The Temporally-Integrated Causality Landscape: Reconciling Neuroscientific Theories With the Phenomenology of Consciousness.

In recent years, there has been a proliferation of neuroscientific theories of consciousness. These include theories which explicitly point to EM fields, notably Operational Architectonics and, more recently, the General Resonance Theory. In phenomenological terms, human consciousness is a unified composition of contents. These contents are specific and meaningful, and they exist from a subjective point of view. Human conscious experience is temporally continuous, limited in content, and coherent. Based upon those phenomenal observations, pre-existing theories of consciousness, and a large body of experimental evidence, I derived the Temporally-Integrated Causality Landscape (TICL). In brief, the TICL proposes that the neural correlate of consciousness is a structure of temporally integrated causality occurring over a large portion of the thalamocortical system. This structure is composed of a large, integrated set of neuronal elements (the System), which contains some subsystems, defined as having a higher level of temporally-integrated causality than the System as a whole. Each Subsystem exists from the point of view of the System, in the form of meaningful content. In this article, I review the TICL and consider the importance of EM forces as a mechanism of neural causality. I compare the fundamentals of TICL to those of several other neuroscientific theories. Using five major characteristics of phenomenal consciousness as a standard, I compare the basic tenets of Integrated Information Theory, Global Neuronal Workspace, General Resonance Theory, Operational Architectonics, and the Temporo-spatial Theory of Consciousness with the framework of the TICL. While the literature concerned with these theories tends to focus on different lines of evidence, there are fundamental areas of agreement. This means that, in time, it may be possible for many of them to converge upon the truth. In this analysis, I conclude that a primary distinction which divides these theories is the feature of spatial and temporal nesting. Interestingly, this distinction does not separate along the fault line between theories explicitly concerned with EM fields and those which are not. I believe that reconciliation is possible, at least in principle, among those theories that recognize the following: just as the contents of consciousness are distinctions within consciousness, the neural correlates of conscious content should be distinguishable from but fall within the spatial and temporal boundaries of the full neural correlates of consciousness.

Functional deficit in hippocampal activity during fear extinction recall in the single prolonged-stress model of PTSD in male rats.

To interrogate whether altered function of the hippocampal-mPFC circuit underlies the deficit in fear extinction recall in rats subjected to single-prolonged stress (SPS), changes in brain region-specific metabolic rate were measured in male rats (control and SPS treated). Brain region metabolic rates were quantified using uptake of 14C-2-deoxyglucose (14C-2DG) during fear memory formation, fear memory extinction and extinction recall. Control and SPS rats had similar regional brain activities at baseline. During extinction recall, 14C-2DG uptake decreased in hippocampal regions in control rats, but not in SPS rats. SPS rats also exhibited a significant deficiency in fear extinction recall, replicating a previously reported finding. Reduced hippocampal activity during fear extinction recall in control animals may reflect reduction in fear overgeneralization, thereby enabling discrimination between distinct contexts. In contrast, persistent levels of hippocampal activity in SPS-exposed male animals during fear extinction recall may reflect the dysfunctional persistence of fear overgeneralization. Future studies in females can test gender-specificity of these effects, with appropriate attention to luteal dependent effects on extinction of fear learning. Detailed knowledge of regional brain activities underlying stress-induced deficits in extinction recall may help identify therapeutic targets in PTSD.

The temporally-integrated causality landscape: A theoretical framework for consciousness and meaning.

Theoretical approaches to understanding consciousness have begun to converge upon areas of general agreement, yet substantive differences remain. Here, I introduce a new theoretical framework for the emergence of consciousness from the functional integration of the thalamocortical system: the Temporally-Integrated Causality Landscape (TICL). TICL presents a novel perspective which addresses important phenomenological characteristics of consciousness that other frameworks, such as IIT, do not. First, the TICL is based upon the observation that conscious experiences are temporally continuous, not discrete. Secondly, the TICL establishes a thalamocortical basis for the point-of-view. According to TICL, consciousness is composed of contents that arise from neuronal subsystems that have meaning from the point-of-view of the larger, integrated system in which they are nested. Meaningful contents emerge from the subsystems because they exhibit a level of temporally-integrated causality (TIC) that is distinguishable from that of the larger system.

Congenital CNS hypomyelination in the Fig4 null mouse is rescued by neuronal expression of the PI(3,5)P(2) phosphatase Fig4.

The plt (pale tremor) mouse carries a null mutation in the Fig4(Sac3) gene that results in tremor, hypopigmentation, spongiform degeneration of the brain, and juvenile lethality. FIG4 is a ubiquitously expressed phosphatidylinositol 3,5-bisphosphate phosphatase that regulates intracellular vesicle trafficking along the endosomal-lysosomal pathway. In humans, the missense mutation FIG4(I41T) combined with a FIG4 null allele causes Charcot-Marie-Tooth 4J disease, a severe form of peripheral neuropathy. Here we show that Fig4 null mice exhibit a dramatic reduction of myelin in the brain and spinal cord. In the optic nerve, smaller-caliber axons lack myelin sheaths entirely, whereas many large- and intermediate-caliber axons are myelinated but show structural defects at nodes of Ranvier, leading to delayed propagation of action potentials. In the Fig4 null brain and optic nerve, oligodendrocyte (OL) progenitor cells are present at normal abundance and distribution, but the number of myelinating OLs is greatly compromised. The total number of axons in the Fig4 null optic nerve is not reduced. Developmental studies reveal incomplete myelination rather than elevated cell death in the OL linage. Strikingly, there is rescue of CNS myelination and tremor in transgenic mice with neuron-specific expression of Fig4, demonstrating a non-cell-autonomous function of Fig4 in OL maturation and myelin development. In transgenic mice with global overexpression of the human pathogenic FIG4 variant I41T, there is rescue of the myelination defect, suggesting that the CNS of CMT4J patients may be protected from myelin deficiency by expression of the FIG4(I41T) mutant protein.

Pathogenic mechanism of the FIG4 mutation responsible for Charcot-Marie-Tooth disease CMT4J.

CMT4J is a severe form of Charcot-Marie-Tooth neuropathy caused by mutation of the phosphoinositide phosphatase FIG4/SAC3. Affected individuals are compound heterozygotes carrying the missense allele FIG4-I41T in combination with a null allele. Analysis using the yeast two-hybrid system demonstrated that the I41T mutation impairs interaction of FIG4 with the scaffold protein VAC14. The critical role of this interaction was confirmed by the demonstration of loss of FIG4 protein in VAC14 null mice. We developed a mouse model of CMT4J by expressing a Fig4-I41T cDNA transgene on the Fig4 null background. Expression of the mutant transcript at a level 5 × higher than endogenous Fig4 completely rescued lethality, whereas 2 × expression gave only partial rescue, providing a model of the human disease. The level of FIG4-I41T protein in transgenic tissues is only 2% of that predicted by the transcript level, as a consequence of the protein instability caused by impaired interaction of the mutant protein with VAC14. Analysis of patient fibroblasts demonstrated a comparably low level of mutant I41T protein. The abundance of FIG4-I41T protein in cultured cells is increased by treatment with the proteasome inhibitor MG-132. The data demonstrate that FIG4-I41T is a hypomorphic allele encoding a protein that is unstable in vivo. Expression of FIG4-I41T protein at 10% of normal level is sufficient for long-term survival, suggesting that patients with CMT4J could be treated by increased production or stabilization of the mutant protein. The transgenic model will be useful for testing in vivo interventions to increase the abundance of the mutant protein.