basal to apical locations
    • An asymmetrical envelope around the displacement magnitude exists at CF.
      • The envelope slope is steeper apically than basally at any single location. This indicates filtering characteristics
    • Wave velocity is highest at oval window and drops off steeply just prior to CF.
    • Finite speed of wave causes delays seen from high freq. responses to lower (takes time to get to apical places).
    • Near the CF pressure waves are very near the BM and small.
    • As stimulus freq. approaches CF spot on BM from lower, phase relative to Scala Vestibuli pressure falls off dramatically and slope gets very steep ~(-inf) (FIG15). Higher than CF there is a plateau where slope goes to 0.
  • Two-Tone Cubic Difference - (2f1-f2) and similar combinations are known to cause small amounts of interference. They can be significant (up to 15%).
    • Only detected in more apical sites.
  • Frequency Tuning - Higher stimulus intensities result in broader tuning and may even shift the peak response toward a slightly lower frequency
    • Basilar - Frequencies lower than CF will excite gradually more and more as they approach BF. N
      • Near BF the velocity and displacement of the BM will coincide with the amount of neural activity.
      • At BF there is a perfect correlation
      • Past BF they remain correlated for a brief severe drop-off period and then flatten out.
    • Apical - Tuning curve is not correlated with disp and velocity but does follow the same trend
      • Lower frequencies begin to excite the response and the curve rises semi-steeply and then falls off in the same manner.
      • Tuning is much less specific for higher than CF frequencies.
  • Amplification - Possible performed through efferent connection from the Superior Olivary Complex. This is conceivable as the SOC receives contralateral and ipsilateral inputs. It may be that the amplification is an active method of amplifying desired sounds.
  • Origin of Compression - Possibly feedback loop between outer hair cells and BM motions. THis could incorporate a damping system for motion due to frequencies without proper phase alignments.
  • 
    

Carney and Friedman - Satiotemporal Tuning of Low-Frequency Cells in the AVCN (1998)

• Method - Ketamine and Xylazinge anesthitized gerbils
  • Played Gaussian noise while recording response of AVCN cells.
  • Used filter bank to simulate representative signals from auditory nerve (AN).
  •  Reverse correllation (revcor) technique used to find spatiotemporal tuning pattern
    • Looked at filter bank to discern the pattern input to AVCN just preceding discharge.
• Spatiotemporal Tuning - Reveals correlation between activity of AN fibers and AVCN.

Plomp - Rate of Decay of Auditory Sensation (1963)

• Method - White noise delivered to observers
• 200ms pulse length
• Varying Intensities and Pulse separations
• Found "just noticeable" time interval between pulses at different intensities
  
• Results - Linear logarithmic relationship
• At 65db/65db minimum time interval was 2.4-2.8ms
• At 65db to 15dB time needed was 73-83ms
• Projected time to intersect hearing threshold (65, 45, and 25dB) was 200-300ms

• Method - Two Experiments aimed at showing that the more rapidly tones are played, the less frequency difference required to segregate them into two streams.
• Experiment 1 - Six tones played on a tape. Three high frequency, three low
• 100ms tones
• HLHLHL and HHLLHL combinations played
• See White (1952) modification of Mann-Whitney test
• Subjects were able to discriminate tones of same frequency range (H or L), but not between the two
• When triplets were played as HLH, LHL, HHL, HLL, ... subjects did slightly better than chance
• When give HHH, LLL subjects did well.
• Experiment 2 - Two loops, one as above with three tones, the other as above but with three more tones between the standard loop
• ex. HHL vs HLHHLL
• Asked if 3 tones occurred in same order on both tapes
• Subjects were able only to identify patterns within streams and not from one stream to another

• Playing band-limited noise then a tone, then noise...no gap between, 125ms long
  
• If the tone overlaps the bottom of the noise by about 400Hz (1.4kHz - 1kHz bottom of noise) there is considerable increase in "pulsation threshold"
• If tone is under noise by 0-200Hz (.8kHz) there is also a considerable increase in "pulsation threshold"

• Over a period of seconds, the auditory system can detect and segregate sounds into multiple streams
• This ability builds up as successive stream-potential sounds are played
• The increased stream segregation can last for several seconds after sounds have ceased.

• Tuning curves resemble masking curves very much
• Effective masker distance from probe seems to have steeper slope on the low frequency side for higher probes.
• It is noted that the typically best masker is just above the probe frequency.
• Psychophysical bandwidths seem to be less than those measured for Auditory Nerve
• Dallos et al (1977) - Cochlear frequency selectivity in the presence of hair cell damage
• Finds that in Chinchilla with hair cell loss, tuning of neurons is broad, psychophysical tuning still good ( in forward masking)
• Vogten (1978) investigate masking with multiple delay times

• Subjects were to adjust amplitude of tone identical in frequency to another until the two became perceptually separate streams
• 100-400ms SOA the difference was +~3dB and -~4db for stream segregation (A above B, A below B B at 35dB)
• "roll effect at lower SOAs (40-60ms)
• When A tones louder, B becomes inaudible...excet that when attention is focused on the lower tones, a repitition rate of A+B is heard for the B tones
• A becomes one string at A repitition rate and another string, at the B intensity and A+B rate.
• Only observed at moderate intensity differences
• Small differences create an ABABABAB string
• Large differences leave B sounding like a continuous tone ("Continuity effect" - Houtgast)
• "Roll effect" is seen between the "fission boundary" (tone sequences are heard separately) and the "pulsation threshold" (heard as one continuous tone)

• Investigating the dB of masker (200ms) required to reduce a fixed probe (30dB 10ms) to inaudibility.
  
• Assymetrical two-tone masking mechanism
• • When masker is just below probe, significantly more masking is seen at SOA of 70-80ms
  • Masker above probe, less masking. Validated by our results
• When masker and probe overlap, they use 1/2pi or 0 phase difference for onset.
• Experiment 2 - Investigate masking at -20ms and +10ms (~ SOA of  30ms and 60ms)
• •  For -20ms there is a similar masking curve of wide below probe and narrow after
  • • Wider for above probe maskers than the +10ms
    • Less wide for below probe
• Read up on "simultaneous masking" to see what has come out recently.

• To be read at a later date
  

• Read Houtgast (1974) - Lateral suppression due to wider noise bands causes reduction in threshold.
• decrease not observed in "simultaneous masking"
• Also see Weber (1978) for detailed study of bandwidth effects on suppression
• SEEMS THAT WITH SMALL SIGNAL DURATIONS THIS HOLDS, NOT FOR DURATIONS 25ms +
  
• Finds that indeed, longer maskers with narrow bands create the most forward masking at 5ms offset-onset

• Shows that at SOA of 120ms with 50ms tones at 60dB, there is no significant masking at the level of the auditory nerve
• Further, a suppressor of 90dB is required to produce masking of a 30dB tone at 120ms SOA

• 300ms pulses delivered to cochlear implant patients
• Multiple SOAs tested
• For signal delays of between 2 and 100ms, data is perfectly aligned with psychophysical data of Plomp (1964 See above)
• complete masking ends at 2-3ms, projected threshold reached at 200-300ms.
• Thus cochlear implants do not affect forward masking recovery in deaf patients.
  
• Conclusion drawn is that Forward Masking must come form an area more central than the VIII auditory nerve.

• Ketamine anesthesia maintained throughout
• Cats - tungsten microelectrodes recording sounds presented from .625 to 20kHz to establish tuning curves
• Pseudo-random wide-band noise of 1s duration presented with gaps ranging from 5-70ms placed in noise
• Gap onset - 5-200ms after noise onset
  
•  second, "late gap" presented 500ms after noise onset
• Forward Masking Model Created and can be found in paper
• Results
• Onset burst at about 10ms after noise and lasting 5ms
• No tonic responses seen
• Independent of Gap size, no gap produced any activity unless the gap ended at at least 55-65ms after noise onset
• Onset burst - no response for 55-65ms - then another onset burst as noise resumes.
• Onset bursting after gap was similar regardless of tone duration preceding gap, so long as trailing onset was +55-65ms from lead onset
  
• 2-4ms additional latency for trailing burst onset
• Trailing onset was <60ms from leading onset
• No trailing onset response seen
• Significant bursting seen at 135ms post lead onset
  
• Perhaps a release from inhibition (After Hyperpolarization AHP)?
• Not seen in awake animals??
• Results match closely with psyhcophyisical data in HUMANS (Phillips et al. - Detection of silent intervals... 1997)
• Exception - Psycho acoustic data shows minimum gap to be ~40ms not 55

• Likely due to the effects of anesthesia
• Neurons in AI. AII. and AAF all share these Gap detection properties
• Time code created by this mechanism is of time between the leading and trailing onsets
• This may not hold true in unanesthetized prep
• Is the gap detection similar?
• Is there more information conveyed?
• With a fully tonic response, you get the duration of the tone and the actual gap between two sounds.
• Hypothesizes that the AHP or any other hyperpolarizing process is responsible for this which depends on "time since leading burts onset and has a ~55ms recovery time"
  
• Other mechanisms possible are GABA_A or other feed-forward, feed-back inhibitory mechanisms
• Douglas - The synaptic organization of the brain (Book - 1998) pp.459-509
• Slowly or non-adapting neurons hypothesized
  
• If GABA is responsible, and not AHP (Ca gated K channels) than we expect a the leading burst duration to produce more inhibition as it gets longer
• Is this what we see?
  

• Ketamine reduces NMDA and nonNMDA response.
• Onset responding cells are activated by non-NMDA receptors
• Partially activated with Ketamine applied - reduced but present onset response
• Contain the AHP, thus are hyperpolarized after about 10ms for 40ms or so.
• "rebound" response at 135ms or so is actually the end of AHP and after re-AHP due to trailing burst?
  
• Through responding cells are activated by NMDA receptors
• Connected to GABA release mechanisms which are responsible for the "tuning" into specific frequency
• Not sufficiently activated in case of Ketamine to produce strong through response or to exhibit strong inhibition

Turrigiano et al - Activity Dependent changes in the intrinsic properties of cultured neurons (1994)

• STG neurons from lobster
• Fire bursts of action potentials when normally released from inhibition
• when isolated to not fire in bursts but rather tonically
• Thought that intrinsic electrical properties of neuron are being modulated
• Isolated STG neurons begin to fire in bursts again after 3-4 days in culture.
• also produced long slow wave depolarization after release from hyperpol
• termed - REBOUND BURST
• in isolation cell modifies itself to produce bursts again
• transition actually occurs in under 1 hours time.
• with stimulation the effects are reversed as would be the case in vivo.
• "rhythmic drive eliminates the neuron's ability to fire bursts endogenously."
  

• Hand-eye coordination when prism goggles are used.
• Patients were given prism goggles and three different scenarios
• Patient's hand was not moved and was instructed to scan hand
• Patient's hand was moved by outside force while patient watched
  
• Patient moved his own hand and watched
• When patients moved their own hands visual localization shifted in a manner consistent with the prism goggles
• Re-afference
• efferent copy is created and must be rectified with the re-afference.

• Plasticity - Adaptation
  

• Same situation as above, more experiments
• Prism goggles and box where patient marks four corners of square
• results as above
• Patient turns himself in relation to visual target before and after wearing goggles on path
• Is either pushed along path or walks
• Change is only noticed when he walks
• De-correlation by prism moving either vertically or horizontally
• As thought, movement was decorrelated only in the plane of prism movement
• Adjustments continuously made even when decorrelated
  
• Indicates we have no conscious control over this
  

• Monkey trained to perform finger tapping sequences
• When trained sequences were performed, M1 response was significantly higher than for untrained
• Shows that there may be more motor cortex devoted to the action once the action is deemed of importance and learned.
• Repeated motions cause changes in M1
  

Nudo et al. - Use Dependent Alterations of Movement Representations in Primary Motor Cortex of Adult Squirrel Monkeys (1996)

• Monkeys trained to reach into very small hole with finger to get treat
• Map of M1 made using electrical stimulation before and after training
• After training the area of parts used for task increased significantly
  
• Area not used decreased
• Total area remained constant
• Behavior was extincted and mapping taken
• Area for fingers, wrist/fing, etc.. shrank without need for intricate control
• Retrained and remapped
• Area again expanded
  
• Monkeys trained on eye-bolt task in which they turned an eye-bolt more and more
• Increased representation of forearm used for eye-bolt
• Bottom line - see title

• Phantom limbs 3 types of issues
• Pain in limb possibly due to uncontrollable clenching of hand
• Can be explained by efferent copy
• Paralysis of limb when limb was paralyzed before amputation
• Ability to generate voluntary movement in phantom limb
• Used mirror box where patient could see hand as if it were his phantom
• patients regained control of phantom and were able to cease pain, etc..
• when mirror is removed phantom again becomes uncontrollable
• When substitute hand was moved without movement commands to patient there was still a sensation of movement
• this is in absence of an efferent copy
• effect was more subdued than when efferent copy present
  

 Sherrington - Notes on the scratch reflex of the cat (1910)

•  1906 Dog Paper - Cut afferent roots: 2,3,4,5,6 lumbar. Later cut 7,8, 9, AND 10 in other dogs.
  • Post mortem analysis confirmed severance
  • Many days later - Scratch reflex persisted in absence of afferent nerves
    • Was at first gone, but returned and strengthened.
  • Proposes that the scratch reflex in not dependent on sensory inputs form hindlimb
• Decapitate Cat - Mostly
  • Receptive Field of scratch reflex behind ear includes skin around shoulder and upper arm, pinna root, external auditory meatus.
    • Reflex most easily initiated by stimulation of the skin at the base of the pinna
  • Electrical stimulation of 5th cranial nerve in decapitate cat and also of afferent 1st and 2nd cervical nerve rootlets elicits reflex.
    • Ipsilateral hindlimb begins with flexion and then alternates extenion/flex.
    • Lasts for several seconds after stimulus ends and gradually recedes.
    • Reflex accompanied by contra-lateral extension of hind limb (non-clonic)
    • "Scratch-reflex is an example of double reciprocal innervation"
  • Two antagonistic stimuli controlling reflex
    • Exteroceptive skin stimulus begins flexion
    • Proprioceptive stimuli form limb movement carries out operation
      • As flexion begins, there is an inhibition of extension
      • Flexion ending lifts inhibition and there is a rebound depolarization
      • Extension begins and inhibits flexion...
      • On and on until skin stimulus is stopped and even for a few moments afterward.
    • Evidence
      1. In decerebrate prep, pain flexion reflex is typically followed by extension
      2. Magnus reports flexion of limb usally precedes extension
      3. In reflex stepping, flexion seems to facilitate extension
      4. Reflex is maintained after removal of stimulation for several seconds. This indicates the rebound effect of disinhibition
         1. Also supported by relfex stopping abruptly when restraining the movement.
      5. Attempts to isolate muscles greatly depresses and often extinguishes reflex completely
    • Evidence against
      1. Occasionally the clonic action is observed in muscles completely separated from all but their own muscle and after severence of all main nerve trunks.
      2. Decapitate prep with only the sartorious left unsevered and only connected by its entrant nerve still exhibits clonic action at each stimulation of neck skin
         1. Similar observation made in soleus
         2. EXPLAINED BY IMPORTANCE OF REBOUND AS A CENTRAL FACTOR
         3. Similar results found in dog with afferents cut

Brown - Act of Progression in Mammal (1911) 

• Late spinal animal can still exhibit walking to some degree
  • Suggests that a mechanism confined to the spinal cord near the hindlimbs controls flexion/extension responses
  • Propriceptive and exteroceptive senses from legs cause inhibition and rebound needed for walking
• When paw pressure response and inguinal stretching is abolished the reflex remains
• Sherrington concludes the following:
  1. A central stimulus starts the act
  2. Proprioceptive stimulus then inhibits primary response and sets antagonistic response in motion
  3. Primary response is re-initiated and cycle begins again
  • Secondary (proprioceptive) stimulus is determined by: Proprioception and "CENTRAL REBOUND"
  • Central Rebound is still possible in DEAFFERENTED preparation meaning it is not CENTRAL (ie. not caused by proprioceptive input).
• Scratch reflex is similar to progression and author proposes two states:
  1. Maintained Flexion
  2. Discontinuous inhibition of flexion
• Suggests that inhibibition of flexion and release followed by inhibition of extension are controlled by spinal centers interacting
  • Inhibition is centrally located and does not rely on proprioceptive stimuli
  • Test this by deafferenting cat and then cutting the spinal cord, should get same as with non de-afferented cat
    • Tests this and it is the same
• Must exist in the spinal cord above the hind limbs a mechanism which both elicits and controls the rhythmic movements
  • Proprioceptive brain communication is used for modulation only.
  • Goes on to propose entire mechanism (CPG)

Wilson - Central Nervous Control of Flight in Locust (1961)

• Finds central flight pattern generator
• Does this by continually dissecting locust and observing flight patterns.
• Is able to remove brain and all feedback to still get rhythmic flight motions.
• Shows multiple oscillatory mechanisms at work.
• Sensory feedback is necessary for the modulation of flight, but not for the actual pattern of movement.

Helmholtz - Perceptions of Vision (1866)

• Describes muscular feeling which accounts for our being able to perceive movement of our own body as being composed of three possibilities
  1. Intensity of the effort of will
     • This is the one, if we desire to move and send the signal we think it is done.
  2. Tension of the muscles: attempting the movement
     • In paralysis, there is not tension of the muscles yet our perception is as if there had been the desired movement
  3. Result of the effort: the actual moving
     • Shown incorrect due to pressing on the eyeball. Muscles move, yet our perception is that the world is moving not our eye.
• Extremely insightful, yet far before his time. Would not be addressed again until 1950!

 Sperry - Neural Basis of the Spontaneous Optokinetic Response (1950)

• Picks up on Helmholtz and furthers the hypothesis.
• Animals with inverted eyes tend to turn in circles continuously
  • Causes visual field to shift in the opposite direction as desired.
• Eye rotated and blinder placed on opposite eye - Circling behavion
  • Blinder Removed - Circling stops
  • Optic lobe sectioned to remove input from un-rotated eye - Circling behavior returns
• Vestibular system most likely source
  • Removal of vestibular system (labarynthectomy) caused loss of most ability to swim and some circling
  • Circling was distinct from eye rotation counterpart
  • After fish regained some swimming ability, eye was rotated and circling resumed. NOT DUE TO VESIBULAR SYSTEM.
• Ablation to forebrain, cerebellum, and inferior lobes does not abolish circling.
• Claims Optic Tectum to be source of integration of movement and vision
• Fish turns, but object it turns to travels twice as far in the other direction. Fish turns farther and harder...
• Corollary Discharge == Intensity of the Effort of Will (Helmholtz)

 von Holst and Middelstaedt - The Reafference Principle (1950)

• Seeks to discredit "Reflex Theory" as it has taken hold and gained many followers
• Prediction of Reflex Theory:
  • "Optomotor reflexes are inhibited during spontaneous locomotion"
  • Fly's head is rotated 180° and placed in a striped jar - jar is not rotated
    • Fly should move about jar normally
    • Instead fly continues to turn in circles or turn left-right until frozen.
    • Reflex theory is inadequate
• Instead of reflex theory, the hypothesis brought forth by Helmholtz then Sperry is furthered.
• Propose the reafference principle
  • Higher order centers send a command to lower centers that a movement is to be made. The center with sensory and motor connection to the effector (muscle, limb, body,...) being moved sends out the movement signal. At the same time, that center stores an "efferent copy" of the command. As the effector is moved an afferent signal is sent back to the command center. The two signals are added and if they do not cancel the remainder is sent upwards where a second movement is initiated to attain the originally desired position.
  • Thus when the signal from the effector is distorted by a means of rotating eyes or other influence, the reafference principle states that the mind will not properly attain the position of the animal.
• Evidence given:
  • In paralysed eye, attempted movement results in perception that the environment has moved (since the eye actually did not)
    • Also, in rapid eye movement we perceive the world as moving for a moment - Due to time taken processing EC.
  • Afference of the muscles could not be vastly important since non-movement results in changed perception.
  • Accomodation of vision: Lens of eye is adjusted for field of view. This results in correct perception of similar sized objects at different distances.
    • Reafference states that we would expect the field to change so that when it does we do not percieve things as having different sizes. Also, when we change the field of view very fast the sizes to appear to change for a moment.
• Reafference is not required for the most simple movements (swimming) but is required for others such as running. Exafference is required for things like climbing or grasping.
• Lowest centers are unconditionally stupid (eyeball cannot "know" it just moved)
• Highest centers are only as smart as their afferences let them be.

Sommer and Wurtz - A pathway in primate brain for internal monitoring of movements (2002)

• Corollary discharge signal must give information about movement yet not be the cause of the movement.
• Monkeys trained on eye saccade task and recorded from MD relay neurons receiving input from SC and sending to frontal eye field (FEF).
  • Activity shown to be sent to FEF before actual saccade indicating efference copy. FEF not related to movement.
  • Muscimol injected (GABA agonist) and effectively blocked corollary discharge.
    • Monkeys were unable to make correct second saccade due to the blockage

Gandevia et al. - Motor commands contribute to human position sense (2006)

• Human subjects tested on hand movement task. Hand was placed in certain positions and subjects were asked what they thought the hand orientation was.
  • Subjects also asked to move hand and tell of final position.
  • Hand was paralysed and removed of any skin sensation by a wrist cuff (sphygmomanometer) and additionally in two cases further deadened with lignocaine
• Did very well in control studies.
• When hand became paralysed, subjects reported it as non-moving when moved by tester.
  • However, when attemting to move hand, subjects believed hand had move appropriately in the direction of intended movement.
• Efferent copy or Corollary Discharge is used in the perception of hand movements.

 To what extent are individual neurons responsible for the generation of a single type of movement or a single behavior?

Kupfermann and Weiss - The Command Neuron Concept (1978)

• Wiersma and Ikeda termed "command neuron" in 1964.
• Studied metacerebral cells in Aplysia and found that they were not sufficient to elicit the behavior
• Modulatory role, not command neuron
• Kup. and Weiss define command neuron
• Neuron that is both Necessary and Sufficient to evoke a particular behavior
• Sufficient - Neuron is normally firing prior to behavior & reporducing stimulus gives full behavior
• Necessary - Neuron not alloed to fire (hyperpolarized) and behavior should cease
• Possible confilct if there is gap junction - Inhibiting "command" neuron could inhibite GAP connected cell
• Motor neurons cannot be considered.
• Mauthner cell may be command neuron

 Eaton et al. - Alternative Neural Pathways Initiate Fast-Start Response Following Lesions of the Mauthner Neuron in Goldfish (1982)

• Mauthner (M) neuron is indicated in "fast escape" truning response in fish.
• Previous experiments show that hyperpolarization of M-cell stops response. Also, developmentally deleted M-cells in zebrafish did not stop escape response swim.
• Tested M-neuron by electrolytic lesion of cell.
• Orthodromic activation is blocked.
• M-cell never fires - tested with electrode
• Escape response is still seen, latency increased
• Mauthner cell is NOT a command neuron

 Sparks et al. - Size and Distribution of Movement Fields in the Monkey SC (1976)

• Foveation Hypothesis - Precise movements result from the sum of activity from a large population of cells with large RF's.
• Mokeys implanted in SC with E.C. recording electrodes
• Used for recording AP before movements
• Trained to track target - Light on, then second light in another position on - Saccade tracking
• 23 neurons found to have strong "movement field" responses and mapped in detail (47 additional neurons mapped in less detail)
• Discharge occuring prior to saccade and for indicative directions and amplitudes regardless of starting position
• Clear gradient of responses to changes in direcion and amplitude seen
• While neurons did respond optimally to a certain direction and amplitude, they also responded decreasingly to more distant amplitudes and directions. 
• Precise information must be coded in population of neuron activity. 
• Problem - Possibly occurs past SC

 Lee et al. - Population coding of saccadic eye movements by neurons in the superior colliculus (1988)

• Deactivated small regions of SC with lidocaine
• Found that effect of saccadic movement was disturbed in a population sense
• Using foveation hypothesis, a large set of SC neurons will average to form the precise movement.
• Remove a portion of that field and the movement will be affected accordingly.
• This is the case here

Georgeopolous et al - Neuronal Popultion Coding of Movement Direction (1986)

• Rhesus monkey trained on visual reaching task
• Trained to press center buton, then touch amother button when lit in another area (3-D space)
• Extracellular recordings of motor cortex
• Found that population vector accurately predicts movement direction.
• Individual cells tuned broadly to 3-D space.

Frost and Katz - Single neuron control over a complex motor program (1996)

• Mollusc found to have potential command neuron
• Dorsal Ramp Interneuron
• Stimulated only DRI and achieved swimming behavior
• Hyperpolarized DRI and movement was blocked
• Did not test DRI by lesion

• Definition - Compulsive, out-of-control drug use in spite of serious negative consequences.

• Relapse persists throughout lifetime often.

• Goals of Current Research

  • Identification of molecular mechanisms responsible for addiction

    • Nester. Molecular basis of long-term plasticity underlying addiction (Nature Rev 2001)

• Berke & Hyman. Addiction dopamine and the molecular mechanisms of memory (Neuron 2000)

  • Heredity of abusive characteristics and the meaning

    • Tsuang et al. Genetic influences on DSM-III-R drug abuse and dependence (Am. J. Med. Genet. 1996)

• Tolerance creates more usage leading to amplification of the changes that lead to addiction

• Dependence - Cells and systems adapting to excessive stimulation

  • Animals may not exhibit use behaviors in light of negative consequences

    • O'Brien et al. Conditioning factors in drug abuse (Psychopharmacol. 1998)

• Initial desire to change or elevate mood followed by habituation

  • Attempt to re-experience the initial times

• Liking switches to WANTING (urges)

  • Incentive Sensitization theory

    • Robinson & Berridge. The psychology and neurobiology of addiction (Addiction 2000)

• Robinson & Berridge. The neural basis of drug craving (Brain Res. 1993)

• Cues associated with drug use can initiate relapse even after long periods of abstinence

  • O'Brien et al. Classical conditioning in drug dependent humans (Ann NY Acad. 1992)

  • Stress causes susceptibility to relapse in animal models

• Consolidation - Activation of prefrontal cortex and amygdala during drug cues.

  • Further activation of NAc and VTA

    • NAc - motivational significance of stimuli - Reward Circuit

• VTA - Ventral Tegmental Area - Dopamine pathway leads to NAc

• Dorsal Striatum - learning and execution of sequences for efficient response to NAc cues

  • Everitt et al. The basolateral amygdala (Neuroscience 1991)

• Di Chiara & Imperato. Drugs abused by humans preferentially increase synaptic dopamine. (Proc. Natl. Acad. Sci. 1988)

• Wise. Addictive drugs and brain stimulation reward

• Robbins & Everitt. Neurobehavioral Mechanisms (Curr. Opin. Neurobiol. 1996)

  • Dopamine begins to fire not in response to reward, but to CUES indicating reward

    • Waelti et al. Dopamine responses comply with basic assumptions of formal learning theory (Nature 2001)

  • Dopamine (NAc and Dorsal Striatum) interacts with projections from cerebral cortex, hippocampus, and amygdala for learning to happen (must).

    • NAc and Dorsal Striatum consolidate "wanting, seeking, and taking".

  • Consolidation very powerful - Drugs stimulate reward circuits more than almost any natural stimulus

  • Specific patterns f information must be stored cellularly

• LTP and LTD - Occurs in mesembolic dopamine structures through addiction

  • Kalivas. Interactions between dopamine and excitatory AA (Drug alcohol Depend. 1995)

• Wolf. The role of excitatory AA in behavioral snsitization to psychomotor stimulants (Prog. Neurobiol. 1998)

• Clark & Overton. Alterations in excitatory AA regulation ( Addict. Biol. 1998)

• NAc - Exhibits both LTD and LTP at excitatory synapses

  • Requires activation of NMDAR receptors

• Studies focus on prelimbic cortical afferents

• DOPAMINE activation NOT REQUIRED

• amphetamine does block LTP (increases dopamine...depressing glutamate?)

• Kombian and Malenka. Simultaneous LTP of non-NMDA and LTD of NMDA in nucleus acumbens (Nature 1994)

  • Dorsal Striatum - LTD and LTP

    • LTD

      • NMDA receptors not required

• Requires opening of Ca⁺⁺ channels

• Requires D1 and D2 dopamine receptor activation (requires dopamine)

• Complex protein kinase cascades are indicated

  • LTP

    • Requires NMDA receptors

• Requires D1-like dopamine receptors (activates cAMP and dependent kinase)

• Inhibited by activation of D2-like receptors (inhibits cAMP and creates inward K⁺ current)

  • Nicola et al. Dopaminergic modulation of neuronal excitability in the striatum and nucleus acumbens (Annu. Rev. Neurosci. 2000)

  • Midbrain and Substantia nigra - Little is known here

    • NMDA dependent - excitatory synapses

• seems to be hard to create LTP here

  • Thomas at al. Modulation of LTD by dopamine in the mesolimbic system (J. Neurosci. 2000)

• Jones et al. Amphetamine blocks long term synaptic depression in the ventral tegmental area (J. Neurosci. 2000)

  • LTD seems to involve an increase in cAMP and PKA activation

    • Inhibited by DOPAMINE

• Both associations made with the drug and the drug itself can increase synaptic strength

  • Cociane increases synaptic strength in vivo for 5 days.

    • Prevented by NMDA antagonist

• No LTP induced in GABA cells

  • Similar results implied for nicotine

• LTD possibly increased by cocaine in NAc at first??

  • LTD later diminished with chronic use??

  • Cocaine treatment increases spine density and number in prefrontal cortex and NAc

• CREB cycle is key player in learning for addiction (cAMP from D1 and Ca++ from NMDA receptor opening)

• Two possibilities for the long-term qualities of addiction

  • Long term modulation of molecular expressions

• Short term genetic modulation leads to release of factors that permanently alter synaptic mechanisms

11/22/06 - Neural Mechanisms of Adiction (Review. Hyman et al. 2006(29))

• Cues are learned very easily which predict the availability of addictive drugs.

  • Drugs begin to take precedence over even goals such as food.

  • Tolerance and Dependence with repeated usage

    • Nestler and Aghajanian. Molecular and cellular basis of addiction (1997 Science)

• Kelley and Berridge. The neuroscience of natural rewards (J neurosci. 2002)

• Dependence and Withdrawal are not necessary nor are they sufficient to explain addiction

  • Dopamine neurons project from midbrain forming long-term associative memory pathways

    • O'Brien et al. Conditioning factors in drug abuse (1998 J psychopharmacology)

• Hyman. Addiction: a disease of learning and memeory (2005 Am. J. Psychopharm.)

  • Re-exposure to CUES which would have predicted drug abuse is common to relapse

    • Stewart and Wise. Reinstatement of Heroin self-administration habits (Psychopharmacology 1992)

  • Addicted humans exhibit drug cue responses of craving - Indication of remodeling intracellularly

    • Kumar et al. Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum (Neuron 2005)

•  Stress indicated in relapse - glutocorticoid stress hormones and endogenous opoids

  • Marinelli and Piazza. Interaction between glucocorticoid hormones. (2002 Eur. J. Neurosci)

• Repeated drug taking often takes the form of a strong habit

  • Tiffany and Carter. Is craving the source of compulsive drug use? (1998. J. Psychopharmacol.)

• DOPAMINE

  • Prefrontal Cortex impairment of function is a leading indicator of addictive behavior

    • Montague et al. Computational roles for dopamine for behavioral control (2004 Nature)

    • Orbitofrontal Cortex (OFC) may act to inhibit or alter normal PFC function

      • Schoenbaum and Roesch. Orbitofrontal cortex, associative learning, and expectancies (2005 Neuron)

• Gottfried et al. Encoding predictive reward value in human amygdala and orbitofrontal cortex (Science 2003)

  • Nucleus Acumbens (NAc) - Increased deposition of dopamine into this area is normally indicated in addiction

    • Kalivas et al. Unmanageable motivation in addiction (2005 Neuron)

• Tapper et al. Nicotine activation of alpha4 receptors (Science 2004)

• Barnes et al. Activity of striatal neurons reflects dynamic encoding and recording of procedural memories (Nature 2005)

  • Dopamine may not be necessary - Blocking dopamine does not always inhibit heroin users and also is shown to be unnecessary for simpler hedonic pleasures in animals

    • Robinson et al. Distinguishing whether dopamine  regulates liking, wanting,  and/or learning about rewards (2005 Behav. Neurosci)

  • Montague et al 2004 - Roles of dopamine

  • LTP is enganced by D1 receptor action

    • Gurden et al. Essential role of D1 but not D2 receptors in the NMDA receptor dependent ltp at hippocampal prefrontal cortex synapses (2000 J. Neurosci.)

• Dorsal Striatum takes on increasingly important role as drug seeking behavior becomes more common

  • Vanderschuren et al. Involvement of  the dorsal striatum in cue-controlled cocaine seeking (2005 J. Neurosci.)

• Dopamine can administer the "reward" or pleasure enhancement...but the actual memories associated with the drug use must be put in place through classical mechanisms (LTP, LTD)

  • See papers above for reviews and information on these mechanisms.