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The GABA-DOPAMINE-5HT HYPOTHESIS


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The thalamic filter and integrator model. The thalamus, within limbic cortico–striato–(pallido)–thalamo–cortical (CSTC) feedback loops, is proposed to function as a filter in the gating of extero- and interoceptive sensory and cognitive information to the cortex and, within cortico–thalamo–cortical (CTC) re-entrant pathways, it is proposed to be crucial in integrating cortically categorized exteroceptive perception with internal stimuli of the memory and value system. Thalamic gating is under the control of glutamatergic cortico–striatal pathways projecting to the dorsomedial (MD) and reticular

nuclei of the thalamus and under the modulatory influence of serotonergic and dopaminergic projections arising from the raphe and ventral tegmentum (VTA) to several components of the CSTC loops (for details, see Ref. [22]). The model predicts that serotonergic hallucinogens disrupt thalamic gating and produce sensory overload of the prefrontal cortex by excessive stimulation of 5-HT2A receptors located in several components of the CSTC loop, including the prefrontal cortex (i and ii), limbic striatum (iii) and thalamus (iv). The blockade of NMDA-mediated glutamatergic (Glu) cortico–striatal neurotransmission (v) (e.g. by ketamine) or the increase of mesolimbic dopaminergic (DA) neurotransmission (vi) (e.g. by D-amphetamine) could lead to a similar neurotransmitter imbalance in CSTC loops, which again results in an opening of the thalamic filter, sensory overload of the cortex and psychosis.

In addition, the excessive stimulation of thalamic and/or cortical 5-HT2A receptors located on GABAergic interneurons by hallucinogens could lead to a disruption of CTC or cortico–cortical integration of distributed neuronal activity (‘binding’) (vii), which, in turn, might underlie the more anxious and fragmented experience of egodissolution that is often reported after high doses of hallucinogens. Although application of serotonergic hallucinogens into the frontal cortex in rodents has been demonstrated to increase pyramidal-cell activity via stimulation of 5-HT2A receptors located on apical dendrites of pyramidal cells (i) and/or GABAergic neurons (ii), it remains unclear whether such a local activation without a subsequent disruption of thalamic gating or integration of information processing leads to psychosis in humans or simply to excitation and/or increased sensory awareness. Abbreviations: VTA, ventral tegmental area; AMY, amygdala; HPC, hippocampus; 5-HT, serotonin, DA,dopamine, Glu, glutamate; receptors: 2A, 5-HT2A; 1A, 5-HT1A; mGlu2/3, metabotropic glutamate receptor subtypes 2 and 3; NMDA, N-methyl-D-aspartate; D2, dopamine D2.

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Functional Segregation of Visual Inputs to the LGN

The primary ganglion cells involved in visual perception with projections mapped to the lateral geniculate nucleus (LGN) are:

The midget ganglion cells.

Small receptive fields

Project to layers 3–6 of the parvocellular LGN.

L2V1.pdf

The parasol cells

Extensive receptive fields

Project to layers 1 and 2 of the magnocellular LGN

The bistratified ganglion

projects to the koniocellular layers of the LGN.

The parvocellular system (P-pathway) is a static firing system that conveys information from the retina to the LGN concerning wavelength selectivity and low-contrast retinal imagery with high spatial resolution

High band-pass resolution perimetry (ring perimetry) is an attempt to selectively evaluate the P-pathway

In contrast, the magnocellular system (M-pathway) conveys high-contrast, low-resolution information that is color blind.

The magnocellular system is a phasic system, thus is well suited for the analysis of moving stimuli. Perimetric techniques, such as frequency-doubled perimetry and motion-detection automated perimetry, are used in an attempt to isolate the M-pathway. The koniocellular system (K-pathway) conveys information concerning blue-yellow color opponency.

The visual cortex in the macaque was initially divided into six sub-regions named visual areas 1–6 (Areas V1–V6). Area V1 is the primary visual cortex, and it corresponds to the striate cortex in both humans and lower primates. Areas V2–V6 are extensively interconnected visual areas that lie anterior to V1 and contain specialized maps of the visual field.

Based on numerous studies of lesions in humans, functional imaging of normal subjects, and experiments in monkeys, it is clear that the information processed by the striate cortex and visual associative areas is projected through two occipitofugal pathways: a ventral occipitotemporal pathway and a dorsal occipitoparietal pathway.

The ventral pathway, often called the “what” pathway, is involved in processing the physical attributes of a visual image that are important to the perception of color, shape, and pattern. These, in turn, are crucial for object identification and object-based attention. The ventral pathway originates in V1 and projects through V2 and V4 to specific inferior temporal cortical areas, the angular gyrus, and limbic structures. It provides visual information to areas involved in visual identification, language processing, memory, and emotion. Thus, a lesion in this pathway may cause a variety of associative defects, including visual alexia and anomia, visual agnosia, visual amnesia, and visual hypoemotionality. The dorsal, or “where” pathway, begins in V1 and projects through V2 and V3 to V5. From V5, this pathway continues to additional areas in the parietal and superior temporal cortex.

These projections are involved in visuospatial analysis, in the localization of objects in visual space, and in modulation of visual guidance of movements toward these objects. Thus, lesions of this pathway may cause a variety of visuospatial disorders, such as Bálint’s syndrome and hemispatial neglect.

Although the ventral and dorsal pathways are clearly involved in the analysis of different aspects of the visual environment, they are extensively interconnected laterally and in feedback and feed forward directions, indicating that the flow of perceptual processing does not necessarily proceed in a stepwise, hierarchic manner.

This “what” and “where” dichotomy of visual processing is an oversimplification of how these cortical areas function, but it serves as a useful framework in which to develop a clinical model of cortical visual processing. A number of specific syndromes in humans involving the central processing of visual information can be localized primarily to one of the six visual cortical areas or one of the two occipitofugal pathways and thus are of clinical value. These are discussed below.

Both primate and human studies have demonstrated that area V2 may play a role in the detection of illusionary contours. This perceptual task is of great importance in the detection of obscured objects, such as a camouflaged predator. Patients with early posterior Alzheimer’s disease demonstrate impaired detection of illusionary contours, possibly due to degeneration of area V2.

The reticular nucleus is of particular interest here because it is thought to serve as a sort of gate for processing signals to the cortex. Synaptic inputs to the reticular nucleus arise from the other thalamic nuclei, and it sends inhibitory projections back into the thalamus, apparently serving a negative-feedback regulatory role in thalamic function. It has been proposed to serve as a sort of ‘‘searchlight’’ of attention (Crick, 1984; Sherman & Guillery, 1996) and to control elements of signal-to-noise or the quality of information being sent to the cortex (see Vollenweider & Geyer,

2001, and references therein).

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  • 3 weeks later...

After reading all of the research and literature about the subject, post 1 in this thread was my best guess of what had been disrupted, the thalamocortical feedback loop.

A good and simple summary of David's post would be that the thalamocortical loop, in an HPPD scenario, recycles sensory information throughout the brain much longer than it should. The failure of the GABA mediated inhibitory response mechanism theory for causing the excessive feedback loop makes the most sense to me.

I've experimented with ridiculously high doses of multiple benzo's a few times and, although I passed out from the hypnotic effects rather quickly, what little I do remember is that the visuals were lessened greatly.

Here's an easy read from wikipedia about this theory.

http://en.wikipedia.org/wiki/Thalamocortical_dysrhythmia

And here a bit more indepth review of clinical studies on the theory.

http://www.pnas.org/content/96/26/15222.full.pdf

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After reading all of the research and literature about the subject, post 1 in this thread was my best guess of what had been disrupted, the thalamocortical feedback loop.

A good and simple summary of David's post would be that the thalamocortical loop, in an HPPD scenario, recycles sensory information throughout the brain much longer than it should. The failure of the GABA mediated inhibitory response mechanism theory for causing the excessive feedback loop makes the most sense to me.

I've experimented with ridiculously high doses of multiple benzo's a few times and, although I passed out from the hypnotic effects rather quickly, what little I do remember is that the visuals were lessened greatly.

Here's an easy read from wikipedia about this theory.

http://en.wikipedia.org/wiki/Thalamocortical_dysrhythmia

And here a bit more indepth review of clinical studies on the theory.

http://www.pnas.org/content/96/26/15222.full.pdf

I doubt many people are going to want to try a surgery like that (even though I don't think you are suggesting it) especially when this is just a theory, maybe if someone here with parkinsons isn't responding to any treatment and also suffers HPPD might be a good candidate for this surgery, I doubt we are going to find someone like that though.

Yes, large doses of benzos seem to have a positive effect short term (until you pass out). high doses and using them frequently should be avoided though, so no one repeat what shaolin has described here, haha.

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  • 2 months later...

I still can't understand anything. If someone could answer me I would like first to ask the basic questions:

1- What are afterimages and why and how they happen?

2- What exactly is HPPD? Death of neurons? Damage on receptors? Changes on synaptic strength? Wrongly rewired synapses? What?

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1- What are afterimages and why and how they happen?

http://en.wikipedia.org/wiki/Afterimage

http://en.wikipedia.org/wiki/Palinopsia

2- What exactly is HPPD? Death of neurons? Damage on receptors? Changes on synaptic strength? Wrongly rewired synapses? What?

Probably any combination of the above, depending on the individual (genes, age, health, diet), cause, duration of cause, how many times the neurons have been ‘assaulted’, and sum total of ‘stressors’ being experienced before, during and after injury(s).

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  • 1 month later...

Unfortunatelly those articles on wikipedia are very poor technically.

I still can't understand what is the exact cause of HPPD or at least what are the possible causes.

I think changes in the density or quantity of receptor proteins on neurons due to extreme environmental stressors caused by drugs is atleast part of the problem. If the neurons that are involved in a feedback loop are disrupted then it will throw the rest of the feedback loop off and everything would become deficient. This would affect, as David has pointed out, several different neurotransmitter systems that operate within the loop. This could explain the feelings of dissociation, anxiety, the visuals, etc.

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  • 2 years later...
  • 6 years later...

Bumping this about six years later and wondering if any more learned individuals than myself can chime in.

 

I wonder if the feedback loops that are referenced could somehow explain my incessant earworms (stuck song syndrome).

 

Perhaps TMS of the VLPFC and TPJ?

 

What do people think?

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