Dopamine’s role in Alzheimer’s Disease

‘Neuropyrosis’ – the process which causes neuron death in depression and dementia

By Anand Madhu

• The roughly 1011 neurons in the adult brain work because they are connected to each other

• by roughly 1014 inter-neuron connections or “synapses” • The neurons’ dendrites and axons act as signal cables, transmitting information in the

form of electrical signals • Below we see a simplified example: a neuron connected to a “transport axon” which

brings in visual information from the eye

Just how leaves pick up light, a dendrite’s spine picks up travelling signals

DendriteDendritic spine

Axon terminal

The Dopamine-linked Micro-system

The Dopamine-linked Micro-system

Axon terminal

Dopamine (D) & Norepi (N)

• Dopamine (D) & Norepi (N), whose micro-systems reside in the dendrite and axon respectively, are the two most important chemicals in the brain (in the psychological frame of reference)

• The systems within which they act – may be called the Dopamine-linked Micro-system (DLMS) & Norepi-linked Micro-System (NLMS)

• These Systems have signal-modification-related (i.e. “quantum psychological”) roles – which are, for now, more interesting than their physiology.

• How do D and N work?• These two chemicals are structurally and functionally similar. • They both work by boosting (valid) signals.

D and N work by boosting Signals• As signals progress through the brain, they either die out due to loss, or, if

regarded as valid as per some biological rules, they are boosted/amplified. • This is how D or N work; they have this boosting characteristic, of which it is said:

– "Intracortical currents are triggered by the release of neurotransmitters”– “neuromodulators like noradrenaline, dopamine or serotonin have indirect modulating

effects" - Frodl-Bauch et al., 1999, as quoted in Nieuwenhuis (12).– They “enhance the synaptic responses of cortical neurons... increasing the gain of cortical

neuronal activity”, thus N “serves to amplify signal conduction" (12).

• Similar is the role of D, since D and N are structurally/functionally similar • Thus these neurotransmitters boost/amplify valid signals. • The DLMS and the NLMS have different preconditions for determining which

signals are to be boosted, as seen in my research here. • To summarize that research: the DLMS carries out what is called monoconditional

signalling, and the NLMS carries out multiconditional signalling.

Monoconditional signalling Multiconditional signalling

Monoconditional vs. Multiconditional signalling

DLMS/Dopamine’s NLMS/Norepi’s

Monoconditional vs. Multiconditional signalling

Monoconditional signalling Multiconditional signalling

Red line denotes incoming signal

DLMS/Dopamine’s NLMS/Norepi’s

Signal incoming

Weak signals come and switch on all signal traps associated with the Norepi task cycle.

Monoconditional vs. Multiconditional signalling

Monoconditional signalling Multiconditional signalling

In Monoconditional signalling, boosting activity occurs on dendritic sideIn Multiconditional signalling, boosting activity occurs on the Axonic side, maybe with the help of the Soma

DLMS/Dopamine’s NLMS/Norepi’s

Dopamine-linked-Micro-system-aided boosting activity

Norepi-linked-Micro- system-aided boosting activity

Monoconditional vs. Multiconditional signalling

Monoconditional signalling Multiconditional signalling

Blue line = boosted (stronger) outgoing signal

DLMS/Dopamine’s NLMS/Norepi’s

On the right, the number 3 is chosen arbitrarily. It is more correctly n, where n>1.

Dendritic (Episodic) Memory – an example of Dopaminic boosting

• One of the simplest forms of receptive boosting is found in dendritic memory…

• Complex forms are found in RQ-type behavioral circuits…

• Memory example: An aspect of an object (data about which is stored) is recalled – that step reflects a signal which, upon several boosting operations, causes, in turn, the recollection of the object in its entirety

The term “Receptive” depicts Dopamine’s type of activity,

due to how it exhibits a linear receptiveness to (that is,

boosting of) incoming signals

hyperlink to last viewed Slide (click only if relevant)

(1) Dendritic “Brute Force” aka Receptive transmission

(2) Axonic “Discriminating” aka Generative transmission

2 modes of boosting-aided transmission in neurons

A B

CD

A

B CD

•Signal strengths at various sites are, for example: A: weak B: weak C: strong D: strong E: strong•The axon transmits signal because the sheer strength of the signals coming from, say, C and D – rams the signal through E – the axon doesn’t fire “of its own will”… axon merely serves as a signal cable…•This is the DLMS-guided mode of transmission and, being away from the soma and more originating in spines, it can be defined as relatively more reactive to stimuli.

•Signal strengths at various sites are, for example:A: weak B: weak C: weak D: strong•This is the NLMS-guided mode of transmission.•The axon fires because the NLMS feels (somehow) the weak dendritic signals at A, B and C…. the axon fires “of its own will”, through E. Axon is also a detector, not a mere signal cable

E

Chris Chatham observes that the left hemisphere has larger dendritic branching than the right, at large distances from the dendrite’s main shaft, and the opposite trend holds at distances closer to the main dendrite. Thus, if axon terminals are more developed (e.g.: right hemisphere, or more generally in “white matter”), there is more branching closer to the soma, which supports the above diagram’s observation….

Summary - I

• Electronic circuits are a good analogy to understand how D-gates and N-gates can be variously permuted to create neural circuits which variously process information

A B C Output0 0 0 00 0 1 01 0 0 00 1 0 01 1 0 00 1 1 01 0 1 01 1 1 1

A Output0 01 1

Natural logic gates

Artificial logic gates

• Thus the brain can be defined as a package of many parallel processing networks (circuits)... each circuit is made up of Dopaminic and Norepic signalling apparatuses

Summary - II

Theneural correlates of RQ

What is RQ (Receptive Quotient)?• Certain behaviors involve more NLMSs and Norepi (and therefore

often involve more structures in the right hemisphere, where N has a majority/controlling presence)– E.g.: Logical talent is a process where a large amount of (quantitative) data is refined to get

a small amount of qualitative data – it is about extracting the logic from a bunch of data, extracting a differing logic from another bunch of data, mating the two to create a product, extracting the logic from another bunch of data, mating it with the former product etc. – it needs more Norepi’s style of working than Dopamine’s brute force way of working. It is a proven fact that Norepi and the right brain is mostly involved with the complexities of (theoretical) logical thinking.

• Other behaviors involve more DLMSs and Dopamine (and often, more structures in the left brain hemisphere)...– An example of such behaviors is analytical logic e.g.: memorization, recall etc. in the “rote”

tradition. There are many more such behaviors where DLMSs are used more.

• “RQ” (Receptive Quotient) is an umbrella term for behaviors which involve circuits with more DLMSs.

The Dopaminic/Receptive Quotient - I• Thus people vary in a “spectrum” – there are brains having more DLMSs

(high RQ) and there are brains having more NLMSs (high IQ).

A general law to identify RQ-type behavioral circuits is that such circuits are more dependent on here & now external stimuli, reflecting the nature of the Dopamine mainly involved in them.

1. An example of RQ can be seen in Obsessive Compulsive Disorder, where the person is responding to external stimuli: minute fragment of dirt, which is the external stimuli which we must look for, if speaking of Dopamine in such a case).

2. When you see people reacting to trivialities and superficialities (having a quantitative mode of function) instead of dealing with the core matters – it is an external stimuli-reactive mode of functioning, involving more of a DLMS component; and the “absent-minded professor” may be the opposite

3. The serial killer, before finalizing his target, checks a lot of things – whether or not anyone is nearby, whether or not all doors and windows are closed, whether or not a road is nearby, whether he has a spare set of clothes and so on; a stimuli-oriented way of functioning, so likely involving more DLMSs.

4. Verbal (quantitative) theory of mind involves habitually registering what is in other peoples' minds (which is external stimuli), for later usage in solution-fetching -- this faculty is very different from the Empath’s qualitative Theory of Mind

Quantitative Theory of Mind & Syllogic• Brains which “comfortably” work with higher order type of data – appear to involve more

DLMSs. • How? • Given the large amount of incoming data (“what is in the minds of X and Y and Z” and … up to

150, as per Dunbar’s theory, to 300 people, in total) – which is a big amount of external stimuli being worked on – these circuits must be having a significant DLMS component

• The circuits involved are unrelated to the logical circuit, as Brownell, Happe et al. show. Instead, hard-set, inherited neural tissues in the PFC process such information (Humphrey, Brownell et al.).

• Another example of RQ-type neural function, is syllogical faculty, which is well-developed in NLDs … In syllogical faculty, verbal “meanings” of statements are deduced out of “known verbal meanings” – it is a linear process involving quantitative signalling and thus relatively more activity of D… It uses the left brain Broca’s area… It is linked to “rote” i.e. memorization and recall, and Dopamine has been shown as linked to memorization. More support for our theory about syllogical faculty’s largely DLMS-linked nature, from how Jacobs et al. say: “Education had a consistent and substantial effect: dendritic measures increased as [formal/“rote”] education increased”.

Greek statue of a “sophist”

• If one understands how high-RQ people follow what’s in other's minds -- he will see why they -- unlike the low-RQ people called “Aspergians” -- are quicker in understanding the below cartoon --

Quantitative ToM

• or why high-RQ people may say “Sally will look for the ball in the basket”… That is because they are somewhat prone to remembering (and living as per – prophetically!) false beliefs – because remembering false beliefs is instinctively felt as profitable (in the craft of solution-fetching, the RQ-linked opposite of IQ-linked problem-solving)

More examples to illustrate the RQ-based lifestyle• Generally speaking, high-RQ people are more expected to subscribe to the stimuli-oriented policies laid out by Robert Greene in "48 laws of power”:-

• “Game theory” is defined as “the study of conflict and cooperation between intelligent rational decision-makers”.

• Above, the placement of the term “intelligent” was just a strategic façade – for, above, the definition of “rational” is stunted, thus it implies merely RQ-type rationality. Now, it is difficult to elucidate that, or how it differs from IQ-type rationality, which is relatively objective and rooted in theoretical logical talent (see paper D)

• For now, suffice to say that “Game theory” or RQ-type rationality would “rationalize” absurdities such as preemptive hostility, arms race etc.

• A rather high RQ person is needed to successfully memorize and “appropriately” apply these “ laws of power”… or is it pseudo-power??? Since true power, like that of the sun, can never be unstable – true power must be in equilibrium with its world…

• But we must reiterate, even more important than the social aspects of RQ, are the sub-logical (syllogical, to be precise), “analytic”, verbal-related aspects e.g.: increase in brain's dopamine levels causes increased talkativeness... Syllogical faculty, as in the scholar or sophist or NLD, which has traditionally donned the mantle of “left brain logic”, is a major user of DLMSs…

Is the “Pro-Dopamine” School mistaken?

• We are presented with the Dopaminergic mind hypothesis – "Dr. Previc presents the provocative theory that, approximately 80,000 years ago, high levels of dopamine led to the profound developmental leaps that most set modern man apart from his human and primate relatives".

• A different viewpoint on Dopamine seems necessary given how several disorders have been associated with excessive or anomalous Dopamine activity: Schizophrenia, Kannerian Autism, obsessive compulsive disorders, ADHD etc. A paradigm shift is required – the theory presented next sees Norepi as the primary brain neurotransmitter, and sees Dopamine as, ideally, adjunct (if king, it’s an outsider), since the brain is an organ whose rise began with rise of Norepi, whose multiconditional signalling had enabled complexities

Neuropyrosis (‘overheating of neurons’)

• The scourge of high RQ people is dementia & depression

• The Neuropyrosis theory of Alzheimer’s disease states:a. Dopamine is nearly an “alien” in the upper brain, an

organ supposed to be the home turf of Octopamine/Norepi ever since the evolution of the brain in the animant (as covered in Paper B, the New Thesis).

b. A state of excessive DLMSs in the brain causes overheating leading to dementia – and before that, depression

a.) Dopamine is alien in the upper brain• The upper brain is the natural ecology for Norepi – it can be plainly inferred from

how Norepi travels farther (right), has a greater range of operation across the brain – as opposed to Dopamine (left), whose regions of operation are limited...

Range of Dopamine

Range Of Norepi

* All the RQ type behaviors which we have studied, are mostly handled by Dopaminergic calculative areas in the Prefrontal Cortex (PFC), where an excessive role as controller played by D, as in high RQ people, is abnormal

*

• The theory of anomalous presence of D, is supported by how Morón et al. characterize the prefrontal cortex as a “region with low levels of the dopamine transporter”.

• Morón et al. note: “In the striatum and basal ganglia, dopamine is inactivated by reuptake via the DAT. In the prefrontal cortex, however, there are very few DAT proteins, and dopamine is inactivated instead by reuptake via the Norepinephrine transporter” (17). The cuckoo characteristic implies that D is thriving (in a hard-set, quasi-calculative RQ role) thanks to an advanced Norepic, upper-brain style neural ecology. The benefits availed to Dopamine are covered by Yavich et al. (18): “The DAT pathway is roughly an order of magnitude faster than the NET pathway: in mice, dopamine concentrations decay with a half-life of 200 milliseconds in the caudate nucleus versus 2,000 milliseconds in the prefrontal cortex.”

• Thus though the lower brain (caud. nucl. etc.) is the natural home of Dopamine, we cannot say that for the upper brain (e.g.: prefrontal cortex).

• Nearly more than half of the body’s dopamine is found outside the brain (governing linear processes which need only monoconditional signalling) – which reinforces the view that the upper brain is taking a “calculated risk”, in harboring D… we can theorize that problems arise due to hyperactivity of Dopamine in the upper brain, as will be discussed in the “Neuropyrosis” theory.

a.) Dopamine is alien in the upper brain

A Hypo-Norepi neurostructural ideology is associated with Alzheimer’s Disease

• Due to their similar structure and function and resulting competition for neural auxiliaries, Dopamine and Norepi exist in a Yin-Yang relationship; that is, excessive dopamine in the brain implies a low level of Norepi and vice versa………………(i)

• The increased presence of Dopamine, and lesser presence of Norepi, in the brains of Alzheimer's disease patients, is reported by Heneka et al.: “Alzheimer’s diseased individuals show ~ 70% loss of locus coeruleus (LC) cells” and “Degeneration of the locus coeruleus might be responsible for increased Aβ deposition in AD.”

Now, the locus coeruleus is directly related to levels of N in the brain; thus, as per (i), a low level of N as well as excess presence of D – characterizes Alzheimer’s disease.

How can excessive Dopamine activity be associated with AD? – The Neuropyrosis Theory

A high RQ brain, in which D is excessively present in a calculative capacity, so that there is more dendrital development (more development of grey matter i.e. dendrites mostly) – suffers damage due to overheating.

Why? A. The D-gate is the quantitative gate, the N-gate is the qualitative gate...

and under-use of the qualitative gate causes big problems.

– A brain/PFC in which DLMSs are in the majority – experiences a greater signal density because, in high RQ behaviours, more DLMSs are needed than the quantity of NLMSs needed in high IQ behaviours, because a relatively simplistic (monoconditional) and archaic (see Paper B here) type of logic gate is being overused in the architecture of the circuits. That fact implies, since each D/N task-cycle adds the same amount of energy to the total -- an overall greater energy density.

B. There is one more important reason, pictorially represented in the next slide.

Collapse of signal volume in a mostly NLMS-involving architecture vs. multiplication of signal volume in a mostly DLMS-involving architecture

• This is an indicative idea about how signal volume progressively reduces in a Norepic milieu.

• In contrast, as seen before, signal volume may progressively increase in a Dopaminic milieu.

Confirming the greater signal density in AD• The increased energy/signal density (which is, evidently, due to more dopamine task-cycles

– quantitative computation) in case of Alzheimer's disease, is discussed by Alice Walton of Forbes:

– "The famous culprit in Alzheimer’s disease, amyloid-beta plaques, is found to accumulate following increased brain cell activity. Specifically, there’s evidence that people who have more activity in their default mode networks may have increased risk for Alzheimer’s disease. As researcher David Holtzman of Washington University says, “people whose default mode networks have an average increase in activity relative to others may be at increased risk to get Alzheimer’s disease later in life... and less activity in this network, less risk.” The default mode network is associated with the dendritic aspects, as shown in paper D. That is further proof for the general theory.

• Note: The “Amyloid” debris associated with AD is particularly pronounced in the Dorsolateral PFC (Murray et al., 2012), where most of the RQ-correlated calculative neural tissues are found, and where Dopamine carries out its activity anomalously.

• The increased signal density in case of Alzheimer's disease is confirmed in how the lateral ventricles, which carry ventricular fluid to support neural activity by cleaning out metabolic waste, are enlarged in Alzheimer's disease; it once again indicates excessive electrical activity (Interestingly, the ventricles are also enlarged in bipolar disorder).

The Neuropyrosis Theory of AD• And quantitative presence of signals in the brain is a devastating thing for

brain tissue. – Each time a signal passes through a neuron, some loss occurs on the way. – This loss is converted to heat (the electrical equivalent of friction). – Greater energy/signal density implies overheating– Overheating causes neuronal collapse and "neuroinflammation" (maybe a repair

reaction) in critical areas like hippocampus (handles conceptualization), EC, PFC etc. • Effect of overheating due to excessive monoconditional signalling activity:

Thus, just how a piece of thermocol rapidly shrinks if exposed to heat, or how the plastic covering of an electrical cable melts if too much current passes through it – hyper-signalling associated with the nature of hyper-D – destroys the substrate (neuron dendrites & axons).

Depression• Dementia is bad by itself. But what is worse about the neuropyrosis process, is

that those who suffer Alzheimer's disease – also seem to suffer depression. • Since similar observations are made in depressed and demented brains: “Default

mode network shows greater activity when depressed participants ruminate” (22). Further, Depression involves enlargement of lateral ventricles (23), like AD.

• “Studies have shown that high concentrations of the neurotransmitter Norepi leads to feelings of elation and euphoria (extreme happiness) (Franken, 1994).” This proves that depression is linked to a DLMSs-majority state of brain circuits.

• The idea that a hyper-DLMS state causes Alzheimer's disease, is confirmed in how, "In Alzheimer's disease (AD), brain atrophy has been proposed to be left lateralized" (19) (more atrophy in the left hemisphere) – in the light of the detail that the left hemisphere has DLMSs in majority relative to the right hemisphere.

• In the neuropyrosis-suffering brain, the overall process doesn’t involve qualitative areas (like the NLT-area), and therefore quantitatively burdens critical areas (e.g.: hippocampus) – which, like over-burdened marchers, might hold up the brain as a whole, leading to motivation deficit, fatalism, pessimism etc.