Semblance Hypothesis

After more than a decade of examination by adhering to best available scientific methods1-5, mounting evidence forces me to regard semblance hypothesis as a theory. Despite several open invitations to disprove the hypothesis through both this website and a large number of scientific presentations and peer-reviewed publications, not even a single objection was received. To my best knowledge, this is the only existing theory of nervous system functions that has provided testable predictions (pdf here with methods to test them). I sincerely hope that scientific community will use the time-tested method of "testing the predictions of a theory"6 with an aim to disprove (or prove) it. Please explain the importance of this to your community leaders and policy makers. I thank all those who have supported me during several difficult times of its development.

Kunjumon Vadakkan, dated 21st March, 2020

References

1. Strobel N. Method for finding scientific truth. Website

2. Strobel N. What is a scientific theory? Website

3. Goodstein D (2007) A testable prediction. Nature Phys. 3:827 Article

4. Lee AS, Briggs RO, Dennis AR (2014) Crafting theory to satisfy the requirements of explanation. Article

5. Lee AS, Hovorka DS (2015) Crafting theory to satisfy the requirements of interpretation. Article

6. Bialek W (2018) Perspectives on theory at the interface of physics and biology. Rep Prog Phys. 81(1):012601 Article

Recent Findings & Explanations

Until now, there were no studies that examined the formation of IPLs. At this time, it is necessary to examine the findings from studies from different laboratories to examine whether some of their findings can be explained in terms of the present work.

A. In physiological conditions

Spine enlargement following associative learning

Experiments have shown that activated ensembles of synapses have significantly larger spine morphology at the auditory cortex-to-lateral amygdala synaptic region after auditory fear conditioning. Fear extinction reversed these ensembles of enlarged spines, whereas re-conditioning with the same tone and shock restored the spine size of the synapses (Choi et al., 2021). In fear conditioning experiments, foot shock is a high energy stimulus and it is likely to generate several inter-postsynaptic functional LINKs (IPLs) in the amygdala in a time-dependent manner. This can explain why fear conditioning is observed after three hours following foot shock (Rumpel, 2005). Furthermore, it was observed that memory is reduced after three hours of blocking of synaptic incorporation of AMPA receptors in as few as 10 to 20% of lateral amygdala neurons (Rumpel, 2005). This needs a timescale-matched explanation. Based on the semblance hypothesis, IPL formation during learning takes place in milliseconds. Intra-spine GluR1 vesicle fusion to the lateral spine head membrane that incorporates membrane segments to the lateral spine head region enables IPLs to advance to more stabilizable states. If this is blocked, then it will lead to reversal of formed IPLs at specific locations of convergence of signals from associatively learned stimuli. It also matches with the delay in the induction of LTP after stimulation (Vadakkan, 2019). Another inference is that internal sensation of memory results from net semblance induced at a minimum number of inter-LINKed spines.

Choi DI, Kim J, Lee H, Kim JI, Sung Y, Choi JE, Venkat SJ, Park P, Jung H, Kaang BK (2021) Synaptic correlates of associative fear memory in the lateral amygdala. Neuron. S0896-6273(21)00502-X. PubMed

Rumpel S, LeDoux J, Zador A, Malinow R (2005) Postsynaptic receptor trafficking underlying a form of associative learning. Science. 308(5718):83-8. PubMed

Vadakkan KI (2009) A potential mechanism for first-person internal sensation of memory provides evidence for the relationship between learning and LTP induction. Behav Brain Res. 360:16-35. PubMed

How does dopamine filter excitatory inputs to nucleus accumbens (NAc)?

Dopamine reduce excitatory postsynaptic currents (EPSCs) generated by paraventricular thalamus (PVT) inputs to NAc, when carried out by whole cell recording from medium spiny neurons (MSNs) of NAc (Christoffel et al., 2021). This naturally leads to the question, “What mechanistic explanation can satisfy the inference that dopamine filter excitatory inputs to NAc?” Based on IPL mechanism, formation of IPLs between dendritic spines of MSNs that synapse with excitatory inputs from PVT neurons and dendritic spines of MSNs that synapse with inhibitory inputs from ventral tegmental area (VTA) takes place when dopaminergic inputs from VTA cause expansion of spines of MSNs that synapse with excitatory inputs (Vadakkan, 2019). The net effect will provide results equivalent to filtering of excitatory inputs to NAc by dopamine.

Christoffel DJ, Walsh JJ, Hoerbelt P, Heifets BD, Llorach P, Lopez RC, Ramakrishnan C, Deisseroth K, Malenka RC (2021) Selective filtering of excitatory inputs to nucleus accumbens by dopamine and serotonin.  Proc Natl Acad Sci U S A.118(24):e2106648118. PubMed

Vadakkan K.I (2019) Internal sensation of pleasure can be explained as a specific conformation of semblance: Inference from electrophysiological findings. Peerj Preprints Article

 

Drift in the set of neurons in the primary olfactory cortex that fire in response to an odour

Fear conditioning does not stabilize the set of neurons that fire in response to odour in the primary olfactory cortex (piriform cortex). Daily exposure to the same odorant slowed the rate of drift, but when exposure was halted the rate increased again (Schoonover et al., 2021). Authors suspected that this instability reflects the unstructured connectivity of piriform cortex. What property of the circuitry will cause such a drift? It was possible to explain a mechanism of perception based on the IPL mechanism (Vadakkan, 2011). During associative learning events, new IPL are formed in the cortices. Even though olfactory stimuli propagate directly to the hippocampus without propagation to an intermediate association cortex (Zhou et al., 2021), outputs from the hippocampus can generate IPLs in the cortex. Insertion of new neurons in the pathways (in the granule layer of hippocampus) through which signals from associatively learned items/events propagate, along with exposure of the system to new associative learning items/events that share elements of the previously associated items/events, will lead to continuous formation of new IPLs in the cortices (Vadakkan, 2010; 2016). This will lead to changes in the summated potentials arriving to the neurons in the olfactory cortex. Hence, firing property of neurons in the primary olfactory cortex during perception of the same stimulus will show continuous drift. Since internal sensation of perception takes place at the inter-LINKed spines in the olfactory cortex, and since units of perception (perceptons) depend on the nature of sensory inputs, qualia of percept will continue to remain the same (Vadakkan, 2011) irrespective of changes in the set of neurons that fire in the primary olfactory cortex.

Schoonover CE, Ohashi SN, Axel R, Fink AJP (2021) Representational drift in primary olfactory cortex. Nature. 2021 594(7864):541-546. PubMed

Zhou G, Olofsson JK, Koubeissi MZ, Menelaou G, Rosenow J, Schuele SU, Xu P, Voss JL, Lane G, Zelano C (2021) Human hippocampal connectivity is stronger in olfaction than other sensory systems. Prog Neurobiol. 201:102027. PubMed

Vadakkan KI (2011) A possible mechanism of transfer of memories from the hippocampus to the cortex. Med Hypotheses. 77(2):234-43. PubMed

Vadakkan KI (2016) The functional role of all postsynaptic potentials examined from a first-person frame of reference. Rev Neurosci. 27(2):159-84. PubMed

 

Changes in the set of firing neurons over a period of weeks during olfactory perception

Several studies have observed correlation between odorants and specific sets of neurons that fire in response to them. Continuous recording from these neurons show that this correlation is lost after several weeks (Schoonover et al., 2021). This naturally leads to the questions, “What is a percept?” “Where is it formed?” Based on the semblance hypothesis, when perception is viewed as first-person internal sensations, it was possible to find a framework of a mechanism for perception (Vadakkan, 2015). Accordingly, internal sensation of percept is formed by integral of all perceptions, unitary mechanisms of perception. It doesn’t matter the locations where the perceptons are generated in the olfactory cortex. What matters is the net integral of them. Furthermore, extreme degeneracy of attenuating input signals in firing a neuron (Vadakkan, 2019) indicates that perceptons are generated at the input level. Correlations with neuronal firing will only be true for those neurons that are being held at sub-threshold activation state and receive additional potentials through inter-postsynaptic functional LINKs (IPLs) at the time of perception. Hence, internal sensation of perception continues to take place even when the set of neurons that fires changes over time due to changes in the circuitry. A slightly different; but the same concept that it is the integral of perceptons that forms a percept was explained in visual perception (Vadakkan, 2015). Following is an example. When eyes are fixed to a point, visual perception of a slowly moving object in the visual field occurs even when perceptons are formed at different locations of the visual cortex.

Schoonover CE, Ohashi SN, Axel R, Fink AJP (2021) Representational drift in primary olfactory cortex. Nature. 594(7864):541-546. PubMed

Vadakkan KI (2015) A framework for the first-person internal sensation of visual perception in mammals and a comparable circuitry for olfactory perception in Drosophila. Springerplus. 4:833. PubMed

Vadakkan KI (2019) Extreme degeneracy of inputs in firing a neuron leads to loss of information when neuronal firing is examined. Peerj Preprints. Article

 

Pathological features of Alzheimer's disease such as tangles & plaques start appearing in normally aging brains (Was able to explain this recently: Aging as a loss of an adaptation that stabilizes last developmental stage of the nervous system)

Examination of IPLs derived by semblance hypothesis has led to the inference that the last stage of its development undergoes an adaptation whereby inter-neuronal inter-spine fusion is prevented by arresting it at/before the stage of hemifusion (Vadakkan, 2020). This is based on the following observations. In the mouse, neuronal precursor cells in the ventricular zone (VZ) undergo cell division. While in the VZ, 100% of precursors in G2 and S phases of the cell cycle couple together and form clusters (Bittman et al., 1997). During this stage, injection of dye into one cell spread to neighouring cells (Bittman et al., 1997). This indicates formation of fusion pores between these cells. This is followed by death of nearly 70% of these cells and survival of the remaining 30% cells (Blaschke et al., 1996). The surviving 30% of cells are expected to have acquired an adaptation most probably during inter-cellular coupling. The adaptation most likely prevents any future coupling between neurons that may result in inter-neuronal fusion. This adaptation is suitable for maintaining IPLs (that generated inner sensations) and prevents any IPL fusion. Aging can be viewed as resulting from gradual loss of this adaptation. Augmented formation IPL fusion events can lead to pathological changes such as those observed in neurodegenerative disorders (Vadakkan, 2019). For example, pathological changes of neurofibrillary tangles and amyloid plaques can result from precipitation of proteins & leakages of certain precipitated proteins through defective fusion pores to the extracellular matrix space in Alzheimer’s disease. If semblance hypothesis is correct, then its corollary that these pathological findings should also be found in normal aging can be verified. Since senile neurofibrillary tangles and amyloid plaques appear in normally aging brains (Anderson, 1997; Saha and Sen, 2019), this forms sufficient verification. This reinforces the need for testing the predictions of semblance hypothesis.

Vadakkan KI (2020) A derived mechanism of nervous system functions explains aging-related neurodegeneration as a gradual loss of an evolutionary adaptation. Curr Aging Sci 13(2):136–152. PubMed

Bittman K, Owens DF, Kriegstein AR, LoTurco JJ (1997) Cell coupling and uncoupling in the ventricular zone of developing neocortex. Journal of Neuroscience 17(18):7037-7044. PubMed

Blaschke AJ, Staley K, Chun J (1996) Widespread programmed cell death in proliferative and postmitotic regions of the fetal cerebral cortex. Development 122(4):1165-74. PubMed

Vadakkan KI (2016) Neurodegenerative disorders share common features of "loss of function" states of a proposed mechanism of nervous system functions. Biomed Pharmacother. 83:412-430. PubMed

Anderton BH (1997) Changes in the ageing brain in health and disease. Philos Trans R Soc Lond B Biol Sci. 352(1363):1781-1792. PubMed

 

Heterogeneity of neurons in the cortex

Studies of cortical neurons show significant heterogeneity in transcriptomic analyses (Tasic et al., 2016; Cembrowski et al., 2016; Tasic et al., 2018; Hodge et al., 2019). In fact, these findings show that there won't be two neurons with same sets of transcripts within them. The above findings naturally raise the question, "What is the functional importance of such a finding?" The actual operational mechanism of the nervous system is expected to provide clues for a suitable explanation. Based on the IPL mechanism, this heterogeneity is necessary for the formation of IPL fusion between spines that belong to different neurons at one stage of development supported by the diffusion of dye injected into on neuron to neighboring neurons (see, Vadakkan, 2020). If neurons are not heterogeneous, then fusion between them will not evoke cellular reactions, which is responsible for cell death of majority of neurons. Most importantly, this IPL fusion is expected to trigger an adaptation in surviving neurons, responsible for restricting IPL fusion to the stage of IPL hemifusion. Thus, neuronal heterogeneity can be viewed as a marker of an adaptation that occurred during that last stages of the developmental of the nervous system. It is most likely that maintaining heterogeneity is essential for maintaining the above adaptation throughout the life-span of the neurons. This prompts to make a testable prediction that, any deficiencies in maintaining this adaptation will trigger IPL fusion between heterogeneous neurons, which can explain aging and other disease associated neurodegeneration.

Tasic et al., (2016) Adult mouse cortical cell taxonomy revealed by single cell transcriptomics. Nat Neurosci. 19(2):335-346. PubMed

Cembrowski MS, et al., (2016) Spatial gene-expression gradients underlie prominent heterogeneity of CA1 pyramidal neurons. Neuron. 89(2):351-68. PubMed

Tasic et al., (2018) Shared and distinct transcriptomic cell types across neocortical areas. Nature 2018 563 (7729):72-78. PubMed

Hodge et al., (2019) Conserved cell types with divergent features in human versus mouse cortex. Nature 573 (7772):61-68. PubMed

  

  Spine depolarization without dendritic depolarization

  It was found that in excitatory synapses, large spine depolarization recruit voltage-dependent channels without dendritic depolarization, due to high spine neck resistance (Beaulieu-Laroche and Harnett, 2018). Hence, it leads to the questions, "What is the functional importance of seemingly isolated spine depolarization?" and "Since this is a conserved property, how to provide a mechanistic explanation in terms of brain functions?" Another finding from the same laboratory is that distal human dendrites provide limited excitation to the soma even in the presence of dendritic spikes (Beaulieu-Laroche et al., 2018). The observation that even dendritic spikes have only a limited role in neuronal firing is of huge significance. This again reinforces the need for figuring out the functions achieved by depolarization of spine heads in excitatory cortical neurons. IPL mechanism can explain how depolarization of spines is associated with generation of units of internal sensations independent of neuronal firing. These experimental findings compel us to undertake dedicated experimental verification of the IPL mechanism.

Beaulieu-Laroche L and Harnett MT. 2018. Dendritic spines prevent synaptic voltage clamp. Neuron 97(1): 75–82.e3. PubMed

Beaulieu-Laroche L, Toloza EHS, van der Goes MS, Lafourcade M, Barnagian D, Williams ZM, Eskandar EN, Frosch MP, Cash SS, Harnett MT. 2018. Enhanced dendritic compartmentalization in human cortical neurons. Cell 175(3): 643–651.e14. PubMed

 

Largest class of neurons in the visual cortex is not reliably responsive to any of the visual stimuli

In a recent report by de Vries et al., (2020), the authors examined firing of nearly 60,000 visual cortical neurons in response to different visual stimuli. They found that while most classes of these neurons respond to specific subsets of stimuli, the largest class is not reliably responsive to any of the stimuli. The latter finding supports the observations made by semblance hypothesis during visual perception (Vadakkan, 2016). Accordingly, the internal sensation of perception takes place at the inter-LINKed spines and is independent of firing of their neurons. Moreover, postsynaptic potentials generated by visual stimuli at these inter-LINKed spines need not necessarily add potentials to raise the summated potentials to reach the threshold level for firing those neurons (Vadakkan, 2019). Therefore, as per semblance hypothesis, the expectation is that a huge set of neurons will not be responsive to any visual sensory stimuli even when internal sensation of vision takes place. The report by De Vries et al., (2020) is in agreement with the expectations of the mechanism of visual perception provided by semblance hypothesis.

Their finding that most classes of visual cortical neurons respond to specific subsets of stimuli indicates that the propagation of stimuli to higher cortical areas is necessary for performing secondary functions such as a) “where” and “what” associative properties of visual stimuli at higher cortical areas, and b) associative learning with other sensory stimuli at different associative cortical areas. Due to extreme degeneracy of inputs in firing a cortifcal neuron (Vadakkan, 2016), two findings are expected. a) a specific neuron will respond to a very large number of visual stimuli if that neuron is being kept at sub-threshold activation level at the baseline state, and b) internal sensation of perception will continue to occur at the inter-LINKed spine of a neuron even without any change in the firing status of that neuron which remains at a supra-threshold activation state.

de Vries et al., (2020) A large-scale standardized physiological survey reveals functional organization of the mouse visual cortex. Nat Neurosci. 2020 Jan;23(1):138-151. doi: 10.1038/s41593-019-0550-9. PubMed

Vadakkan KI (2016) A framework for the first-person internal sensation of visual perception in mammals and a comparable circuitry for olfactory perception in Drosophila. Springerplus. 2015 Dec 30;4:833. doi: 10.1186/s40064-015-1568-4. eCollection 2015. PubMed

Vadakkan KI (2019) Extreme degeneracy of inputs in firing a neuron leads to loss of information when neuronal firing is examined. Peerj Preprints Article

 

Artificial firing of a neuron leads to firing of a set of neurons of the same neuronal order

In a recent work by Chettih and Harvey (2019), authors artificially triggered several spikes (action potentials) in single neurons in layer 2/3 of mouse visual cortex V1area. This resulted in spiking activity in a group of sparsely distributed neighbouring neurons in the same neuronal order and were correlated in time. The small population of neurons that were excited were located at short distance (25–70µm) from the stimulated neuron. The stimulation had no influence beyond 300µm (for a summary, see News and Views article by Ikuko Smith (Smith, 2019). The authors called this lateral spread of activity between neurons "influence-mapping."

There is one important question. How does excitation reach at the laterally located neurons in a time-correlated manner, which is responsible for influence-mapping? This can be explained by the testable mechanism derived by semblance hypothesis (Fig.1). It is related to the previous explanation of visual perception as a first-person property using the derived mechanism of generation of internal sensation at physiological time-scales (Vadakkan, 2016). The units of internal sensation of perception are induced at the inter-LINKed spines that belong to different neurons. When a single neuron is artificially fired, the back propagating action potentials will reach the dendritic spines. It will then continue to propagate through the inter-LINKed spines to the neuronal soma of the inter-LINKed spine’s neuron (Fig. 2). The spines that inter-LINK can belong to neurons that are separated by up to 300µm, a distance beyond which the probability of overlapping of dendritic arbor between neurons diminishes substantially.

                                        Lateral propagtion of current in a cortical layer
Figure 1. Schematic diagram showing the route of propagation of action potential from the artificially fired neuron N1 towards the sparsely located neuron N2 within the layer2/3 in visual cortex. This spread taking place through the inter-LINKed spines Post1 and Post2 can explain what the authors describe as “influence-mapping.” Note that the inter-postsynaptic functional LINK (IPL) between Post1 and Post2 was explained as responsible of induction of internal sensation for perception (Vadakkan, 2015). Overlapping of the dendritic arbors between the neurons N1 and N2 increases the probability of IPL formation when neurons N1 and N2 are separated only by a short distance (25–70µm).

b) When a neuron was fired, the majority of neurons that were tuned to respond to similar features to that neuron were strongly suppressed than the neurons with a different tuning regardless of the distance from the stimulated neuron. Inhibition of the spikes in the neighbouring neurons can be explained by activation of surrounding inhibitory interneurons. Burst of action potentials in excitatory neurons can activate somatostatin expressing inhibitory interneurons (Kwan and Dan 2012). Similar type of inhibition of surrounding areas is seen in locations where the internal sensation of perception is expected to occur in the olfactory glomeruli in Drosophila. When one glomerulus is activated, inhibitory local interneurons (ILN) inhibit all the remaining glomeruli (Hong and Wilson 2015) enabling the specificity of the percept for that particular smell (Vadakkan, 2015).

Orientation tuning is tested by a source of light. This will cause activation of a large number of islets of inter-LINKed spines within one cortical column. But when single neurons are artificially fired the backpropagation of potentials will reach only specific sets of inter-LINKed spines. This explains why only neurons that are located sparsely are fired, correlated in time.

Verification: Based on semblance hypothesis, the prediction that can be made is the presence of inter-postsynaptic functional LINKs (IPLs) between spines that belong to the artificially fired neuron and the sparsely located neurons that were fired in a time-correlated manner.

Chettih SN, Harvey CD (2019) Single-neuron perturbations reveal feature-specific competition in V1. Nature doi: 10.1038/s41586-019-0997-6. PubMed

Smith IT (2019) The influence of a single neuron on its network. Nature. 567(7748):320-321 PubMed

Kwan AC, Dan Y (2012) Dissection of cortical microcircuits by single-neuron stimulation in vivo. Current Biology 22, 1459–1467. PubMed

Vadakkan KI (2015) A framework for the first-person internal sensation of visual perception in mammals and a comparable circuitry for olfactory perception in Drosophila. Springerplus 4:833. PubMed

Hong EJ, Wilson RI (2015) Simultaneous encoding of odors by channels with diverse sensitivity to inhibition. Neuron 85(3):573–589. PubMed

 

Memory retrieval occurs at a frequency of oscillating extracellular potentials similar to that was present during learning

A recent study examined the nature of oscillating extracellular potential both during learning and memory retrieval (Vaz et al.. 2019).
In order to reactivate the same set of IPLs that formed during learning at the time of memory retrieval, it is necessary to have almost similar conditions that were present at the time of learning. Maintaining the same frequency of oscillating extracellular potentials is a major factor in achieving this. Based on the semblance hypothesis, the synaptic transmission in one direction and propagation of potentials in a near-perpendicular direction through the inter-postsynaptic functional LINK (IPL) contribute vector components to the oscillating extracellular potentials, which is essential for binding and integration of units of internal sensations for providing the sensory qualia of memory. The findings of this study that show that similar frequency of oscillating extracellular potentials are present both during learning and memory retrieval support the expectations of semblance hypothesis.

Vaz AP, Inati SK, Brunel N, Zaghloul KA (2019) Coupled ripple oscillations between the medial temporal lobe and neocortex retrieve human memory. Science. 363:975-978. PubMed

 

Dendritic calcium spikes that are related to behavior and cognitive function

Similar to the action potentials (axonal spikes or neuronal firing) occurring at the axonal hillock, there are spikes occurring at the dendrites. These are called dendritic spikes. Based on the strength of summated potentials, a rough estimate shows that they constitute synchronous activation of nearly 10 to 50 neighboring glutamatergic synapses triggering a local regenerative potential (Antic et al., 2010). Depending on the channels involved, there are different types of dendritic spikes. Recently, it was found that distal dendrites generate dendritic spikes whose firing rate is nearly five times greater than at the cell body (Moore et al., 2017). Another group of investigators who have previously shown that dendritic spikes are related to behavior and cognitive function recently found that dendritic calcium spikes contribute to surface potentials that are recorded as electroencephalogram (EEG) (Suzuki et al., 2017). Surface EEG recording is generated by current sink that reflects the net potential changes within the extracellular matrix space. This is expected to be contributed by several factors. It is known that the surface positive potentials are generated mainly by synaptic inputs from other cortical and subcortical regions to the pyramidal neurons located between L2/3 to L4 regions (Douglas and Martin, 2004). Recent studies by Suzuki et al., has found that dendritic calcium spikes at the main bifurcation points of the apical dendrites of L5 pyramidal neurons (note that L5 pyramidal neurons are upper motor neurons that direct motor movement of the body) also generate the surface positive potentials (Suzuki et al., 2017).

The last two findings lead to the questions, “How can two different sources of potentials provide similar surface positive potentials?" "Can we provide an interconnected explanation?" Since dendritic spikes are related to both behavior and cognitive functions and since IPL mechanism can explain generation of concurrent internal sensation of memory and behavioral motor action, can IPL mechanism explain the above findings? Since the apical tuft regions of all the pyramidal neurons are anchored to the pial surface, the dendritic arbor of all the pyramidal neurons is overlapped at the recording location of Suzuki et al., (2017). In this context, it is necessary to examine the potential changes occurring at the neuronal processes around the recording electrode. In the context of the IPL mechanism, it is anticipated that the dendritic spines of different neurons have formed a large number of islets of IPLs between them at these locations. By examining the zone from where low-threshold calcium spikes were recorded (Suzuki et al., 2017; Larkum and Zhu, 2002), the following is possible.

Spatially, main bifurcation points of the apical dendrites of L5 pyramidal neurons are also locations where spines of the L2/3 pyramidal neurons receive their input. Based on the IPL mechanism, several of these spines are expected to be inter-LINKed to form large islets. These islets are also expected to be inter-LINKed with spines of L5 pyramidal neurons for initiating or controlling motor actions. The potentials through the IPLs are expected to arrive at the axon hillock of the L5 motor neurons that are kept at a sub-threshold state (see figure 5 in the FAQ section of this website) for the motor action (Fig.2). For a system that operates to generate internal sensations and initiates or controls concurrent motor actions, the islets at appropriate locations are expected to transmit potentials to the axon hillock of the L5 pyramidal neurons that are upper motor neurons. Calcium spikes are generated at the postsynaptic locations within the islet of inter-LINKed spines possibly due to an increased density of these channels at these locations. Since the pyramidal neurons are found to be under the influence of an inhibitory blanket (Karnani et al., 2014), a function of dendritic spikes is to generate sufficient potentials to overcome this inhibition. In other words, there is a provision for increasing the inhibitory blanket around an L5 pyramidal neuron axon hillock as the size of the islets of inter-LINKed spines that are connected to these neurons increases. This will make sure that the L5 neuron fires only at the activation of specific sets of IPLs that generates a specific conformation of semblance for both the internal sensation and concurrent behavioral motor action.

                                 Islet of inter-LINKed spines

Figure 2. Figure explaining a potential mechanism occurring at the level of the main bifurcation point of an apical dendrite of an L5 pyramidal neuron (based on semblance hypothesis). The circles with different colors represent an islet of inter-LINKed spines (dendritic spines or postsynaptic terminals) that belong to different pyramidal neurons at the level of the main bifurcation point of the apical dendrite of L5 neuron. Note that one of the spines (in violet) belongs to one of the L2/3 pyramidal neurons. Also note that the inter-LINKed spine on the far right end of the islet (in green) belongs to L5 pyramidal neuron. During development, neurons of different cortical neuronal orders descend from the inner pial surface area by anchoring the apical dendritic terminals to the inner pial region. This allows overlapping of the dendritic arbors of neurons from different orders, which leads to abutting of their spines that eventually leads to the formation of inter-LINKs between these spines during learning. The waveform shown at the level of the inter-LINKed spines indicates that the oscillating extracellular potentials recorded have a major contribution from the propagation of potentials through the islets of inter-LINKed spines. Secondary factors can determine different wave forms depending on the locations from where recording is carried out. They include a number of neuronal layers, recurrent collaterals, connections with the projection neurons from other ares of the brain, etc. Figure not to scale (spines in the islet are drawn disproportionately large compared to the size of neurons).

The explanation that synaptic transmission and propagation of potentials through the IPLs provide vector components of oscillating extracellular potentials also becomes suitable. If the arrival of potentials from sensory stimuli evokes dendritic calcium spikes along with the reactivation of specific inter-LINKed spines (and their islets) inducing units of specific internal sensations concurrent with activation of specific sets of motor neurons, it can provide an explanation how dendritic calcium spikes are related to behavior and cognitive function. The findings of Suzuki et al., necessitate examining the role of background EEG wave forms, frequency of which correlates with normal level of consciousness. In this regard, the explanation by the IPL mechanism that the net background semblance induced by reactivation of inter-LINKed spines contributes to the internal sensation of consciousness (Vadakkan, 2010) becomes a suitable mechanism that can be subjected to further studies. 

Antic SD, Zhou WL, Moore AR, Short SM, Ikonomu KD (2010) The decade of the dendritic NMDA spike. J Neurosci Res. 88(14):2991–3001 PubMed

Moore JJ, Ravassard PM, Ho D, Acharya L, Kees AL, Vuong C, Mehta MR (2017) Dynamics of cortical dendritic membrane potential and spikes in freely behaving rats. Science. 355(6331) PubMed

Suzuki M, Larkum ME (2017) Dendritic calcium spikes are clearly detectable at the cortical surface. Nat Commun. 8(1):276 PubMed

Douglas RJ, Martin KA (2004) Neuronal circuits of the neocortex. Annu. Rev. Neurosci. 27: 419–451 PubMed

Larkum ME, Zhu JJ (2002) Signaling of layer 1 and whisker-evoked Ca2+ and Na+ action potentials in distal and terminal dendrites of rat neocortical pyramidal neurons in vitro and in vivo. J. Neurosci. 22, 6991–7005 PubMed

Karnani MM, Agetsuma M, Yuste R (2014) A blanket of inhibition: functional inferences from dense inhibitory connectivity. Curr Opin Neurobiol. 26:96-102. PubMed

Vadakkan KI (2010) Framework of consciousness from semblance of activity at functionally LINKed postsynaptic membranes. Front Psychol. 1:168. PubMed

 

Regenerative spikes at the dendritic arbor - a mechanism for internal sense of a place that reflects binding at the time of learning

Each place field consists of a unique set of CA1 neurons that fire action potential. At the dendritic regions, calcium transients inform about a change in potentials occurring regeneratively either due to back propagating action potentials (bAP) or by dendritic spikes. Recent studies observed calcium transients secondary to regenerative dendritic events in place cells that can predict place field properties (Sheffield and Dombeck, 2015a; Sheffield et al., 2017). These calcium transients have a highly spatiotemporally variable prevalence throughout the dendritic arbor. In some cases only a subset of the observed branches displayed detectable spikes, which indicates that spikes originated at these dendritic branches. None of the observed branches in many cases displayed detectable spikes during place field traversals while the soma (and axon) fired. This means that the bAP did not reach these locations. From the findings of Sheffield and Dombeck, it is clear that dendritic spikes relate to spatial precision. However, this finding needs a mechanistic explanation.

The above finding can be explained by the occurrence of dendritic spike occurs at an islet of inter-LINKed spines that belong to different CA1 neurons (Vadakkan, 2013). This has the following advantages. a) Activation of inter-LINKed spines within an islet of inter-LINKed spines induces units of internal sensations for a specific place. b) One dendritic spike at an islet of inter-LINKed spines that belong to different neurons can explain the firing of different CA1 neurons that are being maintained in a sub-threshold state at the time of the dendritic spike. It also supports why a high percentage of place cells are shared between different places. c) Since potentials degrade as they reach the axonal hillock, it may require potentials arriving from more than one spike to contribute to the firing of a CA1 neuron depending on latter’s sub-threshold level. d) The highly spatiotemporally variable nature of spike depends on the qualia of internal sensations that they induce in response to and matching with the place (which depends on previous associative learning events with different places). The latter property can explain the expected binding feature (Sheffield and Dombeck, 2015b).

Sheffield MEJ, Dombeck DA (2015a) Calcium transient prevalence across the dendritic arbour predicts place field properties. Nature. 517(7533):200-204. PubMed

Sheffield MEJ, Adoff MD, Dombeck DA (2017) Increased Prevalence of Calcium Transients across the Dendritic Arbor during Place Field Formation. Neuron. 96(2):490-504.e5 PubMed

Vadakkan KI (2013) A supplementary circuit rule-set for neuronal wiring. Frontiers in Human Neuroscience. 7:170 PubMed

Sheffield ME, Dombeck DA (2015b) The binding solution? Nature Neuroscience. 18(8):1060-102 PubMed

 

B. In pathological conditions

 Spread of epileptic activity

Epileptic activity in the hippocampus propagates with or without synaptic transmission at a speed of nearly 0.1m/s (Jefferys, 2014). Experiments showed that the longitudinal propagation of epileptic activity from one end of a neuronal order to its other end in the hippocampus takes place independent of chemical or electrical synaptic transmission (Zhang et al., 2014). Since this spread of epileptic activity occurs at a speed of 0.1 m/s and is not compatible with ionic diffusion or pure axonal conduction (Jefferys 2014; Zhang et al., 2014), it requires an explanation at the cellular and electrophysiological levels. In this regard, rapid chain propagation through the inter-postsynaptic functional LINKs (IPLs) explained by the semblance hypothesis (Vadakkan, 2015) offers a suitable explanation for a mechanism.

Jefferys JG (2014) How does epileptic activity spread? Epilepsy Currents. 14(5):289-290 PubMed

Zhang M, Ladas TP, Qiu C, Shivacharan RS, Gonzalez-Reyes LE, Durand DM (2014) Propagation of epileptiform activity can be independent of synaptic transmission, gap junctions, or diffusion and is consistent with electrical field transmission. Journal of Neuroscience. 2014 34(4):1409-1419 PubMed

Vadakkan KI (2016) Rapid chain generation of interpostsynaptic functional LINKs can trigger seizure generation: Evidence for potential interconnections from pathology to behavior. Epilepsy & Behavior. 59:28-41 PubMed

Heterogeneity of clinical and pathological findings in Alzheimer's disease

Alzheimer's disease (and most other neurodegenerative disorders) are highly heterogeneous in its clinical and pathological features (Lam et al., 2013; Esteves and Cardoso, 2020). Since transcriptomic analysis shows that no two neurons are same (Tasic et al., 2016; Cembrowski et al., 2016; Tasic et al., 2018; Hodge et al., 2019) and since IPL formation can occur between abutted spines that belong to different neurons at locations of convergence (Vadakkan, 2019), pathological IPL fusion changes expected to occur in neurodegenerative disorders occur between different sets of neurons in different patients. Hence, depending on the outcome of damage that can occur due to the specific combinations of fusion between different sets of neurons, huge heterogeneity can be expected.

Lam B, Masellis M, Freedman M, Stuss DT, Black SE. (2013) Clinical, imaging, and pathological heterogeneity of the Alzheimer's disease syndrome. Alzheimers Res Ther. 2013 Jan 9;5(1):1 PubMed

Esteves AR, Cardoso SM (2020) Differential protein expression in diverse brain areas of Parkinson’s and Alzheimer’s disease patients. Sci. Rep. 2020, 10:1–22. PubMed

Tasic et al., (2016) Adult mouse cortical cell taxonomy revealed by single cell transcriptomics. Nat Neurosci. 19(2):335-346. PubMed

Cembrowski MS, Bachman JL, Wang L, Sugino K, Shields BC, Spruston N (2016) Spatial gene-expression gradients underlie prominent heterogeneity of CA1 pyramidal neurons. Neuron. 89(2):351-68. PubMed

Tasic et al., (2018) Shared and distinct transcriptomic cell types across neocortical areas. Nature 2018 563 (7729):72-78. PubMed

Hodge et al., (2019) Conserved cell types with divergent features in human versus mouse cortex. Nature 573 (7772):61-68. PubMed

Therapeutic agents effective in unrelated neurological and psychiatric disorders alleviate different types of headaches

 

First, there are large number of distinct headache pains that has their own unique features. Secondly, medications having opposite actions such as a) dopaminergic and dopamine antagonists b) those that increase and decrease oxygenation and/or circulation are used to alleviate different headaches, indicating that there is an optimal state for a mechanism whose changes to either side generate internal sensations of pain. Thirdly, pain is sensed during a conscious state indicating that the mechanism of internal sensation of pain has a deep relationship with consciousness. Fourthly, medications used in unrelated neurological and psychiatric disorders are used to alleviate distinct types of headaches, indicating that there is a deep underlying common mechanism that is being reversed by these medications. Demonstration of the latter is essential to confirm the identification of the mechanism of both pain and neurological and psychiatric disorders where these pharmaceutical agents are effective. IPL mechanism satisfies there requirements. Therapeutic agents act at different targets along the axis of the mechanism as explained below.

 

   1. Reducing consciousness: By forming large number of non-specific IPLs, general anesthetics alter conformation of C-semblance altering consciousness (Vadakkan, 2010; 2015b). When C-semblance is altered, p-semblance cannot be formed. This explains a mechanism how anesthetic agents prevent internal sensation of pain.

      2. Altering sensory inputs: Botulinum toxin, local anesthetic agents, and plastic surgery are used for treating different types of pain (Becker 2020; Robbins et al., 2014;Kung et al., 2011). If sensory inputs act as a noxious stimuli, then removing these input can alleviate pain. Furthermore, qualia of internal sensation takes place by retrograde extrapolation from the inter-LINKed spine towards all the sensory receptors (Vadakkan, 2013). When these sensory receptors are removed by plastic surgery, then it can eventually alter the qualia of pain.

3. Reducing synaptic transmission: Magnesium is used for preventing headaches (Saldanha et al., 2021). It prevents opening of NMDA receptors in excitatory glutamatergic synapses, which in turn reduce reactivation of IPLs, which prevents perception of pain. The same mechanism enables the use of  intravenous magnesium to control seizure disorders.

   4. Altering dendritic spine size:

    

a. Increasing spine size: Dopamine is known to increase spines size (Yagishita et al., 2014). Dihydroergotamine is a dopamine agonist that has been used for treating refractory headaches (Nagy et al., 2011). It is expected to promote formation non-specific IPLs in the cortex and alter conformation of p-semblance

b. Decreasing spine size by blockers of dopamine action: Chlorpromazine is a dopamine antagonist and is used in acute headaches (Hodgson et al., 2021) and also to break the cycle of   headaches. It is expected to reduce the size of spines and that will reverse large number of IPLs. Chlorpromazine was used routinely to treat psychosis until the arrival of newer medications. It mechanism can e explained by its ability to reverse large number of non-specific IPLs present in people with psychotic disorders (Vadakkan, 2012).

Metoclopramide is a dopamine receptor antagonist used in primary headaches during pregnancy, postpartum, and   breastfeeding (Saldanha et al., 2021). It reduces the number of IPLs and change conformation of p-semblance.

   5. Altering IPL formation: Altering the number of IPLs by increasing oxygenation

1. Oxygen is used as a treatment for cluster headache (Cohen et al., 2009). The quick relief of this excruciating pain can be explained in terms of reduction in the number of IPLs responsible for inducing p-semblance. Evidence for this comes from indirect findings that need to be verified. a) Modified Golgi stain showed reticulate pattern of connections between neurons. When this was modified by Ramon Cajal using strong oxidizing agents spread of stain was limited to dendritic spines (postsynaptic terminals). The Golgi stain is formed by the black color of metallic silver when silver nitrate is reduced (opposite of oxidation). Additional oxidizing agents used in the reaction mixture decrease the ability of tissue to reduce silver nitrate to silver and thereby restrict the spread of the reaction beyond the spines. Also note that presynaptic terminal is most resistant to Golgi stain. Hence, it can be inferred that the spread of Golgi stain to form a reticulated pattern when oxidizing agents are decreased most probably takes place through a non-trans-synaptic route. If all the above are true, then a reasonable inference that can be drawn is that maintenance of IPLs is an oxidation-state dependent process. This can be verified by conducting experiments. b) Rapid irreversible brain death due to lack of oxygen also prompts further investigations. If the inferences from modified Golgi staining can be verified, then it means that any lack of oxygen will lead to IPL fusion very quickly. The inference that IPL fusion is prevented by an adaptation (Vadakkan, 2020) also supports this view. This can explain rapid irreversible brain death due to lack of oxygen. The incentive in studying this is that once confirmed, it is possible to use intravenous oxidizing agents to prevent IPL fusion in acute anoxic conditions and prevent brain death.

2. Vasodilatation: Propranolol can increase blood flow that can promote oxidation state dependent alteration in the number of IPLs similar to the effect of oxygen. Since propranolol is the most lipophilic beta blocker, it may interact with membrane lipid bilayers and can cause changes in number of IPLs.

3. Anti-seizure medications: Topiramate is an anti-seizure medication that is expected to operate by blocking rapid chain reaction of IPLs (Vadakkan, 2016). A similar effect can reduce migraine headaches. Similar action of anti-seizure mediation carbamazepine can explain how it is effective in alleviating trigeminal neuralgia, pain of herpes zoster, and neuropathic pain.

4. Sumatriptan cause vasoconstriction and reduce headache caused by vasodilation. By reducing the flow of blood, sumatriptan reduces available oxygen, which in turn alters the number of IPLs to change the conformation of p-semblance.

Since both excessive oxygenation and reduced oxygenation are effective methods in different types of headaches, it can be inferred that alternation either in the number or in function of IPLs is taking place when oxygenations is altered. Alternatively, oxidation state of the environment around IPLs has a role in changing the number or function of IPLs.

Special findings associated with pain

a) Cortical spreading depression: Spreading depolarizationthat propagates across the cortex at a velocity of 2 to 5 mm/min (Ayata and Lauritzen, 2015) can be explained in terms of slow propagation of formation and reversal of IPLs. This is similar to the mechanism explained for seizures, but at a slow rate (Vadakkan, 2016). It can be induced by hypoxic conditions (Dreier and Reiffurth, 2015). Topiramate is known to reduce cortical spreading depression (Akerman and Goadsby, 2005; Unekawa et al., 2012) similar to its expected anti-seizure action. This can be explained by the action of topiramate on different ionic channels that prevents IPL formation.

b) Firing of neurons both with pain: Subsets of anterior cingulate cortical (ACC) neurons neurons fire both during nociception (Koyama et al., 2001). An inhibitory blanket present in the cortex (Karnani et al., 2014) keeps several neurons slightly below the threshold for activation so that they are fired when inter-LINKed spines at the level of lower orders are activated by painful stimulus. These firing neurons are connected to motor neurons for behavioral actions to avoid life-threatening painful stimuli.

Special cases of pain

a) Referred pain: Qualia of internal sensation takes place by retrograde extrapolation from the inter-LINKed spine towards all the sensory receptors (Vadakkan, 2013). If outputs from two primary neurons converge to a neuron of a higher neuronal order in the cortex (e.g. outputs from cervical and trigeminal neurons) before forming an IPL, then a noxious stimulus from the face region can get referred to the cervical region and vice versa (Piovesan et al., 2001).

b) Phantom pain: Retrograde extrapolation towards the sensory receptors provides the sensory features of qualia (Vadakkan, 2013). This informs that a) sensory qualia depends on all inputs that were used to arrive at the inter-LINKed spine, and b) lower neuronal and IPL-mediated pathways need not have to be present for the p-semblance to occur. Reactivation of inter-LINKed spines in the cortex leads to internal sensation of pain occurring at the locations from where pain used to arrive.

c) Post-ictal headache: Many non-specific IPLs generated during seizure (Vadakkan, 2016) takes time to completely reverse back. Severe alteration in the net background semblance can explain why consciousness is lost during seizures. As they reverse back, consciousness is regained. However, the remaining non-specific IPLs generate p-semblance for post-ictal headache.

d) Hemiplegic migraine: Alteration in the number of IPLs changes conformation of semblances to generate specific p-semblance for headache. It can also lead to loss of upper motor neuron activity leading to transient upper motor neuron type of weakness in the limbs.

e) Chronic pain: Perceiving pain in the absence of pain stimulus following initial painful stimuli is responsible for chronic pain. The painful stimuli are expected to make some long-lasting changes in the cortex. This can be explained by stabilization and continued reactivation of the IPLs responsible for p-semblance in different cortical regions responsible for pain.

f) Herpes Simplex Virus (HSV) infection: HSV infection of the brain presents with headache and fever (90%), psychosis (75%), seizures (50%). Viral fusion proteins released by HSV virus increase the number of non-specific IPLs and generate a p-semblance for headache. Formation large number of non-specific IPLs can explain psychosis (Vadakkan, 2012) and seizures (Vadakkan, 2016).

In summary, IPL mechanism provides a common shared mechanism that can explain how medications with disparate actions are effective in headache pains and how they are effective in alleviating symptoms of unrelated neurological and psychiatric disorders. These are testable findings that can be verified.

References

 

Akerman S, Goadsby PJ. Topiramate inhibits cortical spreading depression in rat and cat: impact in migraine aura. Neuroreport. 2005;16(12):1383–1387. PubMed 

Ayata C, Lauritzen M. Spreading Depression, Spreading Depolarizations, and the Cerebral Vasculature. Physiol Rev. 2015;95(3):953–993.

Becker WJ. Botulinum Toxin in the Treatment of Headache. Toxins (Basel). 2020;12(12):803.

Cohen A, Burns B, Goadsby PJ. High-flow oxygen for treatment of cluster headache: a randomized trial. JAMA. 2009;302(22):2451–2457.

Dreier JP, Reiffurth C. The stroke-migraine depolarization continuum. Neuron. 2015;86(4):902–922.

Hodgson SE, Harding AM, Bourke EM, Taylor DM, Greene SL. A prospective, randomized, double-blind trial of intravenous chlorpromazine versus intravenous prochlorperazine for the treatment of acute migraine in adults presenting to the emergency department. Headache. 2021.

Karnani MM, Agetsuma M, Yuste R. A blanket of inhibition: functional inferences from dense inhibitory connectivity. Curr Opin Neurobiol. 2014;26:96-102.

Koyama T, Kato K, Tanaka YZ, Mikami A. Anterior cingulate activity during pain-avoidance and reward tasks in monkeys. Neurosci Res. 2001;39(4):421430.

Kung TA, Guyuron B, Cederna PS. Migraine surgery: a plastic surgery solution for refractory migraine headache. Plast Reconstr Surg. 2011;127(1):181189.

Nagy AJ, Gandhi S, Bhola R, Goadsby PJ. Intravenous dihydroergotamine for inpatient management of refractory primary headaches. Neurology. 2011;77:1827–1832.

Piovesan EJ, Kowacs PA, Tatsui CE, Lange MC, Ribas LC, Werneck LC. Referred pain after painful stimulation of the greater occipital nerve in humans: evidence of convergence of cervical afferences on trigeminal nuclei. Cephalalgia. 2001;21(2):107–109.

Robbins MS, Kuruvilla D, Blumenfeld A, Charleston L 4th, Sorrell M, Robertson CE, Grosberg BM, Bender SD, Napchan U, Ashkenazi A; Peripheral Nerve Blocks and Other Interventional Procedures Special Interest Section of the American Headache Society. Trigger point injections for headache disorders: expert consensus methodology and narrative review. Headache. 2014;54(9):144159.

Saldanha IJ, Cao W, Bhuma MR, Konnyu KJ, Adam GP, Mehta S, Zullo AR, Chen KK, Roth JL, Balk EM. Management of primary headaches during pregnancy, postpartum, and breastfeeding: A systematic review. Headache. 2021;61(1):1143.

Unekawa M, Tomita Y, Toriumi H, Suzuki N. Suppressive effect of chronic peroral topiramate on potassium-induced cortical spreading depression in rats. Cephalalgia. 2012;32(7):518–527.

Vadakkan KI. Framework of consciousness from semblance of activity at functionally LINKed postsynaptic membranes. Front Psychol. 2010:1:168.

Vadakkan KI. A structure-function mechanism for schizophrenia. Front Psychiatry. 2012;3:108.

Vadakkan KI. A supplementary circuit rule-set for the neuronal wiring. Front Hum Neurosci. 2013;7:170

Vadakkan KI. A framework for the first-person internal sensation of visual perception in mammals and a comparable circuitry for olfactory perception in Drosophila. Springerplus. 2015a;4:833.

Vadakkan KI. A pressure-reversible cellular mechanism of general anesthetics capable of altering a possible mechanism for consciousness. SpringerPlus. 2015b:4:485.

Vadakkan KI. Rapid chain generation of interpostsynaptic functional LINKs can trigger seizure generation: Evidence for potential interconnections from pathology to behavior. Epilepsy Behav. 2016;59:2841.

Vadakkan KI. From cells to sensations: A window to the physics of mind. Phys Life Rev. 2019;31:4478.

Vadakkan KI. A derived mechanism of nervous system functions explains aging-related neurodegeneration as a gradual loss of an evolutionary adaptation. Curr Aging Sci. 2020;13(2):136-152.

Yagishita S, Hayashi-Takagi A, Ellis-Davies GC, Urakubo H, Ishii S, Kasai H. A critical time window for dopamine actions on the structural plasticity of dendritic spines. Science. 2014;345:1616–1620.