IS THERE A GENERAL BRAIN DISTURBANCE TO EXPLAIN SCHIZOPHRENIA CLINICAL MANIFESTATION ?

The most striking feature of schizophrenia is the heterogeneity of clinical manifestation and variety of cognitive disturbances. As evident from this clinical description schizophrenia is related to a widespread cortical whole-brain disturbance. It can be useful to describe schizophrenia as a disorder of neural complexity where a segregated brain organization causes fragmentation of experience leading to disorganized schizophrenia and reality distortion, and where total dependence, overly connected brain systems leads to poverty schizophrenia constringing experiential processing, freezing brain-dynamics, limiting it to few repetitive computations resulting in poverty of thought and perseverations. In order to pinpoint the neuro-pathological origin of schizophrenia it is mandatory to discover what regulates neural complexity in the brain. A regulatory structure for neural complexity must have massive, distributed and parallel connectivity with most, if not all, brain formations. It is argued that the basal ganglia with their striatum and thalamocortical connections are most suitable to regulate cortical neural complexity. They are related to both, to the high mental functions of the brain and schizophrenia. It is proposed that the globus-pallidus and subthalamic-nucleus coupled dynamics is a ‘neural complexity engine’ in the sense that it is in a position to monitor and regulate cortical neural complexity. According to this model schizophrenia is essentially a disorder of un-reached neural complexity levels in adolescence, followed by ineffective neural complexity pacemaker activity that plunges the cortex into gradual progressive deterioration of neural complexity via oscillating dynamics of integration-segregation shifts attributing to schizophrenia its typical clinical heterogeneity and prognosis of cyclic deterioration. A testable prediction from the review and the model forecasts the potential of deep-brain-stimulation to the basal ganglia in controlling the symptoms of schizophrenia. IS THERE A GENERAL BRAIN DISTURBANCE TO EXPLAIN SCHIZOPHRENIA CLINICAL MANIFESTATION? The most striking feature of schizophrenia is the heterogeneity of clinical manifestation and variety of cognitive disturbances (Andreasen 1997). In general this heterogeneity was clustered into three overlapping types of clinical descriptions, 1) disorganized, 2) realitydistortion and 3) poverty schizophrenia (Liddle 1987). Schizophrenia typically evolves as a non-reversible gradually deteriorating disease progressing toward poverty schizophrenia with grave deficits of mental and social functioning. Disorganized schizophrenia is characterized by marked disintegration of conscious experience where the experience of reality is fragmented. In reality-distortion schizophrenia, delusions prevail generated from false reconciliation of experiences and from the collapse of logical inference. Poverty schizophrenia sees the patient incapacitated due to destruction of higher mental functions such as volition and emotions, and constriction of experience and thought (poverty and perseverations of thought). As evident from this clinical description schizophrenia is related to a widespread cortical whole-brain disturbance, in effect years of brain research find schizophrenia patients impaired on a multitude of brain structures and functions. Accordingly, in order to pinpoint the psychopathology of schizophrenia a generalized systembased approach should be adopted, one that takes into account the normal workings of the brain when conscious mental experience is coherent, stable, malleably meaningful and logical. The psychopathology Schizophrenia: A Disorder of Subcortical Adaptable Neural-Complexity Pacemaker 2007 © all rights reserved Avi Peled M.D. ‘NeuroAnalysis’ http://neuroanalysis.googlepages. com/home 2 of schizophrenia probably involves some general characteristic of brain organization. Nervous systems facing complex environments have to balance two seemingly opposing requirements. The need to quickly and reliably extract important features from sensory inputs and the need to generate coherent perceptual and cognitive states allowing an organism to respond to objects and events, which present conjunctions of numerous individual features. The need to quickly and reliably extract important sensory features is accomplished by functionally segregated (specialized) sets of neurons (e.g., those found in different cortical regions), the need to generate coherent perceptual and cognitive states is accomplished by functional integration of the activity of specialized neurons through their dynamic interactions (Tononi and Edelman, 1998). The mathematical concept of “neural complexity” (CN) (Tononi, 1994) captures the important interplay between integration (i.e., functional connectivity) and segregation (i.e., functional specialization of distinct neural subsystems). CN is low for systems whose components are characterized either by total independence or by total dependence. CN is high for systems whose components show simultaneous evidence of independence in small subsets, and increasing dependence in subsets of increasing size. Different neural groups are functionally segregated if their activities tend to be statistically independent. Conversely, groups are functionally integrated if they show a high degree of statistical dependence. It can be useful to describe schizophrenia as a disorder of CN where a segregated brain organization (i.e., total independence among cortical systems) causes fragmentation of experience leading to disorganized schizophrenia and reality distortion (Peled 1999; Peled 2004), and where total dependence (overly connected systems) leads to poverty schizophrenia constringing experiential processing, freezing brain-dynamics, limiting it to few repetitive computations (i.e., poverty of thought and perseverations). IS THERE ANY EVIDENCE THAT NEURAL COMPLEXITY DYNAMICS IS DISTURBED IN SCHIZOPHRENIA In the past much has been written to support a ‘disconnection syndrome’ for schizophrenia (Peled 1999), recently more evidence has been added to support this hypothesis. Whitford et al (2007) found that firstepisode schizophrenia patients exhibited volumetric deficits in the white matter of the frontal and temporal lobes at baseline, as well as volumetric increases in the white matter of the frontoparietal junction bilaterally. Furthermore, these first-episode schizophrenia patients lost considerably more white matter over the follow-up interval relative to comparison subjects in the middle and inferior temporal cortex bilaterally. Buchsbaum et al (2007) found that compared with normal volunteers, Schizophrenia patients showed higher relative metabolic rates in the frontal white matter, corpus callosum, superior longitudinal fasciculus, and white matter core of the temporal lobe. Elevated activity in white matter was most pronounced in the center of large white matter tracts, especially the frontal parts of the brain and the internal capsule. In another work Whitford et al (2007) found that although grey matter volume decreased longitudinally in schizophrenia patients, particularly fronto-parietally, electroencephalographic power increased in the slow-wave and beta-frequency bands , suggesting abnormally elevated levels of neural synchrony. Andreone et al (2007) found cortical whitematter microstructure disruption in frontal and temporooccipital lobes in a large sample of sixty-eight patients with schizophrenia and 64 healthy controls. Brambilla and Tansella (2007) conclude that diffusion weighted imaging (DWI) studies in schizophrenia strongly suggest that white matter communication is disrupted. This supports the hypothesis that there is a cortico-cortical and transcallosal altered connectivity in schizophrenia, which may be relevant for the pathophysiology and the cognitive disturbances of the disorder. While these findings can support the idea of reduced dependence among brain systems, is there also evidence for disturbed integration? Recent descriptions of a ‘default network’ organization in the brain may provide such evidence. Recent blood oxygenation level dependent functional MRI (BOLD fMRI) studies of the human brain have shown that in the absence of external stimuli, activity persists in the form of distinct patterns of temporally correlated signal fluctuations (Horovitz et al 2007; Sonuga-Barke and Castellanos 2007). This Schizophrenia: A Disorder of Subcortical Adaptable Neural-Complexity Pacemaker 2007 © all rights reserved Avi Peled M.D. ‘NeuroAnalysis’ http://neuroanalysis.googlepages. com/home 3 spontaneous low-frequency fluctuations (<0.1Hz) in the blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (MRI) signal have been shown to reflect neural synchrony between brain regions. This phenomenon of synchrony between brain regions is also called the "default network. " The default network of spontaneous low-frequency fluctuations has been described in healthy volunteers during stimulusindependent thought and was found to be negatively correlated with regions activated during attentiondemanding tasks (Bluhm et al 2007). This condition was also formulated as two anti-correlated networks taskrelated and stimulus-independent; the stimulusindependent network was proposed to have a role in self monitoring while the task related network had the role of cognitive performance (Williamson 2007). Buckner and Carroll (2007) speculate that the default network is relevant to a set of processes by which past experiences are used adaptively to imagine perspectives and events beyond those that emerge from the immediate environment. Within this default mode network that is engaged during rest and disengaged during cognitive tasks Hampson et al (2007) investigated the posterior cingulate cortex and a medial frontal region incorporating portions of the medial frontal gyrus and ventral anterior cingulate cortex during a working me