Lectures on Sensory Nervous System  by Prof. J. D. Pettigrew

Lecture 1.  Sensory Transduction, Sensory Arrays and Topographic Maps:
Lecture 2.  Visual Stabilisation:  Owl demonstration.
Lecture 3.  Vision
Lecture 4.  Sleep and Circadian Rhythms
Lecture 5.  Hearing
Lecture 6.  Pain
Lecture 7.  Mood and Emotion

1.  Textbook and Coverage:
There is not time to cover all aspects of sensation that are mentioned in the text. I am trying to work from Sherwood, but note that I have my own emphases, which may differ from this textbook.
All exam questions will be based upon the lecture material. There will be no questions from the material in Sherwood not covered specifically in lectures.   2.. Allowing for the 2 hour slot:
Because of the 2-hour slots on some occasions, and the difficulties of sustained concentration (by myself!, leaving aside the students), I have arranged the lectures in an order that takes this into account rather than following in a particular, more logical, sequence.
 

Lecture 1
Sensory Transduction, Sensory Arrays and Topographic Maps:    Chapter 6 of Sherwood.

Receptors and Receptor Arrays:

Sensory Transduction:
Nerve fibres can be activated directly (as in funny bone example), but note the extremely high intensity required to bring a fibre to threshold by direct
activation.

Sensory Transduction is the process by which the energy of a sensory stimulus is converted to a more efficient form for the activation of the sensory
nerve fibre.

Sensory receptors, interposed between the physical stimulus and the afferent nerve fibre, transduce the stimulus into a receptor potential that can control the release of neurotransmitter and so activate the afferent fibre. In class we will concentrate on two very different kinds of sensory receptor, mechanoreceptors (exemplified by hair cells) and photoreceptors. A key goal will be understanding the constraints underlying these two different kinds of receptor.

Types of Receptor:
1. Mechanoreceptors:
Mechanism of transduction still obscure, but involves cationic channels which may be directly sensitive to mechanical stimuli. Shortest latency of all
receptor cells.

A. Tactile Receptors in the skin:
A variety of specialised receptors, often named after the scholar who first described the morphology
1.Pacinian corpuscles; Onion-skin arrangement; glabrous skin; high temporal (in timing) fidelity to vibration; can detect minute (1mm) displacements;
important for Braille; ìacceleration detectorsî
2. Iggo corpuscles; Like Pacinian but on hairy skin; intensity detectors
3. Meissner's corpuscles (glabrous) & Follicle receptors (Hairy); adapt rapidly so that most effective stimulus is rapid rate of indentation; ìvelocity
detectors.

B. Hair Cell Receptors:
Transduce shearing forces: Derived phylogenetically from hair cells responsible for the detection of fluid motion past the lateral line system
(amphibians, fish and other anamniotes).
1. Cochlea; 1 row of Inner Hair Cells (passive frequency coding) and 3 rows of Outer  Hair Cells (supplying frequency-specific electromechanical feedback).
2.  Cupula: Hair cells embedded in gelatinous bulb which bends with fluid motion in the  semicircular canals.
3.  Otolith: Hair cells embedded in gelatinous matrix containing apatite crystals (otoliths). May be involved in detection of substrate vibration,
acceleration of the head due to gravity.

Click here for electron micrograph of stereocilia and (barely visible) tip links

Electron micrograph of bundle of stereocilia
at the apex  of the hair cell. Tip links (barely
visible monomolecular bridges) joins the apex
of one stereocilium to its neighbour.
 

C. Muscle Spindles:
Once thought not to contribute to sensation, but now known to provide important proprioceptive (internal body sense) information. Very sensitive to
vibration, hence illusions of movement if vibration is applied to a muscle during movement.

2. Photoreceptors:
Rhodopsin captures photons. The resulting conformational change is communicated to the photoreceptor synapse by a long chain of  reactions that is diffusion-dependent (cf. mechanotransdution, which is much more direct). Rhodopsin is a G-protein linked receptor that shares the characteristic 7-transmembrane loop structure  with other G-protein-linked receptors such as the beta-adrenergic receptor.
As in other G-protein linked transduction systems, response is amplified (one photon per photoreceptor can be detected by the central nervous system!).
Adaptation is also a notable aspect of phototransduction (note the 9-10 log unit range of visual sensitivity).
The dependence on diffusion and the long chain of reactions (opsin bleaching  to G-protein activation to adenyl cyclase to phospho diesterase to ecreased cGMP to Na+ channel closure to hyperpolarisation) makes for a long latency response compared with mechanotransduction.
Rods: Operate in range 0-5 log units (darkness to dusk); rhodopsin 560nm
Cones: Operate in range 5-8 log units (dusk to bright sun); 3 photopigments, 45nm (ìblueî), 510nm (ìgreenî) and 570nm (ìredî).

Pineal Photoreceptors:  Fig 9b. pp 648-649
Surprisingly, many cells throughout the body, including the epidermis, can detect light and change their internal circadian rhythms accordingly. In mammals, the circadian clock (suprachiasmatic nucleus of the hypothalamus...... SCN) is not light sensitive, but it interacts with a structure that is:-....the pineal organ secretes melatonin and is directly photoreceptive.  The pineal is an important circadian clock, especially in birds. It is sufficiently photosensitive for a sparrow to detect moonlight through its skull!  In humans the pineal may trigger onset of puberty (blind-, country- and pinealectomised girls all tend to have later puberty compared with city girls exposed to lots of artificial light).

3. Chemoreceptors:
Tongue Taste-buds: pH, saccharides, cations, bitter alkaloids.
Hypothalamus: pH, monosaccharides,.
Arterial Chemoreceptors: pO2

4. Thermoreceptors:
Skin: Both hot and cold detectors. ?some overlap with nociceptor.
Hypothalamus: Both hot and cold receptors; involved in thermoregulation; sensitive to pyrogens.

5. Nociceptors:
Note distinction between nociception (the detection of tissue damage) and pain ( a more complex state with elements of motor output or decision
making overlay the sensory state). Nociceptors correspond structurally to free nerve endings, but note that physiology is much more heterogeneous
than anatomy, with some responsive to thermal, others to mechanical, damage.

6. Electroreceptors:
Recently described in the platypus bill and echidna snout, but note that they are well-described from electric fish and from sharks. Enable the detection
of the minute electric currents associated with neuromuscular activity in prey.

7. Magnetoreceptors:
Their presence in vertebrates only speculated upon at present, based on behavioural responses of both birds and insects to earth-strength magnetic
fields. Note that magnetotactic bacteria have crystals of magnetite inside which physically orient these motile organisms in the earthís magnetic field.
 
 

G-Proteins and G-Protein-linked receptors:
 

• G-proteins act to link an external stimulus with intracellular cascades that can change the cellís physiology.
• G-protein signalling pathways are generally used when extreme sensitivity is required.
• G-protein transduction is multiplicative because an activated G-protein can then activate other G-proteins to give a chain reaction with a large degree of amplification.
• The protein that activates the G-protein is called a G-protein-linked receptor.
• All G-protein-linked receptors have the same structure with 7 transmembrane loops of protein.

Topographic Maps

Roger Sperry (Nobel laureate 1981) demonstrated point-to -point connections between retina and midbrain tectum; Sperry postulated a chemoaffinity mechanism. This postulate has now been verified using antibodies to a gradient of chemical labels (Ephrins) specifying a topographic array of cell-to-cell connections. Topographic organisation is a general feature of all interconnections in the brain, but note that the kind of information being represented across the map may not always be known. Some maps are generated directly by point-to-point connections from the sensory periphery to the brain; other maps cannot be generated in this way and must be synthesised centrally (computational maps).

Point-to-Point Sensory Topographical maps:

A. Retinotopic Map: Visual System
Maintains the two-dimensional relationships in the retina; orienting response when linked to a ëmotor mapí of output connections such as the superior
colliculus.

B. Tonotopic map: Auditory System
One-dimensional map of cochlear output so that sound frequency is represented continuously across the surface of most nuclei in the auditory
pathway.

C. Somatotopic Map:  Fig. 5-12, pp140-141
Representation of the body surface receptors (mostly skin).
Computational (Centrally-synthesised) Maps:
These maps have to be generated by the brainís own computations, rather than arising as a consequence of connections to a sensory surface which is
already ordered.
i. Auditory space amp: inferior colliculus;  neighbouring neurons have neighbouring
preferences for sound location (like a retinotopic map); generated in a complex way by a continuous array of sensitivity for differences between the
sounds coming to the two ears.
ii. Orientation map: visual cortex; continuous variation from neuron to neuron across the cortex in the preferred orientation of a visual edge.
 

Lecture 2:
Visual Stabilisation     Chapter 5-4

Visuo-Motor Stabilisation:

"Eye movements evolved to keep the eyes still"  David A. Robinson.

Although this statement has its paradoxical side, given that we primates have intense saccadic activity, if we ignore these rapid square wave eye position
changes that are clearly aimed to change the object of regard as quickly as possible, it is obvious that gaze is very stable despite destabilising inputs such as
head movements.

There are two main visuo-motor stabilising reflexes (VOR and OKN), but note that each one, especially the OKN, can be influenced by higher function.

1. VOR: Vestibulo-Ocular Reflex:

Disynaptic Arc:

Vestibular Hair Cell ...........> Vestibular Nucleus............> Oculomotor Nucleus
 

 .Short latency (Fast conduction, short axons and short latency of mechanotransduction).
 . Best at high head velocities
 . Adjustable gain
 . Cerebellum required for gain adjustment

2. OKN: Opto-kinetic Reflex (Optokinetic nystagmus)

Multi-synaptic reflex arc from direction-selective ganglion cells in the retina to oculomotor system.

 .Photoreceptors......1....>Bipolars.........2.......>Direction-selective ganglion cells.......3........>Accessory Optic Nuclei..........4......>Oculomotor Nucleus

 . Long latency (multiple synaptic station, fine axons, v. long latency out of photoreceptor)
 . Excellent at slow head velocities (accessory optic system can detect movement of sun across sky!)
 Three classes of direction-selective ganglion cells (for the three possible kinds of rotation, pitch, roll and yaw) connect to the 3 divisions of the accessory
optic system, which in term connect to the three divisions of the VOR system, one for each pair of eye muscles.
 . Provides an error signal to the cerebellum.

click here for Vestibulo-ocular reflex circuit.
 
 

Lecture 3:

Vision

Retinal Image Formation:
Cornea contributes 40 dioptres to 60 dioptres total of refractive power of eye; hence need for special optical arrangements underwater where cornea is
eliminated.
Lens is naturally elastic but in human eye is usually flattened by the tension of the zonulat ligaments so that the retinal image is in focus at infinity. During
accommodation, contractcion of the ciliary muscles acts to relieve the tension exerted on the lens by the zonular ligaments so the lens bulges under its own
elasticity to increase its curvature and bring the retinal image into focus for near targets.
Myopia. Eyeball too long for refractive power of lens and cornea; retinal image from infinity focussed in front of retina; cannot be accommodated for and is
therefore unknown in wild animals which are usually 1-2 dioptres hyperopic.
Hyperopia. Eyeball too short for its refractive power; can be accommodated since accommodation can provide an extra 10 dioptres of power.
Presbyopia. As the lens ages, it loses its elasticity. There fore a reduction in the extra lens power provided by allowing the lens to assume its maximal
curvature when the ciliary muscles act to decrease the zonular tension.
Dioptre. Lens power needed to bring rays from infinity into focus at 1m. Example: human accommodative range is normally 10d. Thus the ìnear pointî is
1/10m. In presbyopia this range is progressively reduced; with a range of only 4 dioptres the ìnear pointî would go out to 1/4m.
The Duplex Retina
 Rods Cones
One photo[pigment 560nm Three photopigments 450; 600; 650nm
0-5 log unit range of sensitivity 5-8 log units of sensitivity
Absent from the fovea in humans Concentrated in the fovea
High sensitivity, low resolution Low sensitivity, high resolution
Highly convergent pathway to bipolars  One-to-one connections to bipolars and ganglion and ganglion cells cells

Purkinje shift:
At dusk, when retinal function is shifting over from cones to the more sensitive rods, both are operational for a while. During this time, greens are enhanced
because of the greater sensitivity of the rods to this part of the spectrum. At night ìall cats are greyî because there is only one kind of rod, but at dusk, there
is just enough light for the 3 cones to signal colours, at the same time that the rods are responding most strongly to medium wavelengths, which therefore
look brighter.
Parallel Visual Processing
Vision is a complex task, whose difficulty is belied by the ease with which we appear to carry it out. The task is divided up into sub-tasks, each of which is
carried out by different classes of visual cells with different pathways. For example, at the level of the retinal ganglion cell, there are different ìtrigger
featuresî for each cell.
 

Trigger feature
The combination, in space and time, of photoreceptor activation which is necessary to activate the retinal ganglion cell. Since the ganglion cell receives a
variety of both excitatory and inhibitory inputs, a particular pattern of stimulation must be specified. This spatio-temporal pattern is the trigger feature.

Example of Trigger Feature in Different Retinal Ganglion Cells
1. Local contrast detectors (concentric, or centre-surround antagonistic receptive fields) which are sensitive to local differences in illumination but
which are insensitive to the total amount of light: these are the simplest in organisation and the most common type of feature detector in the mammalain
retina. They project into the geniculo-striate pathway.
2. Direction selective neurons: respond only to movement in a particular direction.
There are 2 kinds:
i) ON-type have slow preferred velocities and project into the accessory optic pathway: they are divided into 3 direction classes that correpond to
the 3 axes of eye rotation, semicircular canal rotation and oculomotor organisation.
ii) ON-OFF direction selective ganglion cells have high preferred velocities and project widely in the visual pathways of lagomorphs and rodents, but seem
to be absent from carnivores, ungulates and primates.
3. Local Edge Detectors and Orientation Detectors: respond to very fine detail on the far horizon. Prominent only in prey animals which scan the far
horizon for approaching predators. Project to the optic tectum. Similar orientation detectors are found in the visual cortex of all mammals.
4. Fast motion detectors: well described in the rabbit retina; respond best to low-contrast, very rapidly-moving shadows I the upper visual field. Have fast
conduction velocity into the brain where they probably trigger escape &/or freezing behaviour.
5. Luminosity Detectors ("tonic units"): respond to changes in absolute illumination, in contrast to the local contrast detectors, on account their absent
surround mechanism. Very few in number, they project into the hypothalamic suprachiasmatic nucleus where they act to synchronise the circadian clock and
into the pretectal nuclei where they are involved with pupillary control.
6. Dual Opponent Colour Detectors: Can detect a particular colour irrespective of the composition of the incident light (ìcolour constancyî). Project to
midbrain.
Targets for Retinal Information
1. Hypothalamus.
Suprachiasmatic nucleus. Circadian rhythm. Input from tonic retinal ganglion cells which signal light intensity (and therefore dawn).
2. Thalamus:
a. Pulvinar: Contributes to the "dorsal stram" of visual processing.
b. Lateral Geniculate Nucleus. Layered arrangements of hemiretinas of both eyes. Stereoscopic vision. Sandwich-like arrangement so that a toothpick would
mark neurons with projections to teh same part of visula space, even though they are on two different retinas.
Six layers in primates provide binocular interaction for different ìchannelsî of visual information such as colour, size and motion.
3. Pretectal Nuclei. Mediate the near-triad; pupil constriction, accommodation, convergence. Binocular input.
4. Optic Tectum (Superior Colliculus). Many different layers with complicated output connections mediating the orientating response. Has various maps, in
register, of visual and auditory space as well as motor maps for the production of orienting movements of the head and eyes.
5. Accessory Optic Nuclei. Three different nuclei corresponding to the three axes of rotation of the semicircular canals. Optokinetic stabilisation. Input from
3 classes of direction selective retinal ganglion cells.

Geniculo-Striate Pathway:
Highly developed in primates and the only visual pathway in most textbooks, but by no means the only one. This pathway is highly developed in those
species with frontally-placed eyes.
Retina  ..........> Lateral Geniculate Nucleus..................> Striate Cortex
Note that there is no relay in the midbrain. Note also that this pathway for binocular visual processing avoids complex feature analysis until after the
pathways from both eyes converge. In other words, of the many types of trigger feature, only the concentric (centre-surround opponency) variety (1 in the
above list) project into the geniculo-striate pathway.

Tectofugal Pathway:
More highly-specialised than the geniculo-striate pathway, with input from many of the more complicated retinal ganglion cells (2-5 in the above list) which
can directly trigger behavioural circuits in the midbrain. Massively developed in lateral-eyed animals like the ungulates.
Retina.................> OpticTectum (S. Colliculus) ...............> Pulvinar.................> Extra-Striate Cortex

Tecto-Fugal                                                                   Geniculo-striate

Extra-striate cortex                            Neocortex                            Striate Cortex

          ^                                                 ^
           |                                                              |
           |                                                              |
 
 

Pulvinar (mammals)                           Thalamus                            Lateral geniculate
Rotundus (birds)

           ^
           |
        |
Optic Tectum                                     Midbrain                              ^
(superior colluculus)                                                                        |
                                                                                                         |
           ^
           |
        |
Ganglion Cells )                                                                             (Ganglion Cells
Bipolar Cells )                                    Retina                                  (Bipolar Cells
Photoreceptors)                                                                              (Photoreceptors
 

Lecture 4:

Sleep and Circadian Rhythms      Why sleep?

Circadian rhythm does not require environmental input and is therefore predictive of light/dark cycle without need for sensory cues.
All living organisms (even cyanobacteria) have circadian clocks, to budget time effectivley, to partition rest-repair from risky exploration etc and to reduce
the need for sensory cueing about the daily cycle. Asking why one sleeps becomes a less urgent question in this evolutionary context of daily rhythms.

Transcriptional Clocks:
Mammals, flies, fungi and cyanobacteria all have transcriptional clocks that work in a similar way, although has a different pair of genes. In mammals, the
genes are per (periodic) and tim (timeless) whose transcription leads to the expression of 2 cytoplasmic proteins (PER and TIM) that dimerise to
produce a hetrodimer that binds to DNA and turns off the transcription of its own genes. It is still not clear how one generates a rhythm as long as 25
hours, but it is thought that one of the keys is the very low concentrations, early in the cycle, of PER and TIM that are under constant degradation.

                                                         Slow Wave Sleep                                                REM Sleep

EEG                                         Synchronised; sleep spindles;                           Desynchronised as in waking (hence "paradoxical" sleep
Skeletal muscle                        Relaxed but active every ~10 min                      Atonic (except for eye muscles)
Temperature Regulation           Good                                                                 Poor
Upper motor neurons               Like waking but more sluggish                         Strong synchronised bursting activity
Dreams                                    Absent (N.B. sleepwalking in SWS phase)       Dreams in this phase: majority have negative affect
Autonomic NS                        Parasympathetic system dominates                     Sympathetic activity dominates
                                                Heart rate down                                                  Heart rate & blood pressure up, Growth Hormone spurts,
                                                                                                                           Penile erection
Hemisphere active                    ?Left hemisphere                                                ?Right hemisphere
 

Thalamic Gate:
Sensory transmission through the thalamus is subject to a gate that is closed in SWSleep. The gate involves inhibitory interneurons that are held down in
wakefulness by activating systems that have an inhibitory action on these interneurons (e.g. the noradrenaline input from the locus coeruleus). With the
onset of SWSleep, the activating systems fall silent and the inhibitory interneurons escape from tonic inhibition. New ion channels also become active at
this time so that long bursts are favoured. The result is that thalamic neurns whose activity is normally desynchronised from each other by fact that they
respond to slightly different sensory stimuli, now start firing in synchronous bursts with long silent periods between. This synchronous activity gives
rise to the "spindle" that visible in the EEG,

Oxidative Damage:
Sleep is directly related to metabolism.
Birds sleep less then mammals, an apparent contradiction of the idea that sleep is related to metabolism, but note that birds also have more efficient
mitochondria (mammalian mitochondrial radical production is 3% compared with avian production of 0.3%).

Active radicals (Reactive Oxygen Species...ROS):   O- (superoxide), OH- (hydroxyl ion), H202 (peroxide).

Dealing with Oxidative Damage: 3 strategies: Quarantine; Scavenge; Repair
All radicals (ROS species) oxidise proteins, lipids and nucleic acids. Each has a slightly different pathlength within the cell before being quenched by the
tissue. There is a huge diversity of strategies that have been adopted by organisms to deal with these nasty poisons. They present a special problem for
the brain, which produces more of them than any other organ in the body by virtue of its high oxidative metabolism.  Moreover, the brain is post-mitotic
and cannot conveniently mark a badly oxidised cell for removal in the same way that occurs in liver and skin.

Here are some general principles for handling oxidative damage:-

1. Quarantine: Mitochondria can be located away from sensitive sites (e.g. spermatogonia of testis to limit damage to the germ plasm; in the inner
segment of photoreceptors away from the outer segments where oxidation of photopigment would increase noise of vision).

2. Scavenge:
A range of molecules and enzymes act to buffer the worst effects of the active radicals. The superiority of the avian mitochondrian is presumably related
to its much higher concentrations (and perhasp even novel forms) of scavengers.
Endogenous:
a. Superoxide dismutase (SOD). These metallo-enzymes come in lots of different flavours, linked to different metal ions (e.g. manganese, chromium).
The mitochondrion is packed with one version and others are cytoplasmic.
b. Glutathione (GSH). The most ubiquitous of all the scavengers and quantitatively the most important. Key role in protecting proteins from oxidation.
c. Melatonin: Very efficient scavenger of OH-. Stable, small molecule that diffuses freely throughout body. Discovered by most living organisms
(!concentrations in green leaves). Huge concentrations in young humans (more than can be accounted for by the pineal). As well as scavenging OH-,
now has a role in signalling (e.g.photoreceptor shedding, immune system upregulation) durng sleep. Amount produced falls off linearly with age.
Exogenous:
Vitamin C: Important in the aqueous medium; concentrated in skin, brain.
Vitamin E. Membrane action to guard against oxidation of lipids.
Proanthocyanidins: Like melatonin, crosses blood-brain barrier, so may be especially important for brain.

3. Repair:
Some proteins (chaperonins) may be involved in the repair of other oxidised proteins in the brain. Note again that putting damaged components into the
garbage is not always available to the brain in the same way as it might be for other tissues....hence a high premium may set on repair of damaged
components.

Adjusting a damaged (i.e. oxidised) circuit is relatively easy in some cases. e.g. the VOR is constantly being updated by the plastic mechanism that uses
visual information about retinal slip. So oxidative damage could easily be compensated, "on the run" as the brain is being used.

But note that declarative memories, many of which are one-off experiences, cannot be repaired in this way. Instead some internally-generated reference
signal (?dreams) must be generated to see if rarely-activated memories have been damaged or not. This may also necessitate that the machinery (i.e.
brain) be shut down during that time (i.e. sleep).

Neurodegenerative Diseases all involve some disturbance of the mechanisms for avoiding oxidative damage.
Friedrich's Ataxia lack's a ion pump that normall keps the mitochondrion free of ferrous ions. A high concntration of ferrous ions leads to increased
oxidative damage and death of highly active neurons in the cerebellar pathways.
Alzheimer;s Disease:
Oxidative cell death of the aminergic fibre systems (e.g. locus coerueus, raphe, basal cholinergic n.) that must supply the expanded cortex of primates
with transmitters and modulators from a cell group the same as found in rodents with a tiny neocortex.
Parkinson's Disease:
Dopaminergic cells of the substantia nigra undergo oxidative damage and death that is a long term consequence of viral infection or ingestion of toxin.
Retinitis pigmentosa involves degeneration of photoreceptors. This may be genetic (the complex biochemical pathways that maintain the high energy
useage of the photoreceptor have numerous weak links, any one of which can have a genetic predisposition to break) or environmental (~50% are not
genetic). Experimentally oxygen deprivation and anti-oxidants delay the progression of the disorder (although note that exogenous melatonin, which is
produced by the eye, seems hasten progression).
 

Lecture 5
Hearing
 
 

Hair cells evolved to detect the minute movements of fluids produced in the aquatic environment. For the detection of airborne sound vibrations in the low impedance medium of the air are matched to the much higher impedance of the fluids in which the hair cells are immersed. Since the impedance of the fluids of the inner ear is about 135 times that of air, if sound energy were presented directly via an air fluid interface, 97% would be reflected and only 3% transmitted. Because of the impedance matching function of the middle ear an estimated 60% of incident energy is in fact transmitted into the cochlea. The middle ear thus acts as an impedance transformer which depends on the fact that tympanic membrane has an area 17 times that of the footplate of the stapes and upon the fact that the long process of the incus is somewhat shorter than that of the malleus giving a mechanical advantage by extra leverage. Pressures at the footplate which are delivered to the fluid of the inner ear are therefore 22 times greater in man than the pressure of sound which moves the tympanic membrane. Conduction deafness corresponds to a defect in the middle ear and can therefore be cured by providing high pressure low amplitude stimulation directly to the bone which then drives the inner ear fluid (bone conduction). Conduction through the middle ear can also be reduced under normal circumstances by the action of the stapedius muscle which pulls on the neck of the stapes and tends to immobilise the footplate in response to sudden loud sounds.

Frequency-tuning of Basilar membrane:
Extremely sharply-localised vibration within basilar membrane (likened by Helmholtz to piano strings).
 Basal end - high frequencies
 Apical end - low frequencies
Three contributing factors:
a) Travelling wave in basilar membrane. Low frequencies travel further along membrane than high. Accounts for high to low array and for the low frequency
ëaproní of low frequency sensitivity on tuning curves of individual auditory nerve fibres.
b)  Intrinsic oscillatory properties of hair cell membrane which give intrinsic electrical tuning for frequency. This varies systematically from cell to cell.
c) Electromechanical feedback to basilar membrane motion from outer hair cells, which are motile themselves and can thereby locally increase the motion
produced by a given frequency and hence increase sharpness of tuning (probably responsible for acoustic emission or "objective tinnitus" where sound
actually emanates from the ear by a reverse driving of tympanic membrane and ossicles from inner ear motion).

A Hair cells Frequency tuning, tonotopic array
B Spiral ganglion cells Sensory relay neurons
C Dorsal cochlear nucleus Start of dorsal acoustic pathway for sound
  quality
D Ventral cochlear nucleus Start of bilateral pathway for sound location
E, F Superior Olivary Complex All cells strongly bianural
E Medial Superior Olive Tonotopic array emphasises low frequencies.
  Phase information about stimulus accurately
  preserved. Beginning of azimuthal location
  analysis based on inter aural time differences.
F Lateral Superior Olive Tonotopic array emphasises high frequencies EI
  binaural interaction. Intensity coding emphasised.
  Beginning of location analysis based on interaural
  intensity differences (in barn owl gives elevation).
G N. lateral lemniscus Relay
H Inferior colliculus Major midbrain structure responsible for
  orientation to sound. The various auditory
  pathways come together here. Complex structure
  and function combining analysis of both quality
  and location (note that these two separate analyses
  can help each other as in the ëstream segregationí
  phenomenon of sorting out individual voices
  from the babble of a cocktail party).
I Medial Geniculate Thalamic relay for the many different auditory
  cortical areas. Plays a major role in gating the
  transfer of signals to the cortex according to
  arousal state.
J Auditory cortex At least six different areas, some tonotopic, for
  analyses of sound not yet well-defined, except in
  bats where the function of each area can be
  directly related to the needs of bat (e.g. echo-delay
  area for range of prey, Doppler-shift area for
  detecting frequency-modualtion of wing-beating
  prey, etc.). In man, probably some areas involved
  in phonemic processing.

Lecture 6: Pain:

Pain:

A Definition:
Pain is an extremely unpleasant feeling, often present with nociception, that is accompanied by a strong desire to seek its termination, by long term changes in behavioural patterns (as opposed to reflex ones) and by autonomic signs of stress such as elevated blood pressure, heart rate and activation of the hypothalamic pituitary axis.

Nociception vs Pain:
A common fallacy confuses these two states. Failure to make the distinction can increase ethical dilemmas as well as underestimating the pain that can be just as distrressing to the sufferer but where there is no nociception (e.g. the pain experienced in some depressions, .......or the pathological pain felt around the edge of the region of lost sensation in paralpegics).

A  useful way to help make the distinction between nociception (sensory detection of tissue damage) and pain is to consider those cases where the is clearly pain without nociception, and conversely, those case where nociception is evident but there is no pain.

Pain without Nociception:
Mental torture is included in the UN Charter governing torture, thus recognising that pain can be produced without activating peripheral nociceptors.

Apart from mental torture, there are a number of painful conditions that arise centrally without activation of peripheral nociceptors:-
* Phantom Pain: Pain in the phantom sensation of a limb following its amputation. This usually arises when the patient has no conscious motor control over the phantom, which may, for example, be a clenched fist with the fingernails digging into palm. This link to motor output will be taken up again later.
* Somatic symptoms of depression: In severe depression, especially in bipolar disorder, there may be extreme physical pain, sometimes to one side of the body and sometimes accompanied by other symptoms that appear physical, such as  distasteful smells or physical shaking or sweating or headaches.
* Cluster headaches: Cyclically occurring, unilateral headaches that appear to originate from unbalanced activity in the posterior hypothalamic group of nuclei.
* Pathological pain/Tic Douloureux: In this syndrome, very light touch stimuli of the skin evoke agonising pain. This is more common over the distribution of the trigeminal nerve where it is called Tic Douloureux. It can also be disturbing feature following nerve injury, such as at the edge of the zone of anaesthesia in paraplegia.

Scanning studies suggest that an important part of pathological pain is activation of the right frontal lobe. The right hemisphere detects discrepancies and is activated in negative mood states (e.g. fear), in nausea and in pain. Mystics with very positive affect in spite of physical privation have intense activation of the left frontal lobe. Achieving or restoring a balance between the hemispheres can alleviate negative symptoms like pain and nausea (see thong len, a meditation for suffering, below)

Nociception without Pain:
There are many anecdotal examples.
1 Pat Wall's famous example of the WWII pilot who crawled through the jagged plexiglass window of his crashed spitfire with multiple compound fractures and lacerations, catching the protruding bone ends as he did so, to avoid the possibility of being incinerated. The process took hours until he had dragged himself safely away from the plane, which was in imminent danger of catching fire........... once he was safe and sound, hours later, then he felt pain.....switching down to the next priority after saving his life, which was to take care of the damaged body by curling up in protective agony!

2. Tibetan monk Galden Pyatso was tortured viciously by his inquisitors, virtually every day for 29 years  before finally escaping. The fury of his torturers was a product of their frustration that this monk did not obey any of the rules, with his spirit somehow continuing to fly free despite the breaking of his body. The monk's mental resistance was probably related to the 12 years experience in meditative and spiritual practice prior to his capture. The instruments of torture that he smuggled out of Tibet testify to the horror of his experiences. I do not want to imply that he was able to keep himself free of pain during this long period of torture, but I do want to emphasise the mental discipline that enabled him to resist the attempts to have him denounce his spiritual leader. There can be few Westerners who would be able to resist that kind of torture for more that a few minutes, let alone 29 years. Perhaps even more remarkable is that it is impossible to detect a bitter molecule in Galden Pyatso's being in 2003. He campaigns in an extraordinarily positive way despite his experiences and looked a picture of health despite his 72 years when I met him recently. (pics of Galden Pyatso)

These examples may seem a bit mysterious if one concentrates exclusively upon the traditional Western cultural emphasis that pain and nociception are closely linked.

3. Acupuncture:
This method of producing pain relief is very culturally-dependent. Because patients in China are usually admitted at least one day ahead of their operation to enable a good relationship to be built with the anaesthetist, there is a move in China toward the simpler Western chemical-based  methods because they require less time. Nevertheless, it is very impressive to see a huge tumour being removed through a large cut in the patient's abdomen when the only anaesthetic is a couple of buzzing needles in the chin and ear!!

Pain is in the Mind, not Out There:
In order to unify these aspects of pain and its apparent central control, it is not sufficient to consider only the pain pathways from nociceptors to the dorsal horn of the spinal cord and then to the brain via the anterolateral column. Instead, central modulation of afferent nociceptive pathways must be considered, for example via the pathways that use endogenous opiates (endorphin, dynorphin, encephalin etc). Such modulation can be the result of complex decision-making (such as the pilot who delayed pain until it was safe). Eastern thought seems to handle these issues more readily, and acupuncture, meditation, and high level interventions all form an important part of the management of chronic pain. Humberto Maturana, in his Chilean clinic, Instituto Matriztica, is having success treating pain using philosophy! By getting a family group to understand his concept of autopoiesis, Maturana can take them to point of realising that the pain is not out there on your body or caused by the world. Rather it is a consequence of the mind's activity patterns and therefore subject to the mind's own control. Getting to this point may take some time, depending on the flexibility and intellectual resources of Maturana's sufferers, but if it is reached by the joint participants in the painful situation, pain can disappear almost magically.

Nociception: = The detection of tissue damage:
Mediated by fine, unmyelinated free nerve endings. The apparent anatomical simplicity of these fibres is belied by the fact that they have much heterogeneity in receptor type. E.g. some have receptors for metallic ions, hence the greater unpleasantness of being cut by a steel knife than by glass.

Nociceptive endings are not distributed uniformly around the body:-
Dense innervation is seen:-
* Meninges (esp. dura and pia-arachnoid mater): many headaches (e.g. dehydration) are caused by stretching of the meninges as the brain shrinks (or expands). Note that the brain itself has no nociceptive endings
* Tunic of the testis
* Periosteum
* Serous mucous linings of pleura, peritoneum and pericardium
* Skin
* Cornea (one of the few sites in the body where nociception has successfully been quantified)
While the gut is sensitive to dilation, note that other forms of noxious stimulation (such as cutting and burning) are not effective.
 
 

Referred Pain:
T1  shared by heart and ulnar strip along left arm.
C6 shared by tip of R shoulder and gall bladder.

The diffuse innervation of nociceptors means that there will sometimes be confusion about the locus of the noxious stimulus in relation to other sensory channels such as light touch.

Analgesia and Anaesthesia:

Opiate Analgesia:

Ketamine analgesia:
Ketamine blocks NMDA channels and interferes with the continuous, plastic process by which one defines self. Noxious stimuli have ìsharpî connotations, but they appear to happening to someone elseís body, rather than to oneself. A very effective analgesic without the depressive side effects of opiates.

Understanding Pain at a Central level:
The phenomena of pathological and phantom pain emphasise the need to understand the central aspects of pain. The fact that phantom pain can be treated by the appropriate combination of sensori-motor stimulation emphasises the central, output or decision aspect of pain. The pilot felt pain once it was safe to do soÖ.a kind of decision-making process rather than a strict sensory one.
 

Right hemisphere Negative Symptoms: John Harris 1999 Cortical origin of pathological pain. Lancet 354: 1464-1465

Thong len: Anti-Pain Meditation:
This may take a little practice to master, especially in impatient youth, but note that some mystics do it automatically, all the time!. It is best to start with a smallish pain and work up to bigger suffering as you achieve mastery.
 If you are suffering, imagine vividly the same pain in someone else, then breath in their suffering. As you breath out, imagine light and good vibes going back to the sufferer. Keep up the cycle and you may be surprised to discover that your pain has disappeared.
The technique works in direct proportion to your ability to imagine exactly the kind and locus of your pain, but in the other person! It also helps if you know someone who is, or has, suffered in exactly that way, ......but with practice one can conjure up someone from the worldís billions who has the same pain.

Setting aside the Buddhist interpretation that you are acting as a karmic filter, the explanation for this remarkable meditation (apart from the fact that one is distracted from thinking about oneís own pain and instead acts more altruistically) may lie with the setting up of two complementary foci of activity in the brain, the negative focus on the right, and positive focus on the left, hemisphere. Hence the need to model the details of the pain exactly , but in another location. There are exact analogues of this mechanism in various nervous sytems that are designed to filter out unwanted sources of stimulation. Balancing the negative focus on the Right is easy for Tibetan monks, who have been shown by electrophysiology (Richie Davidson) to have the most intense Left hemisphere foci of activity ever recorded. No wonder they look so cheerful in the face of adversity!
 
 
 

Declarative vs. Procedural memory:
 
 

	DECLARATIVE MEMORY	PROCEDURAL MEMORY
1. Trials needed to "lay down" memory trace	Single trial memory possible (cf. iguana experiment)	Many repeat trials needed to secure memory
2. Creativity and Sensitivity of memory system	Both Creative and Sensitive: The complete memory can be recalled using only a tiny fraction of the original inputs	"Stupid" and Insensitive: Needs most of the original inputs to recall the memory (cf. riding a bike)
3. Principal mechanism of synaptic plasticity and coincidence detection	Long Term Potentiation.................LTP	Long Term Depression.....................LTD
4. Second Messenger system	cAMP	cGMP
5. Errors	Error-prone (because of 1 & 2).	Error-free (because of 1 & 2)
6. Error correction	Off-line during sleep: Difficult, especially for one trial events.  ?  during REM sleep	On line: Can occur regularly, during actions whose fidelity of execution can be judged.
7. Associated brain structure	Bilateral;; Cerebral Hemispheres (incl. hippocampus)	Midline: Includes cerebellum

 

Lecture 7: Mood, Emotion and Memory: Powerpoint File of the Lecture