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


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

Pathological features of Alzheimer's disease such as plaques & tangles are present in normally aging brains (Was able to explain this recently: Aging as a loss of an adaptation that stabilizes the 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 observation of death of nearly 70% of neurons at one stage, followed by survival of the remaining 30% neurons. The surviving 30% of cells are expected to have acquired an adapation. IPLs that provides the system with inner sensations need to be prevented from 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 true, then its corollary that these pathological findings should also be found in normal aging can be verified. Since senile amyloid plaques and neurofibrillary tangles appear in normally aging brains (Anderson, 1997), 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

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):1781-92. 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