Deficits in glial cell numbers and density have been observed in major depressive disorder, bipolar disorder and schizophrenia. This evidence augments the theory that there is a common neuropatholgy in the three disorders, and from my perspective, the connecting link is the pervasive effects of sustained and profound fear/anxiety/stress on CNS structure and function. Glial cells have traditionally been viewed as supportive to neurons, yet recent research grants them more significant functions involving glutamatergic neurotransmission, glucose metabolism and neurotrophic support (Cotter 2005). Cotter (2005) observed that the functional effect of glucocorticoids (e.g., cortisol in humans) on reducing hippocampal glial cell activation and proliferation mirrors the glial cell deficits seen in major depressive disorder, bipolar disorder and schizophrenia.

Gorman et al (2005) observed reductions in the neuronal marker N-acetyl aspartate (NAA) in persons with schizophrenia in the dorsolateral frontal white matter and the medial temporal white matter regions, bilaterally. The patients also had decreases in the glial marker myoinositol (MI) and elevated glutamate/glutamine in most neural regions. GABA levels and relative anisotropy values assessed by DTI were observed to be significantly reduced as well. I propose that these findings are downstream, i.e., secondary, to chronic stress and profound fear and anxiety.

MRI studies have demonstrated modest reductions in white matter volume in persons with schizophrenia. Newer neuroimaging techniques such as magnetization transfer imaging (MTI) extends our understanding of these white matter deficits from merely assessing volume loss to providing evidence for reductions in myelin content and integrity (Friedman et al 2005). Friedman et al (2005) observed, using regional magnetization transfer ratio (MTR) ratios, decreased myelin content/integrity in persons with schizophrenia. Kumra et al (2005), using diffusion tensor imaging (DTI) to compare fractional anisotropy maps (FA)-FA is understood to be an index of the organization of the white matter tracts, possibly reflecting axonal size and integrity, myelination, and overall structural organization of the tract- between adolescents with early-onset schizophrenia and controls. Patients demonstrated lower FA values in the left anterior cingulate region compared to healthy volunteers suggesting a disruption in the structural integrity of prefrontal white matter. The researchers hypothesized that their data lends support for abnormalities in fiber pathways connecting cortico-limbic regions in this population.

Karlsgodt et al (2005) employed a dizygotic twin design assessing FA in patients with schizophrenia compared to healthy co-twins in order to determine if reductions in FA (lower fractional anisotropy) observed in persons with schizophrenia are of genetic and/or environmental origin. The region of interest (ROI) analysis indicated that in the frontal lobe the difference of FA between members of discordant pairs was greater than the difference in healthy pairs, and this finding was more pronounced in the right hemisphere. In the discordant pairs, healthy subjects had higher FA than their ill counterparts on average. The investigators concluded that there may be an environmental as well as genetic influence on white matter anisotropy.

Garver and Christensen (2005) investigated central immune activation together with white matter diffusivity using DTI in persons with schizophrenia subsequently found to be good responders (GR) or poor responders (PR) during one month of antipsychotic medication treatment. These researchers concluded that GR patients manifest an episodic functional-disconnect syndrome (FDS) during psychotic episodes which is associated with inflammatory cytokine elevation, disruption of white matter integrity, and of information processing. Remission of psychosis was associated with partial recovery of white matter integrity. In regard to the latter research, it has been known for many years that there is an interaction between the immune system and the hypothalmic-pituitary-adrenal axis (HPA). Glucocorticoids secreted by activation of the HPA (such as during times of stress), have potent anti-inflammatory properties. There is a bi-directional influence between the immune and neuroendocrine systems. Cytokines, which are synthesized by immune cells and are key regulators of inflammatory responses, are also synthesized by neuroendocrine tissues and higher neural centers such as the hippocampus, where they contribute to local inflammation. The inflammatory cytokines, interleukin I (IL-1), 6 (IL-6) and tumour-necrosis factor-a (TNF-a), stimulate the HPA axis (Alford & Harbuz 2005). Cytokines, as well as many neurotransmitters, are produced during stress by different organs and cells. Stress may be a key factor in the above findings in disrupted white matter integrity in persons with schizophrenia.

Brian Koehler PhD
New York University
brian_koehler@psychoanalysis.net