Semblance Hypothesis

After more than a decade of examination by adhering to best available scientific methods1-6, 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, no objections were received. This is a theory of nervous system functions that provides 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"7 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. Dutailly JC (2017) Chapter 1.What is science? Theoretical Physics. p1-24. Article

7. 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.

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.

In this approach, large number of examinations was carried out in seizure disorders (Vadakkan 2016b), and neurodegenerative changes after repeated anesthetic use (Vadakkan, 2015b). Furthermore, 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). Possible explanations for alterations in brain functions by COVID-19 virus whose fusion proteins can cause changes in the proposed mechanism that generates inner sensations (Vadakkan, 2021a) is another example. Ability to explain a mechanism for pleasure and its alteration by drugs of abuse (Vadakkan, 2021b) is another example.

In the Galapagos of neuroscience, there are very large number of findings. In the following section, findings in different disease conditions that can form part of the large puzzle or inter-connected triangulations are listed. It is hoped that they can be explained in terms of IPLs. There are several factors that need to be taken care of. Main ones are a) effect of location of lesion in a disease condition and how it is going to affect the overall output (both internal sensations and motor output) from the brain, and b) effect of different neurotransmitters in a region in regulating generation of both internal sensations and motor outputs. This is a work in progress and the hope is that plausible explanations can be searched for various disease conditions.

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 & 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, 2016b).

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 2016b).

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.

3. Headache Pains

 

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 these 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 noxious stimuli, then removing these input can alleviate pain. Furthermore, qualia of internal sensation take 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 (Vadakkan, 2021c). 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, 2016c). 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 oxygenation 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 headache pains

a) Cortical spreading depression: Spreading depolarization that 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, 2016c). 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 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.

c) Migraine type of headache seldom occurs after the age of 45. This is possibly due to slow spread of generation of IPLs due to changes in the ECM.

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, 2016c) 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, 2016c).

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.

------------------------------------------------------------------------------------------------------------------

Following is an expanding list of findings from different neurological and psychiatric disorders that can be examined for their suitablity for explanations in terms of IPL formation and function. I hope to provide those explanations in the due course. You can reach those explanations by imagination based on the logic applied to explain several disease conditions. Many of them can provide testable predictions.

Seizures (see Vadakkan, 2016c)

1. Juvenile Myoclonic Epilepsy - Generalized tonic clonic seizures provoked by sleep deprivation. Childhood absence epilepsy – Children outgrow these seizures

 

2. Juvenile absence seizures – Require life-long treatment

 

3. Eye deviation at the onset of seizure

 

4. Post-ictal aphasia shows that seizure lateralize to dominant hemisphere

 

5. Short-acting benzodiazepines become anesthetics. Clonazepam is useful for myoclonic, absence and partial seizures. Lorazepam is useful for status epilepticus. Midazolam (shortest life) is an anesthetic agent used in status epilepticus. Does lipid solubility increase from clonazepam to midazolam? Note that midazolam become much more lipid soluble at physiological pH.

 

6. One of the effective treatment modalities of certain types of seizures is multiple sub-pial resections. It usually reduces the intensity of seizures. During this procedure, any horizontal connections (IPLs) get severed to stop spread of synchronous seizure activity.

 

7. Frontal lobe seizure has Jacksonian march

 

8. Automatisms are involuntary complex motor activity during impaired consciousness. They can occur with complex partial or absence seizures.

 

   9. Early onset benign childhood occipital epilepsy (Panayiotopoulos syndrome) has visual seizures – elementary or complex visual hallucinations, amaurosis, illusions (e. g. metamorphopsia), which are experience usually during wakefulness. Inter-ictal EEG has nearly continuous bursts or trains of high-voltage rhythmic occipital spikes and spike wave complexes at a frequency of 1-3 Hz localized to uni or bilateral occipital cortices with normal background activity. It increases during non-REM sleep and disappears when eyes are opened. Late onset benign childhood occipital epilepsy (Gestault) – Visual hallucinations are often followed by migraine headache.

 

10. Myoclonic seizure originate from different locations. It should become possile to provide mechanistic explaination for all of them.

             a: Cortical reflex myoclonus: discharge from sensorimotor cortex

             b: Reticular reflex myoclonus: discharge from brainstem reticular formation

             c: Primary generalized epileptic myoclonus: diffuse bursts of polyspike & wave or spike & wave

             d: Non-epileptic myoclonus: most common

11. Seizure is seen in SCA 7, SCA10 & DRPLA

 

12. Valproic acid causes more cognitive defects in seizures patients – matches with the idea that it reduces IPLs (Meador et a., 2009)

 

13. VPA increase IPLs in some locations and decreased IPLs in other locations

 

14. Impact seizure is the immediate post-traumatic seizure

 

15. TCA is an anti-seizure medication – It is likely by IPL mechanism

 

16. Landau-Kleffner syndrome – Seizures and Language defects

17. Prolonged QRS in EKG is a good predictor for seizures. Can this eletrophysiological finding have any relationship with IPL formation at certain areas of the nervous system or is it a feature of a generalized phenomenon?

18. Status epilepticus is a feature of critical illness neuropathy.

 

19. Some seizures are responsive to B6 vitamin.

 

20 HSV infection cause PLEDS, periodic slow wave complexes and diffuse slowing in EEG. Is HSV viral fusion protein is responsible for excesstive non-specific IPL formation?

21. Benign rolandic epilepsy has recurrent headaches or migraines. Are non-specific IPLs responsible for these?

22. Many encephalitis patients have seizures. Eg. HSV1, La Crosse (California) encephalitis.

 

Encephalopathies

 

Hypertensive encephalopathy – symptoms aphasia, hemiparesis – seen in cyclosporine neurotoxicity due to thrombocytopenia – possibly also has IPL fusion as the basic causative pathology.

 

Methanol cause encephalopathy. Long-term effect is Parkinsonism – Likely causing IPL fusion and lead to spine loss & neuronal death.

Hypoxic Ischemic Encephalopathy (HIE): Ischemia cause release of phospholipases – free fatty acids are released from neuronal membranes (Collard & Gellman, 2001). It is possible to prevent encephalopathy by inhibiting action of phospholipases? Does it provide any information regarding stability of membranes & IPL fusion events?

Cytotoxic edema is seen viral infections of the brain parenchyma. One possible explanation is that viral fusion proteins can lead to cytoplasmic content mixing that can lead to, spine loss & neuronal swelling, responsible for cytotoxic edema.

Third stage of Lyme disease has mild encephalopathy – which is manifested as memory dysfunction & psychiatric disorders.

Whipples disease has encephalopathy.

Myoclonus

 

1. Post anoxic myoclonus – is an action myoclonus – this is almost always associated with cerebellar ataxia. Not inhibited by Purkinji outputs. Often, it is a self-limited condition.

 

Head Injury

Concussion: Acute symptoms include headache, confusion, amnesia, dizziness, unsteadiness. Signs include vacant starring, confusion, disorientation, memory disturbances, ataxia, incoordination, slurred speech, & behavioral disturbances.

Depression

There are several findings in the nervous system disease from where information can be taken to synthesize a mechanism for internal sensation of depression.

Antidepressant toxicity generarlly cause hallucinations, tremor, myoclonus, & seizures.

SSRIs can cause hyperkinetic movement disorders. Is it because of increased number of IPLs?

Dementia

Dementia in metachromatic leukodystrophy

Abetalipoprotenemia has acanthocytosis – Is it possible to find a membrane defect in both acanthocytosis and dementia in neuroacanthocytosis?

In MSA, there is atrophy of pons and cerebellum. It is necessary to examine how cells are lost in these areas. Is there any evidence for IPL fusion.

Mutiple Sclerosis

Several studies have shown involvement of the cortex in this disease.

Stroke

Following a stroke affecting the sensoroy cortex, some patients recover from defects in sensations of touch, pain & temperature. However, they still can have significant impairments in two-point discrimination & proprioception. It may mean that some cortical sensations are the result of secondary or tertiary conformations of semblances responsible for primary sensations.

Hypoxic damage

Certain areas of the brain thought to have increased oxidative phosphorylation such as basal ganglia are more prone to hypoxic damage. In addition to its role in oxidative phosphorylation, oxygen can exert its role an oxidising agent to reverse IPLs formed. In the absence of oxygen, IPL fusion can occur at these locations and can lead to spine loss and neuronal death. It is necessary to study whether these regions are rich in spiny neurons, where spines undergo rapid IPL formation and reversal for its functions.

Hallucinations

Both Cogan’s syndrome and Charles Bonnet syndrome have reduced vision. Patients with both these syndromes hallucinate. Is it because the system has IPLs that get reactivated by some mechanism? Reduced light during evening hours can cause "Sun downing" in patients with delirium. Are there any explanations possible?

Heredodegenarative disorders: has schizophrenia like psychosis. At ages between 40 & 60, it causes dementia and Parkinsonism. Dementia is primarily subcortical.

Dopamine related

MAO inhibitor selegiline cause hallucination, vivid dreams, insomnia, dyskinesia, & depression

Viral infections

Viruses release fusion proteins that allow them to enter into cells and also exit from the cells after multiplication. Since IPL mechanism involves initial stages of fusion, neurological and psychiatric findings in these disorders can have direct relationships.

SSPE: a neurodegenerative disorder occurs after nearly 5-10 years. It has 4 phases 1) problems with behavior & cognition, 2) myoclonus, 3) reduced IQ, myoclonus, speech, 4) choreoathetosis, bradykinesia & rigidity.

100% mortality following SSPE and rabies. Does the viral fusion proteins cause fusion of spines and cause substantial neuronal death?

HHV6 cause roseola infantum in infants and young children (also called 6th disease) 1/3 of infected babies have seizures. HHV-6 is associated with MS.

15% infants infected with CMV will have sensorineural deafness; 10% will have microcephaly, microgyria, & seizures.

Nearly 94% of patients with West Nile has tremors.

 St. Louis encephalitis cause frank encephalitis with psychotic features in older patients.

Encephalitis is caused by the following viruses: HSV-1, Arbo viruses (JBE, West Nile, St. Louis, Eastern/Western Equine), & La Crosse (California).

Interconnected findings

Cortical spreading depression in migraine; Jacksonian march in seizure.

Many migraine prophylaxis medications include anti-seizure medications, which shows that a common underlying mechanism is present in both disorders. Spread of formation of IPL that are slow (migraine) and rapid (seizure) can explain these findings.

Seizures are followed by headache pains – It shows that IPL remaining after a seizure alter the conformation of semblances to generate headache pain.

Others: There are several disorders that casue neurological and psychiatric symptoms. Irrespective of their primary defects, the pathophysiology involved in these disorders should be able to explain how they finally lead to different neurological and psychiatric disorders. It is to be noted that they can cause neurological and psychiatric disorders by damaging different cell types that may not have any direct relationship with the IPL mechanism. However, they provide us an opportunity to make a search.

1. Porphyria - Psychiatric symptoms, Abdominal pain. Porphyria also cause anxiety, insomnia, depression, hallucination, and paranoia.

 

2. DRPLA onset before age 20: Usually PME with seizures, dementia, ataxia and myoclonus. If onset is after age 20, ataxia, dementia, and choreoathetosis. All these findings can be explained in terms of changes in IPL mechanism.

 

3. Hypercalcemia patients have severe water deficit. So it can reduce water content of the ECM. It can cause formation of large number of non-specific IPLs. This can explain confusion, weakness, & pseudo-dementia.

 

4. Posterior reversible encephalopathy syndrome (PRES) has convulsive seizures (generalized > focal)

 

5. Sodium oxyabate is an anesthetic agent – so formation of non-specific IPLs can induce a state of reduced consciousness.

 

6. ALS – has laterally spreading sclerosis and it is a pure denervation (no axonal or demyelination)?

 

7. Some of the subfornical organ (SFO)/ organum vasculosum of the lamina terminalis (OVLT) neurons are osmosensitive. Their firing rate increases in response to increases in the tonicity of the extracellular fluid (Zimmerman et al., 2017). ECM changes is likely leading to generation of new IPLs that generates internal sensation of taste and trigger firing of downstream neurons. 

8. Carbon monoxide (CO) poisoning – has pallidal hemorrhagic necrosis at GPi. When there is no oxygen to remove the formed IPLs. In CJD, GPi is not affected. Together, we can say that oxygen induced reversal prevents GPi getting affected in CJD. In other words, oxygen reversal is key in the primary mechanism.

9. TTP patients can develop seizures, confusion, coma, headache, reduced vision, and aphasia. Can certain lipid membrane abnormalities explain both platelet changes and defects in IPL formation?

10. Following radiation, there is somnolence syndrome – anorexia, apathy and headache after nearly 7 days of radiation.  Symptoms last for 4 to 14 days. Usually symptoms reverse back. Severe form has ataxia, focal motor signs, & nystagmus.

11. Peroxisomal biogenesis defects cause encephalopathy, seizures, hypotonia & deafness

12. NCL: features include seizures, regression (could be possibly due to IPL fusion), blindness & psychiatric features

13. GM1 gangliosidosis: has psychiatric features – schizophrenia, psychosis, mood disorder, and dementia, seizures, spasticity & motor impairments. In adults, it causes ALS-like features.

14. Gaucher’s disease patients have seizures, memory problems, spasticity, ataxia, & regression. 

15. Porphyria patitents have anxiety, insomnia, depression, hallucination and paranoia. Porphyria: has seizures & anti-seizure  medications exacerbate acute porphyria.

16. Episodic ataxia respond sto treatment with a diruretic acetazolamide. Is it helping to generate IPLs for normal functioning of cerebellum? 

17. Manganese toxicity: Cause headaches, memory disturbances, hallucinations, aggressive behavior, apathy, irritability, social withdrawal, personality changes, psychosis (manganese madness) & extrapyramidal symptoms.

18. Whipples disease has seizures, encephalopathy, coma, dementia, hyper-insomnia, and cerebellar ataxia. Cofactor of heat shock protein 70 from T. Wipplei has fusion property (Weigt et al., 2017). Can this increase formation of non-specific IPLs?

 

Abbreviations

ALS: Amyotrophic lateral sclerosis

CJD: Creutzfeldt-Jakob disease

CO: Carbon monoxide

DRPLA: Dentatorubral-pallidoluysian atrophy

EEG: Electroenephalogram

EKG: Electrocardiogram

GPi: Globus pallidus interna

HHV6: Human herpes virus 6

HIE: Hypoxic Ischemic encephalopathy

HSV: Herpes simplex virus

JBE: Japanese B encephalitis

MAO: Monoamine oxidase

MS: Multiple sclerosis

MSA: Multi-system atrophy

NCL: neuronal ceroid lipofuscinosis

PLEDS: Periodic lateral epileptiform discharges

PME: Progressive myoclonic epilepsy

PRES: Posterior reversible encephalopathy syndrome

SCA: Spinocerebellar strophy

SSPE: Subacute sclerosing panencephalitis

SSRI: Selective serotonin reuptake inhibitors

References

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

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

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

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

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

Collard & Gellman Anesthesiology. 2001: 94: 1133

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

Hodgson SE, Harding AM, Bourke EM, Taylor DM, Greene SL (2021) 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. 61(4):603-611. Article

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

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

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

Meador et al., (2009) Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med. 360(16):1597-605. Article

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

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

Robbins MS, Kuruvilla D, Blumenfeld A, Charleston L 4th, Sorrell M, Robertson CE, Grosberg BM, Bender SD, Napchan U, Ashkenazi A (2014) Trigger point injections for headache disorders: expert consensus methodology and narrative review. Headache. 54(9):144159. Article

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

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

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

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

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

Vadakkan KI (2015a) 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. Article

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

Vadakkan KI (2016a) The functional role of all postsynaptic potentials examined from a first-person frame of reference. Reviews in the Neurosciences. 27(2):159-84. Article

Vadakkan KI (2016b) Neurodegenerative disorders share common features of "loss of function" states of a proposed mechanism of nervous system functions. Biomedicine and Pharmacotherapy. 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. 59: 28-41. Article

Vadakkan K.I (2019) From cells to sensations: A window to the physics of mind. Phys Life Rev. 31:4478. Article

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. Article

Vadakkan K.I (2021a) Neurological disorders of COVID-19 can be explained in terms of both "loss and gain of function" states of a solution for the nervous system. Brain Circulation. Article

Vadakkan K.I (2021b) Framework for internal sensation of pleasure using constraints from disparate findings in nucleus accumbens. World Journal of Psychiatry. Article.

Vadakkan KI (2021c) Golgi staining of neurons: Oxidation-state dependent spread of chemical reaction identifies a testable property of the connectome. OSF Preprints

Trotta L, Weigt K, Schinnerling K, Geelhaar-Karsch A, Oelkers G, Biagi F, Corazza GR, Allers K, Schneider T, Erben U, Moos V (2017) Peripheral T-Cell Reactivity to Heat Shock Protein 70 and Its Cofactor GrpE from Tropheryma whipplei Is Reduced in Patients with Classical Whipple's Disease. Infect Immun. 85(8):e00363-17

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

Zimmerman CA, Leib DE, Knight ZA (2017) Neural circuits underlying thirst and fluid homeostasis. Nat Rev Neurosci. 18(8):459-469. Article