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June 3, 2005 We often hear that the second generation antipsychotics ameliorate negative symptoms (e.g., anhedonia, affective flattening, alogia, avolition, abulia, anergia, etc.), however there is strong evidence that any agent which saturates D2 receptors in the striatum is highly correlated with an increase in negative symptomatology. There are researchers who suggest that too much dopamine in the striatum/mesolimbic areas (thalamus, hippocampus, oritofrontal, paralimbic areas, etc.) results in intensification of positive symptoms (e.g., hallucinations). Therefore the strategy is to create a psychopharmacological balance between dopaminergic hyper- and hypo-stimulation in various neural networks (mesolimbic and mesocortical regions, respectively). Hughlings Jackson (1927) distinguished between positive and negative symptoms in schizophrenia according to evolution of the brain. He theorized that the evolution of the brain renders more complex centers, e.g., frontal and temporolimbic areas, more vulnerable to illness-associated dysfunction. The resulting loss of function leads to negative symptoms, and as a consequence, evolutionarily older centers may become disinhibited leading to the emergence of positive symptoms (release phenomena). This theory separates the limbic-affective and prefrontal-executive areas much more sharply than, I believe, nature has. As Watt (2005), neuroscientist and attachment theorist, pointed out: "...our extended cortical capacities and our prolonged period of infantile and childhood emotional dependence are two sides of a coin...The more cortical the creature, the longer the period of infantile dependence required to ensure cognitive learning and motor mastery, and thus the more profoundly important attachment processes must be to the brain" (p. 194).Melanie Klein was one of the first psychoanalysts to draw attention to the relationship between learning and cognition and positive or negative relational experience. Functional neuroimaging with PET and SPECT (“Functional mapping with single-photon emission computed tomagraphy and positive emission tomagraphy” by Andreas Heinz, Berenice Romero & Daniel Weinberger in “Schizophrenia: From Neuroimaging to Neuroscience” edited by Stephen Lawrie, Eve Johnstone & Daniel Weinberger in 2004 for Oxford University Press) have demonstrated three patterns; First, abnormal blood perfusion of the dorsolateral prefrontal cortex (DLPFC) associated with impaired working memory, executive functions, and negative symptoms; Second, dysfunction of temporal-limbic circuits associated with disinhibition of subcortical dopamine release and the emergence of positive symptoms; Thirdly, positive symptoms such as auditory hallucinations have been associated with increased blood perfusion in subcortical, mesial-temporal and limbic neural areas. I have previously posted a significant number of research studies which demonstrate that the above are exactly what happens during times of acute and chronic stress/fear and anxiety. A Proposed Neuropsychoanalytic Theory of Schizophrenia And Experimental Paradigms To Put It To The Test I believe that Gaetano Benetti and his colleague, Maurizio Peciccia, have come very close to an accurate understanding of the dilemma of the psychotic individual (and all of us on a continuum!): how to integrate autonomy (separateness) and relatedness (therapeutic symbiosis)-that in schizophrenia there is a de-integration of separate and symbiotic selves (Peciccia uses the quantum theory of light being both waves and particles as an analogy for the process (symbiotic) and structure (separateness) of self). In the language of Louis Sass: self as all (e.g., grandiose delusions, paranoid self-referential thinking) and self as nothing (severe feelings of personal non-existence warded off by hallucinations, self-referential thinking, etc.) I understand the neuroscience of schizophrenia to be the neuroscience of self-loss/annihilation due to this de-integration of separate and symbiotic selves-self-loss at the pole of isolation and autistic retreat and self-loss at the pole of invasion/colonization/intrusion (self-referential paranoid experience-fusion transferences with the world-what Freud described as the fusion between ego and world) anxieties. I believe that we can experimentally test some of these ideas in various neuroimaging paradigms. For example, ask both controls and persons diagnossed with schizophrenia to strongly imagine a state of loneliness and isolation as well as a state in which in a relationship to another person they feel submissive, controlled, invaded, ‘taken over by.’ fMRI would be a viable neuroimaging tool to investigate this. Then ask both groups of subjects to strongly imagine being in a supportive safe relationship with another person in which her/his autonomy is respected and validated, i.e.,to constitute a ‘within’ which could comfortably and safely include another person. Another area of potentially fruitful non-reductionistic neuroimaging research would be to investigate mirror-neuron activity in emotional paradigms. Mirror neurons allow us to replicate within our own minds/brains the experiences we observe and participate in and with others. Do our psychotic patients have simultaneous excessive mirror neuron activity and then a ‘down-regulation’ of such activity to protect the self from feeling invaded and controlled? I am excited by these possibilities for deriving comprehensive models of the schizophrenic disorders in which the neurobiology is more congruent with the phenotypic expressions of the disorder. I realize that there are many limitations to the above theory and experimental paradigm to explore its validity. However, I believe it is a step in the right direction. And unlike the reductionistic neurogenetic and neurobiologic paradigms, it is more congruent with patient experience and the pathways from geneotype (e.g., environmental control of gene expression and genetic control of sensitivity to the environment) to phenotypic expression (e.g., the clinical symptomatology and lived subjective experiences which patients tend to report once they are in a safe and sustained relationship to a trusted other or caregiver). Brian Koehler PhD |