Beyond Antipsychotics Consciousness and Schizophrenia Neuroanalysis

Abraham Peled M.D.

This article presentation is intended for Continual Education in Psychiatry taking the students BEYOND the typical knowledge currently (2022) taught. ???

Regarding the mechanism of Antipsychotics what we traditionally know is that they block Dopamine receptors.

This blockade has to do with the dopaminergic system as we know it and the therapeutic effect is predicted to accrue in the Mesocortical pathway regulating prefrontal cortical regions ?

Typically, the theory is simple arguing to much dopaminergic activity, as the therapeutic effect is ‘block’ i.e., reduction of activity. But better investigation into the circuitry of the prefrontal connections draws a more complicated picture. The dopaminergic synapses excite both the Pyramidal Neurons and the interneurons. The interneurons inhibit the Pyramidal neurons and thus the Pyramidal Neurons receive both inhibitory (through interneurons) and excitatory signals. What dose this mean?

To understand this lets take a broader look at brain global circuitry we see that the prefrontal regions act as ‘Hubs’ with massive efferent and afferent connections Fig 5, 6 and 7.

In Fig 6 it is evident that there is a cortical loop going from cortical connections of the prefrontal cortex inward to subcortical basal nuclei and Substantia Negra and back to the cortex (directly via ascending Thalamic pathways) and specifically via ventral cortical pathways of the Dopaminergic system to the prefrontal cortex. The prefrontal cortex is known to serve as a critical Hub in a major well known brain organization network, the Central Executive Network Fig 7

?As evident from Fig 7 the Central Executive Network is instrumental in high level?cognitive functions?such as maintaining and using information in?working memory, problem solving, and decision-making executive control tasks and IQ.

The Hubs of the Central Executive Network are in affect the higher level junctions of brain hierarchical ?organization (white regions in fig 8) where according to this review the highest levels of sensations are acted upon in an interactive loop with the environment, where Emergence of sensation and cognition give rise to very high level brain properties such as Volition and Motivation. Figure 8 and 9

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?Another characteristic of Global millisecond range brain organization is that of ‘Consciousness.’ ?Figure 10 shows how hierarchically and globally Unimodal A (Auditory) and V (Visually) processors integrate into Multimodal Auditory Visual regions and the entire brain find its instant full organization second after second in the time Domaine.

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The idea of consciousness emerging from global brain organization has been described by ?Bernard Barrs in his Global Workspace Theory. Fig 11. Partial processes which do not participate in the conscious content, compete to get access to the global process of the global workspace thus participating and at the same time, influencing the global conscious message.

Later on, authors such as Giulio Tononi and Stanislav Dehene expanded on this concept describing unconscious subconscious and consciousness as levels of global brain organizations. Tononi also devised a method to extract levels of brain organization from brain-imaging analysis ?Fig 12. ??

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?Tononi was among the first authors to discuss Breakdowns and pathology of global brain organizations relevant to brain psychiatric disorders, he discussed the possibility that disconnection and over-connection dynamics are relevant to psychosis ( disconnection and fragmentation of consciousness) and negative signs schizophrenia (over-connection with restriction and poverty ?of thought) ?Fig 13

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?A dynamic Neural Network model we built in 2000 shows how dynamic oscillations of neuronal thresholds can regulate thought organization using Attractor Hopfield network combined with asymmetric connections Fig 14

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?By increasing (Fig 15) and reducing (Fig 16) threshold oscillation amplitudes we modelled disconnection (fig 15) and over connection (Fig 16) with a metaphoric effect of Loosening associations (Fig 15) where the dynamics showed jumps from one attractor to another. ?Metaphorically over connection (reducing thresholds Fig 16) we obtained preservation and poverty of thought models.

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By manipulating threshold dynamics, we succeeded to simulate the entire spectrum of thought disorders we encounter in schizophrenia. Fig 17

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With EEG correlation analysis applied to real patients (compared to controls) we showed the Disconnection in the frontal brain regions of schizophrenia patients finding that have been replicated abundantly before and after our study Fig 18

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?The insights obtained from working with these models offered the possibility to reformulate schizophrenia spectrum phenomenology in terms of brain network disturbances Fig 19 ??

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Advances in our knowledge of brain organization can take us a step further in this direction. We know that the brain organizes as a Small World Network and the imbalance between Clustering Coefficient and Long Pathway provides for the Disconnection and over connection dynamics Fig 20. Thus, by extracting Small World Graph Parameters from imaging analysis we can assess the connectivity dynamics relevant to schizophrenia Brain pathology and thus offer a brain-related etiological diagnosis to schizophrenia.

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However more importantly now we can understand the connection between the local activity of Dopamine on the frontal cortex and whole brain organization with its influence on conscious integrity and network disturbances causing schizophrenia

Researchers (such as Ofer Yzhar fig 21) have succeeded to control Gamma Activity (i.e., global connectivity) by intervening in the activity of interneurons in the prefrontal cortex of rats. This is an example for future brain pacemakers which will use relevant brain hubs to regulate and balance spread out networks of global brain organizations to eliminate psychiatric symptoms and cure mental disorders. ????

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