This is a video uploaded on 8th July, 2023.  If you are new to this website, then please read this front (home) page and FAQ section of this site before watching.   An explanation for associative learning in terms of semblance hypothesis    Video  (Note: Qualia of inner sensation is estimated by a retrograde extrapolation from postsynaptic terminal D towards the sensory receptors. Even though it is shown as part of the video for demonstration purpose, there is no back propagation of potentials in that direction. Generation of inner sensation is a system property of systems that has oscillating extracellular potentials whose vector components are contributed by synaptic transmission across synapse A-B & propagation of potentials along the inter-postsynaptic functional LINK B-D in a perpendicular direction to the synaptic transmission). This video provides an explanation for changes that occur when sound & foot shock are associatively learned. It then explains how sound alone (after learning) triggers inner sensation of memory of foot shock & cause foot withdrawal. Neutral sound is the conditioned stimulus (CS). Aversive foot shock is the unconditioned stimulus (US). Both reaches neurons of Lateral Amygdala (LA). Certain learning-change is expected to occur at locations of their convergence in LA. After associative learning between sound & foot shock, sound alone causes an inner sensation of foot shock & triggers foot withdrawal. A testable explanation for a link between pathways of sound & foot shock where they converge in LA is expected. At the location of convergence, sound should specifically generate inner sensation of foot shock (in the absence of foot shock). This is like a sound-induced hallucination of foot shock. Marvin Minsky gives us some guidance (see the link below). https://onlinelibrary.wiley.com/doi/abs/10.1207/s15516709cog0402_1 Questions are a) "Is there a suitable location where hallucinations can be triggered by sound during memory retrieval?" b) “What are the pre-conditions that set a stage to trigger hallucination of foot shock when sound arrives?” This can be explained using two examples. a) Initial patting followed by tapping with increasing intensity over a neck vein enables a veterinarian to suddenly place a needle in between the fingers of the tapping hand to get inserted to that vein without notice. b) It is easy to get pickpocketed while climbing stairs (e.g., in a railway station) since the gluteal region is constantly moving. From both, it is possible to insert/remove something in a continuous sequence of events in a system without system’s notice. In both cases, newly inserted stimulus is perceived as one of the frequently occurring events. i. e., the newly inserted stimulus leads to a hallucination (at the location of insertion) that it is receiving a usual stimulus that has been occurring prior to it.   A postsynaptic terminal (spine) is continuously being depolarized by quantally released neurotransmitter molecules (NTMs) from its presynaptic terminal. When an action potential arrives, the latter releases a volley of NTMs to trigger a large postsynaptic potential. For a postsynaptic terminal (spine), it receives inputs from its presynaptic terminal all the time & sometimes from the environment via its presynaptic terminal (until learning occurs). This is the dominant state of the system. In the above contexts, if learning cause formation of an electrical link between spines to which associating stimuli arrive, then we can examine whether it will facilitate a mechanism for memory retrieval. Later, arrival of one of the associatively learned stimuli through the link that reaches the lateral side of the spine (and depolarizes the entire spine) to which the second stimuli had arrived during learning will be perceived as if the second stimulus has arrived from its presynaptic terminal. This forms the basis for a hallucination. In other words, depolarization of a spine from its lateral aspect tricks the latter to hallucinate that it receives an input from its presynaptic terminal (from the environment).   Since mean inter-spine distance is more than mean spine diameter https://pubmed.ncbi.nlm.nih.gov/12838576/, the above link is expected to occur between spines that belong to different LA neurons. The potentials elicited by sound propagates through the link to reach the postsynaptic terminal through which shock arrived in the past to trigger hallucination (inner sensation) of shock. Potentials then propagate further to trigger foot withdrawal. There should be a mechanism to integrate units of inner sensations originating at many nodes of convergence to cause inner sensation of foot shock. The brain functions only in a narrow range of oscillating extracellular potentials. At the location of a link generated between spines through which sound & foot shock arrives, depolarization propagates in perpendicular directions - through synapse A-B (see video) and link B-D. These can provide vector components to oscillating extracellular potentials. Thus, we have a mechanistic explanation for a testable change that occurs during associative learning & a mechanism for cue-induced cue-specific hallucination that generates inner sensation of memory of foot shock & foot withdrawal.

If you are new to this website, then please don’t read content in this box first. Please read about the hypothesis and come back here. A new explanation for flash-lag effect using a testable mechanism for first-person inner sensation of perception When a flash is briefly presented in a specific location adjacent to the path of a uniformly moving object, the former is perceived to lag the latter. Different experimental conditions carried out to qualify this flash-lag effect (FLE) have led to several seemingly unrelated first-person reports from which several constraints are available to synthesize a testable mechanism for FLE. Using a derived mechanism for the generation of first-person internal sensation of perception, present work provides new interconnected explanations for disparate findings associated with FLE. By verifying testable predictions arising from the hypothesized mechanism of first-person inner sensations, it may become possible to understand timescale-matched neurobiological changes responsible for perception. Article

If you are new to this website, please don’t read content in this box first. Please read about the hypothesis and come back here. Golgi staining of neurons: Oxidation state-dependent spread of chemical reaction identifies a testable property of the connectome Abstract: Camillo Golgi observed reticular nature of the nervous system by his staining method. Ramón y Cajal modified this protocol and obtained staining restricted to individual neurons, which was in agreement with the cell theory. Close examination shows that Golgi used an oxidizing agent to pre-treat the brain tissue before the staining reaction and Cajal used an additional oxidizing agent for the same step. It shows that oxidation state of the tissue has a crucial role in determining the spread of Golgi chemical reaction between neurons. Since a) dye injected into a neuron spreads only within that neuron's cytoplasm, and b) it is possible to grow individual neurons in primary culture, oxidation state-dependent spread of chemical reaction should take place through a gate while keeping the cell membrane intact. This gate should prevent mixing of cytoplasmic contents between neurons. These constraining features guide towards the solution where formation of such a gate between spines of different neurons is a suitable mechanism that can take place during learning. As long as this gate exists, it should allow propagation of depolarization from a cue stimulus across the gate and provides options to a) generate internal sensation of associatively-learned item, and/or b) provide potentials to cross the threshold to fire neurons to generate motor action reminiscent of the arrival of associatively-learned second item. These constraints led to the derivation of a crucial connection that can define the connectome. Matching findings from Golgi staining indicates that this gate is an oxidation state-dependent reversible connection of the connectome. All these findings are testable. Article

 

In simple words, what is semblance hypothesis? Systems in the body are being studied by observing them from outside (e.g. pumping of the heart, filtering by the kidneys, structure of DNA and synthesis of proteins). Third-person approaches are suitable for their studies. In contrast, functions of the nervous system such as perception and memory are first-person inner sensations (within the "mind") to which only the owner of the nervous system has access. But, we have been studying these functions by examining the nervous system from outside using third-person approaches at various levels (biochemical, cellular, systems, electrophysiological, imaging, and behavioral) and we were trying to find correlations between these findings with an aim to understand the system. By these approaches, the first-person internal sensations of different higher brain functions have been remaining unexplored. Reality is that the examiner should become an insider in a subject's nervous system (and become part of the system) to sense the first-person internal sensations! This is not practically possible. This means we are facing a brickwall in our current approaches to understand its operations. This can be overcome by undertaking a theoretical approach. Since a universal operational mechanism is expected to be present in the nervous systems of different animal species, we should be able to find it without much difficulty if we are on the right path. We had no previous experience of searching for a biological mechanism that gives rise to virtual first-person inner sensations. This should not hinder our efforts in any way. In fact, we must prepare ourselves to look for a unique mechanism that has the ability to evade our attention! By keeping these in mind, a theoretical examination was carried out to arrive at a specific location where such a unique mechanism can be expected to take place. Further examination of this location has enabled identification of a set of unique features necessary for a feasible operational mechanism whereby the system can generate units of inner sensations at specific conditions (that are physiologically present). This mechanism is expected to interconnect all the findings made by third-person approaches at different levels. Until now, results using this observation are able to explain and interconnect a large number of findings from different levels. Pathological changes of this cellular mechanism can explain several neurological and psychiatric disorders. Predictions made by this hypothesis are testable.

Is there a different way to view semblance hypothesis? In order to understand the brain, we must understand how it's unique function – generation of first-person internal sensations of perception, memory, and thought processes is taking place. Associative learning between two stimuli is expected to produce certain changes (in a few milliseconds (see FAQ for explanation)) that allow one of the associatively learned stimuli (cue stimulus) to generate the internal sensation of memory of the second stimulus (also, in a few milliseconds). For this to occur, changes during associative learning are expected to take place at the locations of convergence of sensory stimuli within the brain. Here, we need to ask the following questions, “Is there a possible cellular location where the processes of neurons through which associatively learned sensory input signals arrive can converge and make some signature changes during learning?" "If associative learning can produce certain changes at this location (in a few milliseconds), can it be used by one of the stimuli (the cue stimulus) to generate internal sensation of memory of the second stimulus (in a few milliseconds)?” “At what structural location and by what mechanism does the cue stimulus spark internal sensation as a first-person property?” “What is necessary to spark internal sensation?” “What is the basis of sensory features or qualia of internal sensation?” “What holds the system together so that the internal sensations generated from different locations of convergence of sensory stimuli can allow the cue stimulus to generate first-person internal sensation of the second stimulus?” "How can the mechanism that holds the system together relates to the narrow range of frequency of oscillating extracellular potentials (as evidenced by EEG findings) at which both learning and memory retrieval take place?" "In other words, is there a mechanism that integrates internal sensations induced at different points of convergence to provide memory?" "How does the mechanism of generation of internal sensations relate to behavioral motor activity?" “Can the derived mechanism be extended to explain different brain functions in an inter-connectable manner?” If we look hard enough, we are expected to find a mechanism that can explain all the above features at the location of convergence of sensory input signals. When an inquiry was made to solve this puzzle, it was possible to derive a solution. This testable hypothesis was named semblance hypothesis.

Is it possible to explain semblance hypothesis by yet another way? Studies of the nervous system have been facing three major challenges. 1) Due to limitations of methods that can be used to understand memories in their true sense as first-person internal sensations, memories have been studied using their surrogate markers such as speech and behavioral motor activity. 2) Current investigations are primarily based on the following postulate made in 1949 by Professor Donald Hebb. "When an axon of cell A is near enough to excite a cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A's efficiency as one of the cells firing B is increased" (Hebb D. O. The organization of behavior. New York: Wiley & Sons). Modification of this postulate is generally known as synaptic plasticity thesis. Until now, this thesis was not able to provide a mechanistic explanation how learning-induced changes are used for the generation of inner sensation of memory. 3) Behavioral markers of memory retrieval are being correlated with the firing of a set of neurons with the hope to understand the mechanism. The fact that only a minor fraction of input signals (nearly 140 input signals that arrive from different locations on the dendritic tree) can fire a cortical neuron having thousands of input terminals (dendritic spines where postsynaptic potentials are generated) (Reference) shows extreme degeneracy of input signals in firing a neuron (Reference). Input signals (postsynaptic potentials) attenuate as they propagate towards the neuronal cell body. Since many neurons are being held at sub-threshold activation state at rest, it is possible that even fraction of one postsynaptic potential can fire a neuron from its resting state. In these contexts, to avoid loss, information storage most likely taking place using a mechanism occurring at the location of origin of postsynaptic potentials (input signals). This storage mechanism is also expected to provide an explanation how first-person internal sensation of memory is generated. In the past, we kept certain notions such as 1) operating mechanism is occurring at the synapses, and 2) a neuron is an operational unit of the system. Those notions were necessary to initiate experimentations. Since we have already spent enough time to test those ideas and since we are not approaching towards a foreseeable solution, we should try to find testable solutions to understand how the first-person inner sensations of different higher brain functions are generated. During the last several decades, we have made very large number of observations at different levels of the nervous system. Now, we are in a position to use constraints available from all these observations to try to derive a theoretically-fitting testable mechanism that can explain how first-person internal sensations are being generated. If successful, this will provide a solid scientific basis for the mechanism that we are seeking. The mechanism is expected to operate in synchrony with the synaptically-operating nervous system and occur at physiological time-scales of milliseconds. It is also expected to operate in agreement with the observation that there is a huge redundancy of input signals that can fire a neuron. If a hypothesis can explain all the features of the system in principle, then we can start verifying both its structural features and predictions. Semblance hypothesis resulted from this approach.

Can we explain semblance hypothesis by a fourth method using some pictures? The unknown mechanism is shown as a black box in Figure 1 below (Note: After reading this and FAQ page of this website, one is likely to understand the contents of this black box, which can be subjected to further verification).

                                       

Figure 1. How to solve the black box of the nervous system? Let us imagine about associative learning between two sensory stimuli in a learning event. Stimulus 1 and Stimulus 2 activate their corresponding sensory receptors and the stimulus-induced depolarizations propagate through their synaptically-connected neuronal paths (Neurons along the pathways of Stimulus 1 Stimulus 2 are marked N1 to N5 and N6 to N9 respectively). We want to know where and what type of a change occurs during learning. What is expected is that when Stimulus 1 arrives after learning (as a cue stimulus), it should be able to generate an internal sensation of features of Stimulus 2, which we call as memory of Stimulus 2. From the above figure, it is reasonable to expect certain changes at the location of convergence of Stimulus 1 and Stimulus 2. From the figure, we can ask "Where does neuron N9, through which Stimulus 2 arrives, meet with the pathway through which Stimulus 1 arrives?" The learning mechanism at the location of convergence should also explain how the cue stimulus (Stimulus 1) can produce behavioral motor actions reminiscent of Stimulus 2. If we can provide explanations for these, then we are moving in the right direction for solving the nervous system. Previous studies examined both 1) changes occurring presumably in all the synapses along the pathways through which both Stimulus 1 and Stimulus 2 propagate during learning, and 2) a cluster of adjacent spines on a neuron (for example, on a dendritic branch of neuron N5 where Stimulus 1 (cue stimulus) arrives) with the presupposition that single neurons have the capability for information storage. During memory retrieval, previous studies tried to correlate the changes at the synapses following learning with behavioral motor actions indicative of memory retrieval. But these studies did not search for a mechanism of generation of first-person internal sensations of memory. To understand its operational mechanism, our task is to use all the available information and examine the exact location where and how the learning-change is occurring that allows one of the stimulus (cue stimulus or here, Stimulus 1) to spark memory of the associatively learned second stimulus (Stimulus 2) in physiological time-scales of milliseconds along with provision for generating behavioral motor actions. Note that neuron N5 has two dendritic spines on its dendrite. Also note that inter-spine distance (mean) is more than the mean spine diameter. Our task is to discover where the interaction between pathways through which Stimulus 1 and Stimulus 2 propagate. In other words, we have to discover where and at what level the connections from neuron N9 will interact with the path through which Stimulus 1 propagates. Later, on arrival of Stimulus 1 that learning-induced interaction should be able to exhibit a unique mechanism to generate units of first-person inner sensations of memory of Stimulus 2. When the interaction remains only for a short period, it should be responsible for generating working memory. It is also expected to have the capability to get stabilized for long duration responsible for generating long-term memory. Inset: A synaptic junction between neurons N4 and N5 (marked Pre 1 and Post 1) along the path through which Stimulus 1 propagates is shown. The still unknown mechanism is shown as a large black box next to the synaptic junction. To decipher the secret, it is necessary to view memories as first-person inner sensations generated within milliseconds. Since learning can occur in milliseconds, it is also necessary to search for a learning mechanism that occurs in milliseconds from which memories can be generated. Semblance hypothesis has provided a solution for the contents in this black box that can explain how 1) the association between Stimulus 1 and Stimulus 2 is stored specifically and "completely" during learning within milliseconds, and 2) at a later time when the Stimulus 1 arrives (as a cue stimulus) how it generates internal sensation of memory of Stimulus 2 as a first-person property within milliseconds, which can only be accessed by the (owner of the) system. It can also explain how the Stimulus 1 (cue stimulus) can generate motor actions reminiscent of the arrival of Stimulus 2 as expected of a conditioning paradigm. In addition, it provides explanations for a large number of features of the system observed at different levels. It is hoped that the readers will be able to find a testable mechanism by the end of reading this page and FAQ page of this website. This hypothesis has made several testable predictions.

There are several unsolved problems in neuroscience (Adolphs, 2015) and they have been observed from different levels (Edelman 2012; Gallistel & Matzel 2013). Nervous system functions observed at different levels are being studied by different faculties of science - biochemistry, cell biology, electrophysiology, systems neuroscience, psychology and consciousness studies. The system is similar to a puzzle lying in multiple dimensions. Solving it requires finding the correct pieces of the puzzle at the right level with the right operational function. If we examine only one or a few levels of the system, we might arrive at certain solutions that will allow fitting together pieces of the puzzle only for those few levels. Features of the unexamined levels will most likely remain unexplainable and we won't find the solution for the system. Diverse nature of findings from different levels strongly indicates that the solution is going to be a very unique one. At the same time, it is also expected to be a simple one. In order to solve the system and find out the correct mechanism, it is necessary to simultaneously examine representative functions from all the levels.

   A second view of the problem can be described as follows. It begins by examining the following situation: The heart pumps the blood and the kidneys filter the waste materials from the blood; these functions are observed by us from a third-person perspective. We understood their functions quite well, as evidenced by our ability to develop methods to replace their functions - using artificial heart and dialysis. What functions does the nervous system carry out? Knowledge of the function of the brain that is essential for replicating/replacing it? Brain generates an inner sense of the external world during perception, stores sensory information by associative learning and later produces the internal sensation of retrieved memories of the learned item when the associatively learned cue stimulus arrives, induces thought process to connect different items from different sets of learning events – all of which are first-person properties that cannot be accessed by third-person observers. The only sensory stimuli from the owner of the nervous system that are available to a third-person are from the surrogate markers consisting of motor activity - specifically, speech and behavior. Therefore, the pieces of the puzzle mentioned in the above paragraph should be capable of explaining both first- and third-person accessible functions.

 

   A third view of the problem becomes evident when examined from the viewpoint of a builder. Here, the job is to replicate the nervous system in an engineered system. Since intentionality to feed and carry out all the actions for survival and reproduction are present even among the members of lower level animal species, a robust evolutionarily conserved circuit mechanism for generating internal sensations is expected to be present in all the nervous systems. Since the first-person properties cannot be accessed by third-person observers, they cannot be studied directly using biological systems. Hence, we should keep replication of the mechanism in engineered systems as the gold standard proof. These systems need to be built to provide readouts for the first-person internal sensations that can be accessed by the third-persons. As a builder, we will feel the pressure to know how the system can operate to generate different functions. We are forced to speculate all the possible mechanisms and figure out the correct one. We will be concerned mostly to explain the formation of internal sensations in physiological time-scales. Before building the system, we need to draw a sketch of the systems operations.

 

A fourth view becomes possible by observing the “loss of function” states of the system occurring at various levels. This can help understand the nature of the pieces of the puzzle. Early genetics research has gained valuable information from "inborn errors" of metabolism that provided guidance to understand the allelic organization of genes. In this context, examining the neurological and psychiatric disorders can help to understand the nature of the operating mechanism. Since the exact pathological features of many of these diseases are not yet known, it is expected that the loss of function of the operational units that induce both the first-person and third-person features is expected to provide information about the pathologies from which the function can be verified.

 

Large number of features observed by different subfields of neuroscience and psychology are required to be explained by a solution for the system. Since these features are very diverse, only a unique cellular mechanism will be able to explain all of them. This unique mechanism is expected to be a unique structure-function mechanism occurring at the intersection between the third-person observed features and first-person properties. In other words, it is a dynamic, but stabilizable structural feature that can provide basic units of first-person internal sensations of different higher brain functions. It is necessary to verify whether the derived solution can explain findings from different specialized faculties within the large fields of neuroscience and psychology and test whether the explanations are inter-connectable. Since our current research efforts in each field are moving towards more specialized and super-specialized areas, finding and verifying the unique solution (to put the pieces of the puzzle together) require an effort in the opposite direction. Anticipating this is the most important requirement for solving the system. It is necessary to explain how the nervous system functions occurring at different levels, such as - a mechanism that directs potentials to induce the internal sensation concurrent with the activation of motor neurons at physiological time-scales (interconnecting central mechanism), dendritic spine changes, long-term potentiation, place cell firing, consolidation of memory, and association of memory with a feasible framework for consciousness - are interconnected.

 

For arriving at an operational mechanism that can explain both third-person and first-person properties, a theoretical approach is the most efficient method. Among different brain functions, memory has the advantage that experiments can be carried out both to associatively teach the system and verify the theoretically found learning-induced changes and understand how they are used during memory retrieval. Very large amount of experimental data is available in the field of memory research. Since no cellular changes are observed during memory retrieval, the memory retrieval is likely taking place by a passive reactivation of a learning-induced change. Memories were classified into working, short-term and long-term memories based on the differences in the period of time, following learning, during which they can be retrieved. Studies have been carried out with the assumption that the cellular mechanisms during learning that leads to memories classified in this manner are different. Since qualia (virtual first-person internal sensations) of these retrieved memories are almost same, it prompts one to ask, "What if a) a common cellular mechanism is taking place during learning, and b) the retrieval of different types memories can be explained by reactivation of learning-induced changes that are retained for different durations?" To undertake such an experimental approach, one may ask, "Can we directly examine the memories themselves instead of examining the motor activity such as behavior and speech at the time of memory retrieval?" This will also eliminate our dependence on correlating memories with slow molecular changes occurring after learning. In this context, it is necessary to re-define the question: "What are memories?" Memories are first-person virtual internal sensations of an item (in the absence of that item) induced within the nervous system (in response to a cue stimulus or occurring spontaneously). Sensation of a stimulus in its absence is hallucination. Therefore, memories can be viewed as cue-induced hallucinations. Can we search for a learning-mechanism that can allow induction of virtual first-person internal sensations of memory as a cue-induced hallucination? This is the basis of developing semblance hypothesis which was published first as a book in 2007 (a copy is uploaded in Publications section). Revised editions were published in 2008 and 2010.

In summary, there are three main reasons why we had difficulties in solving the nervous system.

1) Frame of reference problem: Every time we had a frame of reference problem in the past, we needed to pause for some time to make further progress. Examples include a) Difficulties in sensing the rotation of Earth (note that the speed of rotation of Earth on its axis is 1670 km per hour). Our sensory systems cannot sense rotation of Earth since we are located in the same frame of reference as that of the Earth. b) Special and General relativity - while moving at ordinary velocities by us on Earth (for example, 100km per hour speed of a car), our sensory systems cannot sense any changes in time or length. But calculations show that at velocities close to that of light (1.07 billion km per hour), time slows down significantly & we can appreciate it quickly in graphical representations. The predictions made by relativity theory were found to be true. This knowledge is currently being used to make corrections in the instruments that are used to locate positions on Earth using satellite transmission. A second example is that we can only sense the movement of the Sun and not the rotation of Earth. The fact that third-person observers cannot sense first-person inner sensations in a subject can be viewed as a frame of reference problem. Until now, only physics has developed methods to solve frame of reference problems. In the case of the nervous system, we need to use the principles of methods used in physics to cross the frame of reference to become successful in solving it. Since this is new for neuroscience, there will be some difficulties in thinking about it in the beginning. But eventually, we will appreciate the problem and will move towards the correct solution.  

2) Difficulty to study the “virtual”: Another difficulty is the virtual nature of first-person inner sensations. However, we have the experience of dealing with virtual items in the past. For examples, numbers do not exist. We made them. In fact, they are virtual in nature. We can say that they represent real counts of items. What about negative numbers (integers?). They can exist only in our imagination. Yet, we use them routinely in mathematics. On a graph, we don’t feel their virtual nature at all. Going one step further, we have invented complex number (imaginary number). This solved our difficulties to find square roots of negative integers, which helped to further advance mathematics. In a similar manner, once we understand where and how units of inner sensations are sparked within the system, we will be able to perceive a virtual space where we can position them and navigate that space to understand their different conformations.

3) Access problem: Inner sensations of various higher brain functions such as memory and perception occurring within a person's brain cannot be accessed by a third-person's sensory systems. How to understand something that cannot be accessed by our sensory systems? There are several examples where we are comfortable with solving this access problem. For example, we cannot see DNA inside cells or in a gel. But we stain it with ethidium bromide that will allow us to see the stain through our eyes. This means that our access problem is only one step away from what we can sense using our sensory system (here, our eyes). We sometimes go two steps. For example, we use a primary antibody to an antigen, followed by a secondary antibody with florescent property that can then be visualized through our eyes. Even though our sensory systems do not have direct access, we believe in the presence of the antigen based on the logic and reason that we apply. After using this method several times, we have become comfortable in using this method to discover properties of Nature that cannot be directly sensed by our sensory systems. Understanding inner sensations will need another such indirect method that we will eventually become familiar.

How did Galileo show us to put together observations to make an inference even when our sensory systems cannot agree with such an inference?

When are many observables are present in a system, putting them together can provide a totally new inference that our sensory systems may not be able to directly sense. So, naturally such type of an inference often will not be accepted by our community quickly. But every scientist has learned how to uphold the importance this scientific method. An often-cited example is that of the inference made by Galileo Galilei using different observations that he made using his new telescope. Galileo published his findings in his book “The starry messenger.” While observing Jupiter on 7^th January, 1610, Galileo found four moons that were orbiting Jupiter. He immediately made the conclusion that if these moons are revolving around the Jupiter, then it is unlikely for the Earth to be at the center of the Universe. A video explains this. www.youtube.com/watch?v=NXOYqTUpkaM

Galileo then turned his telescope towards the Venus. It showed phases similar to that of Moon - New to Full Moon. Galileo observed both New and Full faces of Jupiter. When it is New, it is very big. When it is Full, it is very small. Galileo concluded that this can happen only if Jupiter revolved around the Sun and therefore, he made the inference that Sun must be at the center of the system. A suitable fit with this observation is that Earth and other planets are also revolving around the Sun. What we now know is that Jupiter is New when it comes close to the Earth, blocking the light from the Sun. When the Jupiter is on the other side of the Sun during its revolution around the Sun, it is farthest from the Earth. Here, Jupiter is seen as small and its face is Full. A nice video explains it is here. www.youtube.com/watch?v=W-6x3XRuWVg

The above two observations made Galileo to conclude that Earth is not at the center of the solar system. Galileo saw the simplicity if all planets revolved around the Sun. Galileo was making logical arguments that allowed him to fit all the findings together. We have such a rich tradition in science to gather information from different observations and then put them together to make an inference even though we cannot appreciate it immediately with our sensory systems. Another example for the limitation of our sensory systems is their inability to sense the speed of rotation of the Earth on its axis. Since the circumference of the Earth at the equation is nearly 40,000 kilometers and one day has 24 hours, we can make the inference that the speed of rotation of the Earth is nearly 1650 kilometers per hour. Even though, we cannot sense this speed using our sensory systems while on Earth, our inference about the speed of rotation of the Earth (and ours) must be true. When we observe the Earth from space, we see rotation of the Earth. See NASA’s video from the international space station (ISS) located 408 kilometers from Earth. https://www.youtube.com/watch?v=86YLFOog4GM (This time-lapse video from ISS needs to be converted to real-time video).

In short, we must find ways to overcome the limitations of our sensory systems! So, the question is, "How can we understand the operation of the nervous system even without replicating the mechanism in engineered systems?" In the case of the nervous system, our job is to put all the observations together to make an inference that will be able to interconnect all those observations. It is obvious that main function of nervous system is generation of inner sensations as a first-person property. The solution that can explain how first-person inner sensations are generated will not be directly accessible to our sensory systems. We have been thinking that it is the most difficult function to understand. However, from the above examples of a non-sensible (that cannot be sensed by a third person observer) inference that we have to derive from different observations, we may view the first-person inner sensations only as an apparent difficulty for which we can find a solution. We must be willing to derive a testable solution at least with a non-sensible component in it using observations from multiple levels of the system.

We need to bring all the observations of the nervous system together and make an inference (solution). In this exercise, we cannot afford to leave out even a single observation since we have to make sure that we reach a solution that can interconnect all the features of the system. When we become able to derive a solution that can provide explanations for all the functions, then we can make a reasonable assumption that the derived solution is correct. We must use this solution to make testable predictions that we can go and verify.

Footnotes:

  It was Copernicus, who based on observations, first proposed that the Sun is stationary and that the Earth and other planets revolve around it. So, the credit must go to him as the first person who reported that Earth is revolving around the Sun. Even though Gallio thought that planets are moving in circles, Kepler found about the elliptic path of motion of planets.

How can we solve the nervous system?

As we face situations that have more steps away from reality, we have to rely on our logic and reasoning capabilities. We have a very large number of findings from different levels and we have to discover the solution that can interconnect all of them. We need to overcome a) the frame of reference problem, b) the access problem, and c) to deal with the virtual nature of internal sensations. But, what if we cannot sense one part of the solution directly by our sensory systems while trying to find the solution? In this case, it is possible to seek examples of approaches that are used by other fields of sciences. For example, physics study particles and fields that are not accessible to our sensory systems. What is the deep underlying principle behind their success? A summary is given in Table 1 below.

Physics	Neuroscience
1) First, a large number of observations are made that appear to be disparate in nature. This means that these findings cannot be explained in terms of each other.	1) There are a large number of disparate findings in neuroscience (see Table 2) that need inter-connectable explanations. Example: How does the operation of the system related to sleep and also to the electrophysiological finding of LTP?
2) The above indicates the presence of a deep underlying principle that should interconnect these disparate observations.	2) There should be a deep underlying principle behind all those observations in Table 2.
3) The effects of the above principle are the ones (e.g. particles and fields) that cannot be directly sensed by our sensory systems.	3) There is a principle, the products of which (inner sensations) cannot be sensed by our (third-person's) sensory systems. Yet, the principle of the mechanism should be able to explain and interconnect all the observed findings.
4) The next step is to search for any possible solution that can interconnect all the findings. Constraints provided by disparate observations are what guide towards the solution. This is done either by initial deduction followed by mathematical approximations (Special and General Relativity) or by pure mathematical derivation (Higgs Bosons).	4) A structure-function mechanism has to be sought by logical deduction & trial and error methods. All the constraints offered by a large number of findings can be used to derive the solution. Success depends on moving through the path by taking guidance from all the constraints. Only when we reach the correct solution, we will be able to explain all the findings in an interconnectable manner.
5) The solution is then confirmed by verifying the predictions that can be made by the solution.	5) Testable predictions made by the derived mechanism can be verified.

Table 1. Steps that are taken by physics when it tries to unify different findings, which usually result in the discovery of particles and fields that are not accessible to our sensory systems. These steps are numbered from 1 to 5. A parallel approach is necessary to understand the non-accessible first-person internal sensations formed in the brain (given in the right column).

The deep underlying principle of many studies in physics has similarities to the method used in linear algebra for solving a system of large set of linear equations that has a unique solution. If one tries to solve such a system, one can find that the relationships between the variables in each equation provide hints and guide us towards the solution. If there are a large number of variables, there should be at least an equal number of equations to find the unique solution. Since there is a large number of findings that show their relationship with each other at different levels of the nervous system, we can (and we must) use all the non-redundant relationships to find the solution. It is a gigantic exercise since there are no easy methods in biology like that are used in linear algebra.

In linear algebra, Gauss-Jordan elimination method is used to find the solution for a system of linear equations. If we look carefully, we can see that easy methods in linear algebra were designed by someone who understood the deep underlying principle and worked on to make it simple for others by developing easy methods. We can examine how the relationships between variables in each equation define the unique solution for a system of linear equations and how Gauss-Jordan elimination method was invented. It is to be noted that we can also solve linear algebra problems using trial and error methods. But it will take some extra time. In other words, in mathematics easy methods are developed only for convenience. Whichever method is used, the deep underlying principle is the same - A system exhibiting a large number of disparate findings (equations) most likely has a unique solution that binds (interconnects) all the findings (equations) within that system. By finding a solution that can interconnect a subset of findings and by repeating this approach using different subsets of findings, one can hope to reach a common overlapping solution, which is the correct solution. One can start attempting to solve the (nervous) system by using subsets of disparate findings. The optimism with this approach is that there is only one unique solution for the nervous system and it is easy to verify whether the derived solution is correct or not. Using the above principle, subsets of constraints provided by findings from various levels (Table 2) were used to derive a mechanism that can explain and interconnect findings made by different faculties of brain research. This approach is expected to lead to the derivation of an operational mechanism for the generation of internal sensations, of which the non-sensible component will continue to remain non-sensible to our sensory systems even after its discovery (Figure 2). However, it is expected to show testable learning-generated change that gets reactivated at the time of memory retrieval to induce basic units of internal sensation whose integrational product can provide sensory qualia of the retrieved memory. Structural and electrophysiological changes that are expected to occur from these changes are explained using experimental results from different laboratories.  

Figure 2. Method to find a solution for the system from third person observed findings. (A) Features of the system are sensed either directly (represented by capital letter K) by our sensory systems or indirectly (represented by capital letters D, E, G, H) through findings such as staining of proteins, observing behavior, etc. (represented by small letters (u, w, v, x) connecting the features through straight lines (for example, observation of u enables sensing D). (B) Using both commonly used direct and indirect methods, three clusters of interconnected (represented by dotted lines) findings are found at separate levels (observations from different fields of brain science). In most cases, it was not possible to interconnect these clusters. For example, it was not possible to find interconnected explanations between 1) learning changes and inner sensation of memory both occurring in millisecond timescales, and 2) sleep and LTP. Using constraints from findings within each cluster, it is possible to arrive at overlapping common features such as A, B, and C. In the case of the nervous system very large number of such features is expected. (C) Using constraints available from key features (such as A, B and C) of three clusters of funrelated indings, it is necessary to try to derive a deep underlying principle (a structure-function solution m) that allows interconnection between them and therefore all the findings within each cluster. This solution is expected to provide a mechanism for generation of internal sensations within the mind in millisecond timescales. (D) The solution m enables explaining how various findings within each cluster are interrelated with each other and with the findings from other clusters shown in B). While remaining non-sensible to our senses by any known methods used in current biological investigations, ability of the solution m to hold different findings from all the clusters together makes it a further verifiable solution (Figure from Vadakkan KI (2019) From Cells to Sensations: A Window to the Physics of Mind. Physics of Life Reviews. 31:44-78).

There are very large number of observations from different levels of the nervous system functions (Table 2). In this context one may ask, "Since third person observers do not have any direct access towards the first-person inner sensations, will it be possible to confirm the operational mechanism, even if we derive a theoretically-fitting solution?" An example of store receipts (this is also the deep principle behind some of the approaches carried out in physical sciences to understand Nature) provides us confirmatory evidence that we can reach a final correct solution, if it becomes possible to obtain large number of findings that together contain all the variables in the system.

	Findings	Constraints offered by findings (on the left side) that direct the enquiry towards a correct solution/ What needs to be explained?
1	Nervous sysem is made of synaptically-connected neuronal circuitry	Mechanism should operate synchronous with the synaptically-connected circuitry
2	Learning-induced changes occur at physiological time-scales (in milliseconds)	A learning-inducible change that can occur (and completed) at physiological time-scales (to explain the ability to retrieve memory instantly following learning)
3	Memories that can be retrieved long time after learning are also capable of getting retrieved immediately after learning (working memory)	Learning should generate retrieval-efficient changes within milliseconds at the time of learning. These changes should have a provision for remaining in a stable form for long period of time, responsible for long-term memory
4	When exposed to a cue stimulus, internal sensation of memory takes place at physiological time-scales (in milliseconds)	A learning-induced change should be capable of inducing internal sensation of memory at physiological time-scales (should be able to complete within this time)
5	Memory is an internal sensation with certain specific sensory features (qualia)	Mechanism is expected to have elements that can provide sensory features to the retrieved memory
6	Ability to store large set of learning-induced mechanisms responsible for retrieving very large number of memories	Neurons and their processes are finite in number. Therefore, an efficient operation for storing very large number of learning-induced changes becomes possible if common elements in each learning can be shared. This becomes possible if each memory gets induced from a combination of unitary mechanisms
7	Instant access to very large memory stores	A specific cue stimulus should be able to induce a specific memory by combinatorial reactivation of a specific set of learning-induced unitary changes
8	Absence of cellular changes during memory retrieval	A passive reactivation of the changes that occurred during learning should be getting used at the time of memory retrieval to induce units of internal sensations. This should take place at physiological time-scales of milliseconds
9	Firing of a subset of neurons during memory retrieval that were not firing before learning in response to the same cue stimulus	Learning has opened certain number of new channels & cue stimulus leads to propagation of depolarization through these channels to provide additional potentials to a subset of neurons that are being held at subthreshold activation state to fire
10	Operates at a certain range of frequency of extracellularly recorded oscillating potentials	Expected mechanism provides vector components of the oscillating potentials
11	Motivation promotes learning	Motivation is associated with a specific factor and its specific action to augment the learning-induced change and possibly to retain this change for longer period of time than that occur in its absence
12	Internal sensations of working, short and long-term memories have similar qualia	Same learning-induced change is retained for different durations. Long-term memory might lose some unitary mechanisms and it might affect clarity
13	Working memory lasts only for a very short period of time	Learning-induced change must have a quickly reversible mechanism
14	Retrieval of memories very long period of time after the learning	A feasible mechanism for long-term maintenance of learning-induced change
15	Simultaneous existence of previous two conditions (above two rows) within the system	Learning-induced mechanism should have an initial quickly reversible change that if prompted can progress towards a stage where it can get stabilized for long period of time
16	Ability to induce internal sensation of memory in a cue specific manner	Specific sensory features from the cue stimulus induce a combination of internal sensory units to generate internal sensory features of the item whose memory is being retrieved
17	After associtive learning between two items, arrival of one of the items generates memory of the other item	The learning mechanism should have features to explain how either one of the associatively learned items can act as a cue stimulus to generate memory of the other item. Hence, the mechanism should have the ability to show bidirectionality in it
18	Even partial features of one of the associatively learned item is capable of retrieving memory of the second item	The mechanism should have features to explain how stimuli from partial features of one stimulus can retrieve memory of the second item
19	Ability to store new memories without needing to overwrite the old ones	Sharing of unitary mechanism for common features, reversal of learning changes by forgetting and provision for formation of new units with new associations are expected to be present in the system
20	Consolidation of memory	Mechanism for gradual transfer of locations of learning-induced changes and ability to generate memories by a global integrational mechanism
21	Mechanism to use schemas inter-changeably	How changes induced by one learning are shared by another learning event and how  these shared changes are used at the time of memory retrieval?
22	A constantly adapting dynamic circuit mechanism is expected	Provisions should be present to accommodate large number of new learning events
23	Framework of a mechanism that can generate hypothesis by the system	When there is a common element in two pairs of associative learning events, how can the operational mechanism generate a hypothesis of relationship between associated pairs?
24	System needs an unconscious state of sleep for nearly one third of its operational time	Substantive nature of sleep in the operation of the system. In other words, it is necessary to explain why the system won't be able to exist without sleep
25	While living in space, requirement of sleep reduces by more than one hour.	The role of sleep as an integral part of the system should provide an explanation for this
26	Internal sensation of memory has the option to cause motor actions such as behavior or speech	Mechanism should show how internal sensation of memory is associated with motor action
27	Mean inter-spine distance is more than mean spine diameter in pyramidal neurons	Neuronal processes that belong to other neurons is occupying the inter-spine space. Since no such spacing is observed between presynaptic terminals, there is some functional importance for inter-spine spacing. Are the spines that belong to different neurons interacting with each other?
28	Activation of a single dendritic spine can fire a neuron (when that neuron is at sub-threshold activated state). Retrieval of memory is associated with firing of certain neurons.	Need explanation for a mechanism that can cause both firing of a neuron and at the same retrieve information as units of first-person internal sensation of memory with specificity just by activating one dendritic spine
29	Place cell firing in response to specific spatial stimulus	How internal sensation of memory for a location is linked with firing of a set of CA1 neurons?
30	Firing of an ensemble of neurons during a higher brain function	How internal sensation generated during a higher brain function is related with firing of an ensemble of neurons?
31	Firing of a set of neurons during a specific higher brain function (for example, during both learning and memory retrieval)	How both learning and induction of internal sensation of memory are associated with firing of separate sets of neurons?
32	Firing of a cortical neuron (axonal spike) is possible by summation of nearly 140 postsynaptic potentials (input signals) arriving from random locations. These cortical neurons have tens of thousands of dendritic spines where postsynaptic potentials can get generated	These neurons have to be maintained at a sub-threshold state at the background state and the mechanism of induction of internal sensation has to be associated with providing additional postsynaptic potentials for crossing the threshold for firing of these neurons
33	Since any set of 140 input signals arriving from random locations on the dendritic tree can fire a neuron. There is extreme degeneracy of input signals in firing a neuron. This was selected from large number of variations since it was offering functional advantage to the system	While it guarantees an output function (neuronal firing), some function is going on at the input level, exactly like in the case of the codons. Degeneracy of codons means presence of >1 codon for most amino acids (AA). It means each codon is able to function independently to bind tRNAs with complementary sequences at the binding sites that matches with codons & carry a specific AA that the codon codes. Similarly, extreme degeneracy of input signals in firing a neuron is expected to perform a function at the input level
34	Many neurons are being held at sub-threshold activation state. Even a fraction an input can fire a neuron if it is being held at sub-threshold activation state short of that fraction of an input	This informs that minimum necessary input for a neuron to generate an output (neuronal firing) is the arrival of a fraction of an input. Minimum necessary condition for this to occur is depolarization of one spine head that generates a postsynaptic potential that attenuates and arrives at the axon hillock as the necessary fraction to cross the threshold to fire that neuron. Hence it can be inferred that if there is a function at the input level that needs firing of its neuron, then it takes place at a spine head region whose depolarization can generate potentials that can reach cell body as the nth potential for crossing the threshold to fire that neuron
35	Input signals (postsynaptic potentials) have maximum strength at the location of their origin, which is the spine head region. As they propagate further to the dendrite and towards the neuronal cell body, they get attenuated. A major attenuation takes place in the spine neck region	When signal from a stimulus attenuates, the attenuated signal may not contribute to an efficient learning mechanism. Furthermore, signals from different spines mix together (inseparably) in the dendrite. Hence, most likely location for a learning mechanism that can maintain specificity until the time of its retrieval is expected to be at the spine head region
36	Dendritic spikes occur by the summation of nearly 10 to 50 postsynaptic potentials at the dendritic region	It is necessary to explain which spines contribute to the potentials and explain their significance
37	Oscillating extracellular potentials	While synaptic transmission provides one vector component, what constitutes the other vector component/s that is/are expected to take place nearly perpendicular to the direction of synaptic transmission?
38	Apical tuft regions of all the cortical neuronal orders are anchored to the inner pial surface resulting in crowding of the dendritic arbors of neurons from different orders	What purpose does it serve by having dendritic spines of neurons that belong to both the same order and that belong to different neuronal orders overlap with each other?
39	On an average, inter-spine distance is more than the spine head diameter	What is occupying the inter-spine region and what possible functional contribution can they make? Based on the above row, what are the possible implications?
40	Following learning, initially there is conscious retrieval of memory and eventually this becomes sub-conscious after repeated retrievals	What change is taking place when there is repetition of learning? How does this affect consciousness? Does this contribute to subjective aspect of consciousness? Must be able to explain at least as a framework of a mechanism
41	Experimental finding of long-term potentiation (LTP) has several correlations with behavior associated with memory	It must be possible to explain how cellular changes during LTP induction and learning are correlated
42	Learning takes place in milliseconds, whereas LTP induction takes at least 20 to 30 seconds and even more time	What cellular change during learning can get scaled up during LTP induction in a time-dependent manner? Explain the mechanism behind this?
43	Blockers of membrane fusion blocks LTP	Need to explain the cellular location where they act and explain how it blocks LTP
44	Induction of LTP at the CA2 area of the hippocampus becomes possible by the removal of the peri-neural net proteins chemically	Why should the extracellular volume be devoid of such proteins? How does it affect LTP induction and natural learning?
45	Several seizures spread lateally to adjacent cortices	Cellular mechanism is capable of spreading laterally.
46	Several seizures are associated with hallucinations	Seizure mechanism should be able to explain how internal sensation of certain stimuli occur in the absence of those stimuli
47	Relationship between LTP, kindling and seizures	Need an interconnecting explanation
	Transfer of injected dye from one CA1 neuron to the neighboring ones is observed in animal models of seizures (Colling et al., Brain Res. 1996)	Need an explanation for a physical connection between two CA1 neurons through which dye can diffuse
48	Loss of dendritic spines after kindling	Specific reason to explain the loss of spines
49	CA2 area of hypocampus is resistant to seizures	What can block the mechanism of seizures, which is related with kindling and HSV infection?
50	Seizures and memory loss by herpes simplex viral (HSV) encephalitis	Mechanistic explanation for both these features is expected to provide some information about the relationship between these findings in HSV encephalitis
51	Anesthetic agents alleviate seizures	Mechanism of action of anesthetic agents should be able to explain how seizure generation and propagation is stopped by anesthetic agents
52	Cognitive impairment in patients with seizure disorders	Mechanim of learnig, memory retrieval and behavioral motor actions is expected to be affected by the mechanims of seizures
53	Intracellular electrophysiological correlate of epileptiform activity is paroxysmal depolarizing shift (PDS), which is a giant excitatory postsynaptic potential (EPSP)	What possible mechanism can give rise to such a giant EPSP at the dendritic spines, has the propensity to propagate laterally to other cortical regions?
54	Mechanism of neurodegenerative disorders	How contiguous spread of pathology cause spine loss and neuronal death? Is there an explanation for the sporadic occurrence of these changes?
55	Dementia in neurodegenerative disorders	How can loss of spines lead to dementia? How does it cause loss of internal sensation of various higher brain functions along with concurrent behavior?
56	Perception as a first-person internal sensation	How a variant or a modification of the mechanism of induction of internal sensation for memory can explain perception?
57	Flash-lag effect, apparent location of the percept different from the actual location, homogeneity in the percept for stimuli above the flicker fusion frequency, mechanism for perceiving object borders and generation of pressure phosphenes	Matching explanations using the mechanism of induction of units of internal sensation for all these features
58	Inner sensation of consciousness	A testable mechanism for the generation of inner sensations that depends on/contributes to the frequency of oscillating extracellular potentials. Explain what contributes latter's vector components and their role. What determines qualia during perception?
59	Loss of consciousness by anesthetic agents	Using all the known properties of anesthetic agents and how they alter the framework of consciousness
60	Loss of consciousness during a generalized seizure and its reversal	How the explanation for seizure generation is linked with alteration of the framework for consciousness?
61	Changes in consciousness with the alteration in the frequency of oscillating extracellular potentials	How a specific range of frequency contributes to the state of normal consciousness? What are the vector components?
62	Effect of dopamine in augmenting anesthetic action	Explain a mechanism how dopamine augments anesthetic action. Now verify if this explanation matches with the explanation for the action of dopamine in augmenting learning
63	Phantom sensation or pain	Explain a mechanism for the internal sensation of pain from a lost limb at the time of phantom sensation or pain
64	Referred pain	Explain a mechanism for the internal sensation of pain from a location different from the location where the cause of pain is present
65	Mechanism for innate behavior that enables survival	A mechanism evolving from heritable changes to explain innate behavior in response to a stimulus
66	Comparative circuitry in a remote animal species	Comparable features that show relationship of a mechanism that induces units of internal sensation using synaptically-connected neuronal circuitry among different species of animals
67	Neurodegeneration resulting from repeated general anesthesia	How mechanism of loss of consciousness by anesthetics, if induced repeatedly, cause loss of spines and other features of neurodegeneration?
68	Large number of years of education (increased number of associative learning events) reduces dementia risk	Should be able to explain how learning-induced changes can contribute to reducing dementia risk
69	Certain functions appear to be located at specific brain regions based on the findings of lesions/lesion studies	These minimum locations that cause loss of function are most likely locations of convergence of specific input signals responsible for those functions (they can also be locations of converging fiber tracts)
70	Astrocytic pedocytes cover less than 50% of peri-synaptic area in nearly 60% of the synapses in the CA1 region of hippocampus	Suitability of the distribution of astrocytic processes in the operational mechanism
71	Present nervous systems have evolved over millions of years and are also the results of certain accidental coincidences. They have different survival features	It is expected to become possible to explain how the circuitry that provides all the features can be evolved through simple steps of variations and selection
72	Significant neuronal death (70%) and spine loss (13 to 20%) are observed during development	It is necessary to explain the cause for these observations and provide an explanation how new variants were selected to prevent such events in the future
73	Dye diffusion is observed from one neuronal cell to another as the cortical neurons move from periventricular region towards their final destination, which indicates formation of inter-cellular fusion	It is expected to become possible to explain how an event of inter-cellular fusion leads to selection of variants that prevents further inter-cellular fusion. Since neurons cannot divide further, a transient stage of fusion is expected to trigger fusion preventing mechanism in the surviving neuronal cells. It is also necessary to explain whether this last stage has any role in the unique functional property of generation of first-person internal sensations within the nervous system
74	Both learning and retrieval of memory take place at a narrow range of frequency of oscillating extracellular potentials	a) Both the mechanism for learning and memory retrival contribute vector components of the oscillating extracellular potentials. b) The specific mechanism for both learning and memory retrieval depends on the frequency of oscillating extracellular potentials
75	Artificial triggering of spikes in one neuron in the cortex causes spikes in a group of neighboring neurons in the same neuronal order located at short distance (25–70µm) from the stimulated neuron	It should be possible to explain a mechanism that can lead to lateral spread of activity between neurons of the same neuronal order within a short radius. Its temporal relationship suggests occurrence of a mechanism through a path other than trans-synaptic route
76	Protein complexin blocks SNARE-mediated fusion by arresting the intermediate stage of hemifusion. Since complexin is present in the spines and since docked vesicles are not found inside the spines (in contrast to what is observed in the presynaptic terminal), which inter-membrane fusion is getting arrested by complexin?	It is necessary to explain an inter-membrane fusion process that can be mediated by SNARE proteins and blocked by complexin by arresting the process at the intermediate stage of hemifusion or before, in the spines
77	Transcriptomic analyses show heterogeneity of even adjacent neurons of the same type in the cortex	What is the functional importance of such a finding? The actual operational mechanism of the nervous system is expected to provide a suitable explanation [Newly added. Explanation]
78	Heterogeneity in clinical features and pathological changes in Alzheimer's disease (& other neurodegenerative disorders)	This needs an explanation [Newly added. Explanation]
79	In excitatory neurons, spine depolarization can occur even without dendritic depolarization due to spine neck resistance (Ref1; Ref2)	Why such a mechanism got selected? What is the functional significance of depolarization of the spine head? Is there any link between depolarization of the spine heads, oscillating extracellular potentials & different brain functions? [Newly added. Explanation]
80	Histological features of amyloid (senile) plaques and neurofibrillary tangles observed in normal aging (Ref) are also the pathological features in Alzheimer's disease & several other disorders in the spectrum of neurodegenerative disorders	A mechanistic explanation for how & why intracellular neurofibrillary tangles & extracellular plaques that are key pathological features in neurodegenerative disorders are observed in normal aging (but without symptoms) [Newly added. Explanation]
81	Therapeutic agents developed for treating seemingly unrelated neurological diseases such as seizure disorders, Parkinson's disease, spasticity, and hallucinations can alleviate different headache pains	Explanations for mechanisms of different disorders (given on the left side) & explanations for the findings in the rows above should match. The operational mechanism should also provide interconnected explanations for the effectiveness of therapeutic agents in different headaches [Newly added. Explanation]
82	Since learning etches changes in a background matrix (like writing on a blackboard), this background must be produced using "heritable" information	It must be possible to explain how structural and functional proteins from gene expression can provide a background for generating learning-changes in the system
83	"Representational drift" - meaning that when a brain function is repeated, set of neurons that fire changes with time.	In the case of memory, it is necessary to show redundancy in its operational mechanism
84	Controversial views (pdf) expressed by Camillo Golgi against Ramón y Cajal's interpretations of results obtained from modified Golgi staining protocols	Chemistry behind the modification of original Golgi staining protocol must be able to provide reasons for this controversy. Such an explanation is expected to become possible when we understand the operational mechanism of the brain
85	Formation of new neurons in the hippocampus, especially in non-stationary environments. Their new connections at the incoming and outgoing locations will continuously alter the existing circuitry	The operational mechanism should be able to explain functional advantage provided by insertion of new neurons
	Notes: 1. It is possible to obtain more than one constraint from some of the above findings. Here, only one constraint is given against each finding. If there is a new finding whose constraint/s cannot match with the solution derived by this work, then the solution can be rejected. 2. When we use only few observations from a system, we may be able to come up with more than one solution (similar to many solutions as in Step I in the example of store receipts). As we increase the number of observations, number of possible solutions will decrease drastically.  3. The findings and constraints provided by them will continue to help solve the system. Hence, the above table will be of use to anyone who is interested to solve this system.

Table 2. Features of the system from different levels that need to be explained independently and in an inter-connectable manner using a derived solution. Even though several possibilities can be excluded (for example, biochemical reactions that occur slower than the physiological time-scales of milliseconds in which learning (using which memory needs to be retrieved) takes place that can help exclude candidacy of several biochemical intermediates as storage molecules), a systematic approach is necessary to find the correct solution. Please note that the listed findings are so disparate and the constraints offered by them are so strong that there can only be one unique solution. In other words, this unique solution for the system should be compatible with all the previous experimental observations. Constraints provided by each of the observations help to narrow down the possibilities to arrive at the solution. A subset of the above list of observations can be used to derive the solution and the rest of the features can be used to verify whether the derived solution is correct or not. Please note that we cannot arrive at a solution using few mathematical equations. Once we have a unitary solution, we need to search for the principle of their integration where mathematics is expected to have a role.

 

A complete understanding of the operational mechanism leading to the first-person properties will only be achieved by carrying out the gold standard test of its replication in engineered systems. Even though replication of motor activities to produce behaviorally equivalent machines may seem adequate, the work will not be complete until first-person properties of the mind are understood. Engineering challenges with this approach include devising methods to convert the first-person accessible internal sensations to appropriate readouts. Experiments to translate theoretically feasible mechanisms of its formation both by computational and engineering methods are required. Feasibility to explain various brain functions both from first-person and third-person perspectives qualifies it as a testable hypothesis. Research findings from different laboratories have been examined in terms of the semblance hypothesis. The present work resulted from curiosity to understand the order behind the seemingly complex brain functions. In this attempt, I have used some freedom to seek a new basic principle in order to put the pieces of the puzzle together. This work wouldn't have become possible without a large amount of research work painstakingly carried out by many researchers over many years. Even though the present hypothesis is compatible with experimental data, it must be considered unproven until further verification of its testable predictions are made.

 

Video presentations

1. A testable hypothesis of brain functions

2. How to study inner sensations? Examples from mathematics

3. Neurons and Synapses

4. List of third-person findings and the derivation of the solution for the nervous system

5. Constraints to work with

6. Induction of units of inner sensation

7. Why do we need to sleep?

8. Potentential mechanism for neurodegeneration

9. LTP: An explanation by semblance hypothesis

10. A framework for consciousness

11. A potential mechanism of anaesthetic agents