Numerous definitions: Note that Tibetan Buddhists describe at least 7 different levels of consciousness, from wakefulness (ìcoarse mindî) to ìthe very subtle mindî (ìClear light consciousnessî) The latter appears to persist for days (or even weeks in the most accomplished meditators)  after breathing and the heart stop (?low level neural activity still present, as the mediastinum stays warm during this time).

 
The Neural Operation of Consciousness: (after E. Schrodinger ìWhat is Life?î:
The neural conjunction of what IS, with what is EXPECTED TO BEî.  Fig. 1.

* Highly integrative
* Graded (Many levels from ìCoarse Mindî to ìVery Subtle Mindî)
* Memory and Plasticity
* Neural Timing
* Emotion and Motivation
* Sleep/Wakefulness

In this lecture, consciousness will be considered in two related contexts (according to JDP : cf. Viewpoint in Resource Description that separates these).:-

1. As in ìLoss ofÖÖÖ.î
a. General anaesthesia
b. Head injury
c. Hypothermia
d. Syncope

In the class I will survey how many have experienced this disturbance of consciousness, with the resulting gap or rearrangement  in experience, in memory, in time perception, in emotions etc.

2. As in ìAltered states ofÖÖÖÖî
a. Individual variations in consciousness: e.g. of time; fast vs. slow switchers (Demo. in lecture)
b. Drug-induced
 i. Psychedelics such as LSD; phenylethylamines such as MDMA: 5HT  system
 ii. Dissociative anaesthetics: NMDA receptor blockers (e.g. Phencyclidine, Ketamine).
 iii. Opiates: Endogenous opioid receptor activation
 iv. Cannabis: Endogenous PUFA system (anandamide)
 v. Muscarinic ACh receptor system: ìTwilight sleepî of scopolamine (muscarinic antagonist)

2a. Perhaps the greatest failing of modern medicine, particularly in psychiatry, is the ìone size fits allî approach that assumes a commonality of conscious experience when there is in fact wide variation, even amongst ìnormalî humans. I will try to bring this point home using some demonstrations of perceptual rivalry switching (presumed interhemispheric switching) and colour perception, where it will be made obvious that everyone in the class has a different conscious experience of the SAME visual input. This leads to a philosophical problem that is central to, but glossed over by, modern psychiatry:- viz:- ìconsensus realityî . (How many modern equivalents are there of Bruno, who was burnt at the stake for his veridical view of the solar system because it conflicted with the consensus view of authority at the time).

Why Slow Switchers are More Sensitive:
The risk of substance abuse is greater in the more sensitive, slow switching phenotype, for a variety of interlinked reasons. Greater sensitivity means greater effect of the ligand or signaling molecule on G-protein signaling pathways (e.g. bipolar individuals have 6-10X the amount of light-induced suppression of melatonin, a G-protein-linked 5HT receptor effect in the pineal). This order-of-magnitude increase in sensitivity means a greater risk of addiction that goes along with the bigger ìhitî, but also explains the propensity of these individuals to excel (e.g. Winston Churchill, a famous but often unrecognized bipolar,  could see light at the end of the tunnel in the Battle of Britain when the rest of the population could not see any light at all!). Greater sensitivity can also lead to the use of substances, famously ethanol, to blunt inputs from an overharsh and unfeeling world, most of whose inhabitants may indeed not understand the problem, given that they need a 10X larger stimulus for detection
 

JDPís Synthesis of the Neural Machinery Underlying Consciousness and Unconsciousness:
A working hypothesis that accounts for most observations about the chemical basis of consciousness places the focus of attention on the neuromodulatory executive systems of the brainstem, particularly the interconnected VTA (ventral tegmental area) [dopamine],  raphe [5HT] and locus coeruleus [NA]. It is hard to separate these interconnected systems, particularly as the brain seems to use a contrapuntal interaction between the catecholaminergic VTA and LC systems and the indoleaminergic raphe systems. Some of the most potent drugs simultaneously influence all systems, such as LSD, whose ìdirtyî action on a variety of receptors at the same time (5HT 1a and 2a agonism, NA agonism) may explain its high potency in producing disturbances of consciousness. In the lecture I will focus on the Dopaminergic VTA, whose complex chemistry and neurobiology seems better capable of explaining many aspects of consciousness so long as it it seen to be imbedded within the ìcore machineryî that includes the contrapuntal 5HT system.

Neuromodulatory Executive Systems:
Brainstem (ìreticular formationî in older text books) neurons that project ìEVERYWHEREî  and must therefore be involved in a high level executive decision. This system cannot be involved in the specific details about this or that sensory event or motor act, except in relation to a context or outcome. Executive systems are thus too general (global, integrativeÖÖ..there is only one body, so at some point that has to integrative machinery to provide a single outcomeÖ.hence the difficulties of describing what consciouness is and doesÖÖîunity from diversityî). Describing these systems with words is problematicalÖ.(not that this stops the pigeon-holers and list-generators!). They are core functional systems of the brain. As a result, they affect core functions such as:-
* motivation (approach-avoidance, addiction etc),
* emotion (see Damasioís ìLooking for Spinozaî for a readable account of emotion as the irreducible core of brain function,Ö. as opposed to an add-on extra, like an ìemotional lobe of the brainî that can be localized and treated separately),
* wakefulness (hypothalamic suprachiasmatic nucleus gates VTA-mediated arousal via orexins).
* memory (core executive neuromodulation includes the gating of plasticity, such that whole cortical memory systems can be switched on, such as dopamineís action in regulating NMDA receptors into the ìUPî state).

Neuromodulation implies that effects are more than would be expected from the direct effects of a neurotransmitter at a synapses. Neuromodulation has the following features distinct from conventional neurotransmission:-
a. Widespread action beyond the point of release: e.g. CSF-borne neuromodulators can reach all the surface neurons of the brain, so that in sleep, for example, sleep peptides act like hormones to trigger the shift.
b. Specificity depends upon the receptor system involved and does not require physical wiring: This is a corollary of (a) and helps to explain why there are so many different signaling molecules. If it all depended on the wiring of excitatory and inhibitory connections, only two different molecules would be involved. The endocrine-like aspect of neuromodulation also explains why it is extremely rare for any therapist to intervene by injecting a molecule into the cerebral milieu. There is tough legislation that prohibits this in the US, based upon the recognition that the brain is not just a telephone exchange of specific wiring, but a neurohormonal system immersed in its own milieu, which we should not attempt to manipulate pharmacologically, except with extreme trepidation.
c. Time course can be exended, to minutes, hours, days and even longer: Neuromodulation explains how neurons with action potential lasting only a millisecond or so can control behaviours with time-course measured in hours.
e.g. dopamine will uncoupled connexin molecules so that autologous neurons are no longer electrically coupled. This occurs via a camp-gated second messenger system that phosphorylates the connexins so that they uncouple. The change will be very long-lasting because it involves structural changes in the neurons that are triggered by the neuromodulator.
Current research may reveal the neuromodulatory systems that re linked to memory and plasticity. We already know that catecholamine neuromodulators (NA and DA) are necessary for some kinds of learning and memory in the neocortex and olfactory system.
When such a system is active, the subjective state we experience is likely to be strongly affected. In fact, as formulated by Seymour Kety, the strong feelings we experience at key moments are epiphenomena that reflect the activity of these systems.

For example, if you have just been chased by a lion, the intense feelings are connected to the recognition by the executive that the moment is important for survival. The widespread diffuse projections of the LC will be augmented by catecholamines that diffuse to their site of action as well as being released at noradrenergic terminals originating in the LC. By ìbringing the whole brain to attentionî this system increases its plasticity (NMDA receptors into UP state) and so makes it more likely that any small sensory cue will be memorized and thence be available at some future encounter with the lion. [ Try to recollect your most vivid memory: I think that you will find that it occurred in a situation of great emotional impact and significance, such as a traumatic or sexual one). In contrast, if you are lying on your cave floor, safe, sound and gastronomically and sexually satisfied, it does not seem particularly adaptive to memorise every contour and crack on the ceiling. The reduced plasticity in this situation is the result of greatly reduced activity in the catecholaminergic executive systems (LC and VTA). In sleep they cease activity altogether.
2. Relevance to this weekís PBL:
The plasticizing effect of memory systems of the DA and NA systems of VTA and LC respectively, is highly relevant to drug addiction, since these systems are firing strongly in the lead-up to a fix (Note that ìcold turkeyî is a classic catecholamine syndrome, with skin vasculature and pilo-erection, cardiovascular changes etc). For this reason, all of the sensory-motor context leading up to the ìfixî will be strongly ìwired inî by the repeated intense experiences that preceded the fixes. This has to be borne in mind in rehabilitation, since ìdrying outî and removing the physical and pharmacological effects on the brain will still leave intact all the circuitry of ìmemoryî preceding a fix. This wired in circuitry would have to be replaced (in similarly exciting conditions and similar repetitions) if the old behaviours are not to be re-initiated the next time the ìrehabilitatedî person finds themselves in the old prelude situation.
 

GABA Receptors:

Many anaesthetics act upon the GABA A receptor. Since this receptor is the most widespread inhibitory receptor in the brain, general anaesthesia might be the collective action of the anaesthetic action of the widespread inhibitory synapses. JDP would argue that it is also likely that the this action is mediated via the GABA receptors in the LC and VTA, whose intense activity would thus be reduced. Either way, you need to know about the GABA receptors.
* 7 or more genes!! For the subunits. Unexplained diversity.
* Large protein with many allosteric sites around the central Chloride ion channel
* 3 potentiating sites: GABA-induced Inhibition is increased when these sites are occupied. Note that all man-made ligands for these sites are general anaesthetics.
i. Benzodiazepine site: Anxiety-related endogenous ligand still not known
ii   Barbiturate site: Endogenous ligand not yet identified
iii  Steroid site: Testosterone metabolites believed to be the endogenous ligands. Note interaction with oestrogens via aromatase.

Ethanol and gas anaesthetics also interact with the GABA receptor (to potentiate GABA action).
* 2 antagonistic sites: Binding here decreases GABA-induced inhibition:
i. Picrotoxin/bicuculline site
ii    L-barbiturate site: Yes, stereoisomers of barbiturates can be convulsant instead of sedating!!
 
 

 
Desferrioxamine Coma:
This bizarre state is illustrative of both our present ignorance of the fundamental machinery of consciousness, but also of the key role that must be played in consciousness by redox chemistry and by energy metabolism.
What is it?
Desferrioxamine is a heavy metal chelator with a very high affinity ofr Fe2+ and Mn2+ ions (Km = 10 <-9>). It has been used without side effects to treat hemosiderosis, malaria, and rheumatoid arthritis.
Chloperazine and chlorpromazine are neuroleptics that act on the D2 dopamine receptor to produce a mild tranquilliser effect at moderate doses.
In combination with desferrioxamine, a low dose of a neurolept that would produce no noticeable effect, results in a deep coma that lasts for about 3 days, during which the patient is unresponsive even to strongly nociceptive stimuli!! On recovery from the coma, these patients can have retinal lesions.
?Explanation:
VTA has the highest concentration in the brain  of the enzyme glutamine synthetase, a Mn2+ enzyme that is inactivated by heavy metal chelators.

Neurotransmitters, neuromodulators, receptors, drugs and cell biology affecting consciousness:
1. GABA: GABA A receptor: Benzodiazepines, barbiturates, steroid anaesthetics, ethanol, inhalation anaesthetics
2. Glutamate: NMDA receptor: Ketamine
3. 5HT: 1a and 2a receptors: SSRIs, LSD, MAO inhibitors etc.
4. DA: D2 autoreceptors: Neurolepts
5. Endorphins: Mu opoid receptors: Naloxone.
6. Acetyl Choline (via Raphe): Nicotine:
7. Anandamide: Cannabis
8. Orexins: [Peptides: Link to hypothalamic circadian and appetite system; no drugs yet]
9. Retinoic Acid: Isoretinoin (Roaccutane). [Note that VTA and other Limbic areas are the only parts of the ADULT brain that express retinoic acid].
10. Connexin: [Intracellular proteins implicated in anaesthesia from Drosophila mutants]