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

Galapagos of neuroscience

There are a large number of symptoms and signs in “loss of function” states of the system manifested as neurological and psychiatric disorders. Several unrelated disorders have certain similar features. In addition, it is possible to examine the effect of a large number of pharmaceutical agents in these conditions. Often it is found that one pharmaceutical agent produces improvement of symptoms in several disparate neurological and psychiatric disorders. In fact, several of these medications were found effective in different disease conditions by accidental coincidence and not by application of knowledge directed towards those disorders. This is due to the lack of knowledge of the mechanism that cause these disorders. These findings immediately open huge possibility for undertaking a scientific approach to verify any hypothesis of nervous system functions. In this context, semblance hypothesis is examined. It is not possible to understand the details of all the findings now. However, both the similarities and the diagonally opposite findings in various disorders and the observed effects of pharmaceutical agents can be used to examine whether we can make inter-connectable explanations that make sense. At this stage of inquiry, the inferences that can be arrived are expected to provide huge benefits towards understanding the details of the normal operation of the system. This is going to be a long journey.

Readers are expected to have finished reading at least the first and the FAQ page of this website before examining the rest of this webpage to get an understanding of what we can infer from the observations from “loss of function” states of different disorders. Specific references to publications are provided wherever necessary. The content of this webpage is a rough draft of a new project that I just started and will be updated as it progresses. It was started with the idea that dissemination of these findings should not be delayed since so many people are suffering from neurological and psychiatric disorders and I believe that those patients will have expectations about undertaking such an effort at this stage of development a hypothesis of nervous system functions. After all, these findings were made possible by those patients.

As the journey begins, our key questions are, “If the semblance hypothesis is correct, what would we find in a particular disorder?” “Can the observations in a disorder and the effect a specific pharmaceutical agent makes sense in the light of the hypothesis?” Please note that at this stage we may not be able to find explanations for all the findings in every disorder. If the hypothesis is correct, then it is reasonable to find explanations for a large number of observations and that we should be able to find inter-connectable explanations for similar symptoms and effectiveness of medications in unrelated disorders. I must admit that I was implicitly influenced by findings from a large number of nervous system disorders during the development of the semblance hypothesis. However, I began to carry out conscious effort to examine majority of these findings in terms of the hypothesis only after the initial derivation of the hypothesis.

Without further ado, let us begin our journey.

Why are we taking this journey? What is the motivation behind this? It was not long ago that we discovered the DNA and the genetic code. This led to the understanding of "One gene-one polypeptide" concept. Following this, we were faced with the task of identifying the functions of a large number of proteins. The best method by which we were able to understand this was to make mutations in the genes and observe their effect on the phenotype. Several advantages of the fly Drosophila were utilized to generate random mutations in different genes that generated specific "loss of function," and in some special conditions, "gain of function" states. These experiments allowed us to understand the genotype-phenotype relationships and the role of specific proteins. In this context, it is reasonable to argue that one of the powerful tools to understand the nervous system functions is to examine its altered functional states. Nature has been generating a large number of these disease states of the nervous system with several shared features. In addition, we have been observing the effectiveness of specific pharmaceutical agents in alleviating features of unrelated neurological and psychiatric diseases. Nervous system disorders provide a particular type of puzzle that can be examined for testing theoretically feasible hypotheses. In this journey, our aim is to verify whether these disorders can be explained as defects in the operating mechanism derived by the semblance hypothesis (Fig.1). This reminds me of the journey of Charles Darwin on the Galapagos Islands to figure out how life on Earth reached the present state. Present examination is of a different type since it is used for examining whether the alteration in the findings made by a derived mechanism of nervous system functions leads to different diseases. Galapagos Islands also reminds us how adaptations can be brought into heritable traits within short periods (Video). Nature is the biggest laboratory where a large number of experiments have already been taken place and it is up to us to serch for the results and seek the order behind them.

The guiding principles for examining the disease states to verify the derived mechanism was previously explained (Vadakkan 2016d). Further examination was carried in seizure disorders (Vadakkan 2016c), and neurodegenerative changes after repeated anesthetic use (Vadakkan 2015b). It was surprising to find a potential reason for age-related neurodegenerative changes as a consequence of the defects in maintaining the last stage of evolution of the nervous systems towards optimizing generation of internal sensations within the nervous system (Vadakkan, 2019).

Defects in normal functions of a system

Figure 1. Disease conditions of different systems can be and should be explained in terms of “change of function” states of the normal operations of those systems. Only when we understand how a system operates, we can explain the causes of different diseases of that system in an inter-connectable manner that makes sense. On the left is a general outline of genomic function and how defects at different levels cause its different disorders. On the right side is the derived inter-postsynaptic functional LINK (IPL) mechanism of nervous system operations and the potential defects that can arise at its different levels. Note that vesicle (V) exocytosis at the inter-spine locations leads to membrane reorganization that can promote IPL formation. Also note that defects in the IPL formation can lead to IPL fusion (see the figure 8 in FAQ section of this website). What is not shown in the figure is the observation that dopamine leads to the enlargement of spines, which can facilitate IPL formation. Our job is to examine all the nervous system disorders to find whether the disease processes can be explained in terms of the defects of the derived normal IPL mechanism. For details of the figure, please see the figure legends of figures 6 and 8 in the FAQ section of this website.

1. Huntington's Disease: Early disease symptoms include slight memory problems, clumsiness, depression, mood swings such as irritability and erratic behavior. Later, the patient starts developing involuntary, hyperkinetic movements called chorea (uncontrollable, graceful, excessive movements of limbs similar to that of performing a dance). At advanced stages, chorea settles down and the patient develops severe parkinsonian features.

What is currently known? This disease occurs due to the formation of excessive dopamine. So, it has been thought that it causes an effect on the direct and indirect pathways in the basal ganglia, which is opposite to that of the Parkinson's disease (Calabresi et al., 2014). No further explanations are available. It is treated with tetrabenazine, which depletes dopamine within the synaptic vesicles of dopaminergic neurons by inhibiting vesicular monoamine transporter type 2.

Explanations based on IPL formation:

Basic explanation for the pathology: Excessive dopamine leads to spine expansion that lead to the formation of non-specific IPLs and eventually IPL fusion that leads to spine loss and eventually neuronal death. These changes are expected to be formed at the locations where dopaminergic inputs arrive and eventually cause expansion of spines of synapses having other neurotransmitters. Experiments that added dopamine artificially to synaptic regions in both striatum and nucleus acccumbens (O'Donnell and Grace, 1993; Onn and Grace, 1994) have shown fusion between neurons as evidenced by dye diffusion between neighbouring neurons. Based on semblance hypothesis, IPL formation is taking place between spines that belong to different neurons as a default mechanism and that excessive dopamine is generating IPL fusion that allows dye to transfer between the neurons whose spines undergo IPL fusion. Note that IPL fusion is at the far end of the spectrum of different IPLs (Figure 8 in the FAQ section of this website; Vadakkan, 2016a). 

Subcortical dementia: Non-specific IPLs cause dilution of specific semblances, expected to form during retrieval of a specific memory, with non-specific semblances. This results in memory lapses.

Psychiatric features: Formation of non-specific IPLs can lead to hallucinations (Vadakkan, 2012a).

Hyperkinetic movements (chorea): Formation of excessive number of IPLs leads to excessive activation of motor units. When regulatory pathways are brought in place, this can generate excessive graceful movements of chorea.

Parkinsonian features during the last stages: IPL fusion leads to spine loss. Large number of spines on the medium spiny neurons undergo IPL fusion, which leads to spine loss and eventual loss of these neurons. This eventually reduces the number of medium spiny neurons and their spines that can form IPLs, which will have an equivalent effect of having a reduced amount of dopamine for facilitating rapid IPL formation as expected in Parkinson's disease (Vadakkan 2016d).

Later stage shows loss of volume of the caudate head in brain imaging: This can be explained in terms of neuronal loss secondary to IPL fusion changes.

Patients have reduced saccadic movements of the eyeballs. It will be possible to find out the exact location where excessive IPL formation leads to this sign, which is routinely used to diagnose this disorder at an early stage.

The abnormal protein, namely Huntingtin, produced in Huntington's disease is a component of vesicle membranes. This may have additional influence on IPL fusion.  

Extreme delta brush is an EEG finding: There are large wavy patterns that have excessive horizontal component in the waveforms. It will be possible to explain this finding in terms of excessive number of IPLs that form large islets of inter-LINKed spines in the cortices.

Westphal variant of Huntington's disease starts at a young age. The main features include is akinetic rigidity, seizures (Vadakkan, 2016c) and myoclonus. These symptoms can also be explained in terms of the formation of excessive IPLs.

Interconnected findings that provide support for the IPL mechanism include the following:

1) Excessive dopamine leads to excessive enlargement of spines, which leads to the formation of non-specific IPLs.

2) IPL fusion resulting in memory problems, hyperkinetic movements and hallucinations.

2. Parkinson's disease: Disease symptoms include tremor, rigidity bradykinesia and postural instability. Later cognitive defects, dyskinesia and hallucinations develop.

What is currently known? It is caused by damage to the substantia nigra (pars compacta) neurons that release dopamine at their axonal terminals that synapse with medium spiny neurons (named due to the relatively large number of spines on them) of the basal ganglia. Dopamine activates both direct and indirect pathways in the basal ganglia to regulate the thalamic output to the upper motor neurons of the motor cortex to smoothen the motor actions. L-DOPA is used in the treatment. It is converted to dopamine and binds to the dopamine receptors. It then leads to both activation of the direct pathway and inhibition of an indirect pathway that together smoothen the motor actions. The effect of a fixed dose of L-DOPA reduces gradually. As the disease progresses, patients will require a  higher dose of the drug at more frequent intervals to have the same initial effect. Eventually, even with high doses of L-DOPA the disease become uncontrollable. Moreover, side effect of L-DOPA limits usage of this medication beyond a certain amount. After a few years, patient gets mild cognitive impairment. At advanced stages, patients suffer from more cognitive problems and often get hallucinations.

Explanations based on IPL formation:

Basic explanation for the normal actions: Normal concentration of dopamine reaching the dopaminergic synapses leads to the enlargement of spines of medium spiny neurons and generates IPLs (without causing IPL fusion) that facilitates activation of thalamic outputs to the motor cortex. This helps to make smooth motor movements.

Basic explanation for the pathology: Since the initial use of L-DOPA just before 1970, every Parkinson's disease patient is using dopaminergic medications. This has affected the natural history of the disease that we observe currently. Dopamine leads to the enlargement of the spines. Artificial increase in dopamine levels by the administration of L-DOPA is different from the physiological concentration of dopamine released to the dopaminergic synapses. Furthermore, it is not known how different factors can influence the consequences of spine enlargement by dopamine. It is probable that dopamine eventually leads to fusion between the spines that belong to different medium spiny neurons and can lead to loss of spines. The factors predisposing to inter-spine fusion include changes in lipid membrane composition, lack of proteins that can stabilize the inter-spine hemifusion stage of fusion, etc. At advanced stages, spine fusion can eventually result in spread of pathology to the dopaminergic presynaptic terminals that synapse to the medium spiny neurons. Based on the explanations by the IPL mechanism, in addition to supplementing dopamine, it is necessary to find methods to stabilize the IPLs to prevent them from progressing to the IPL fusion stage.

Memory problems: During the initial stages, lack of dopamine affects both the motor actions and cognition. Later, administration of dopamine result in enlargement spines and IPL fusion that can lead to loss of spines and neurons.  

Bradykinesia: Due to a lack of dopamine, the net output from the direct and indirect pathways to the thalamus is reduced.

Hallucinations: At the advanced stages of the disease when the patients need more dopamine for maintaining movement, they suffer from hallucinations. Treatment with dopamine leads to the enlargement of non-specific sets of spines that can lead to the formation of non-specific IPLs, which in turn can induce non-specific semblances responsible for hallucinations.

Interconnected findings that provide support for the IPL mechanism:

1) Parkinsonian features during the last stages of Huntington’s disease: Since a large number of spines of medium spiny neurons in Huntington’s disease undergo fusion, there will be both losses of these spines and their neurons. This produces symptoms of hypokinetic movements of Parkinson’s disease resulting from the reduced amount of dopamine that can facilitate IPL formation (Vadakkan 2016d).

2) The increased movements causing chorea is most commonly seen in patients with Parkinson's disease who are taking neuroleptic medications that are dopamine receptor D2 blockers. When D2 receptors are blocked, whatever dopamine is available from substantia nigra pars compacta binds to the D1 receptors and results in unopposed activation of the direct pathway leading to hyperkinetic movements of chorea. This can lead to IPL fusion between spines belonging to different neurons. The end result will be similar to that of Huntingon's disease.


Calabresi et al., (2014) Direct and indirect pathways of basal ganglia: a critical reappraisal. Nature Neuroscience 17(8):1022-1030 Article

O'Donnell P, Grace AA (1993) Dopaminergic modulation of dye coupling between neurons in the core and shell regions of the NAc. J Neurosci 13(8): 3456-3471 Article

Onn SP, Grace AA (1994) Dye coupling between rat striatal neurons recorded in vivo: compartmental organization and modulation by dopamine. J Neurophysiol 71(5): 1917-1934. Article

Vadakkan KI (2012a) A structure-function mechanism for schizophrenia. Frontiers in Psychiatry. Article

Vadakkan K.I (2015b) A pressure-reversible cellular mechanism of general anesthetics capable of altering a possible mechanism for consciousness. SpringerPlus. Article

Vadakkan KI (2016c) Rapid chain-generation of inter-postsynaptic functional LINKs can trigger seizure generation: Evidence for potential interconnections from pathology to behavior. Epilepsy & Behavior. Article

Vadakkan KI (2016d) Neurodegenerative disorders share common features of "loss of function" states of a proposed mechanism of nervous system functions. Biomedicine and Pharmacotherapy. Article

Vadakkan KI (2016e) The functional role of all postsynaptic potentials examined from a first-person frame of reference. Reviews in the Neurosciences. Article

Vadakkan K.I (2019) A mechanism of nervous system functions capable to have evolved: through the generation of an inducible variant of inter-cellular fusion. Peerj Preprints. Article