In a recent review of neuroimaging research (MRI, fMRI, MEG, PET, SPECT, etc.) in schizophrenia (“Neuroimaging in Psychiatry” edited by Fu et al 2003) the authors concluded that the schizophrenias are best characterized by difficulties in intra-and interregional functional connectivity (prefrontal-temporal, prefrontal-thalamic-cerebellar-prefrontal) as opposed to isolated regional deficits. The dysfunction appear to be task- contingent, i.e., its emergence is contingent upon the neuropsychological tasks being performed at the time, e.g., working memory, attention and executive functioning, affective facial recognition, etc. At the same time there is robust evidence for structural cortical abnormalities, e.g., cytoarchitectural abnormalities and volumetric loss. Loss of cortical volume is evidenced in multiple cortical regions: medial frontal, anterior cingulate, insula, white matter tracks, amygdala, hippocampus, parahippocampus and superior temporal gyrus.
Ron and Foong (2003) noted:
“Evidence from functional and structural imaging studies has led to the view that abnormal connectivity between different brain regions may provide an explanation for the cluster of symptoms that typify schizophrenia...Although aberrant functional connectivity may occur in the absence of an anatomical substrate, the integration of abnormalities in structure and function is still central to our understanding of the cause and pathophysiological mechanisms of schizophrenia. Harrison (1999) has suggested that the neuronal, synaptic and dendritic abnormalities reported in schizophrenia are consistent with aberrant functional connectivity” (pp. 133-134).
Ron and Foong (2003) in their article “The application of neuropathologically sensitive MRI techniques to the study of psychosis” (in “Disorders of Brain and Mind: II” edited by Maria Ron & Trevor Robbins in 2003 for Cambridge University Press) highlight the advantages of the most recent developments of MRI: magnetization transfer imaging (MTI) and diffusion tensor imaging (DTI). MTI and DTI can detect abnormalities not visible with conventional MRI
Magnetization Transfer Imaging (MTI)
MTI is based on the interactions between protons in a relatively free environment and those with restricted motion.The MTR (magnetization transfer ratio) signal is determined by the size of the bound pool and it depends on the density of the macromolecules in a given tissue. Pathological processes that damage these macromolecules, axonal membranes and myelin in particular, reduce the MTR. MTI has recently been applied to patients with a schizophrenic disorder. Foong et al (2001) detected widespread areas of cortical MTR reductions in the inferior and medial frontal, inferior and medial temporal and superior occipital gyri, parietal-occipital regions and adjacent white matter. This suggests abnormalities in frontotemporal circuits.
Recent neuropathological findings in schizophrenia provide a tentative explanation for these imaging abnormalities. Ron and Foong (2003) conclude that reductions in the neuropil (mainly dendrites, axons and synapses) account for the volume reductions detected in neuroimaging research. Neuropil reduction would lead to MTR reduction by reducing the size of the bound proton pool. They noted: “Neuropil abnormalities may also explain the aberrant interneuronal connectivity postulated to be the key functional abnormality in schizophrenia” (p.135).
I have for many years been impressed by the large convergence of research findings in the neuroscience of schizophrenia, bipolar disorder, depression, PTSD and in the neuroscience of stress and anxiety.In the hippocampus alone, a key structure implicated in research in schizophrenia, stress has been shown to affect synaptic plasticity, dendritic morphology, neurotoxicity and neurogenesis (Kim & Yoon,1998).
Stress and glucocorticoid secretion can lead to reversible neuroplastic changes (Fuchs & Flugge 1995) such as atrophy of excitatory apical dendrites on the pyramidal cells in the hippocampus. Glucocorticoids reorganize dendritic arborization in the medial prefrontal cortex. Dendritic pathology very consistent with stress-induced changes has been observed in both the hippocampal formation (Rosoklija et al 2000) and the prefrontal cortex (Glantz & Lewis 2001).With this neural diathesis’,’ mesolimbic release of dopamine can increase in response to stress (Lipska et al 1993), as part of a stress cascading effect. Chronic stress results in a reduction of dopaminergic activation of the prefrontal cortex (and a simultaneous hyperactivation of limbic areas)-what researchers sometimes refer to as “hypofrontality” and attribute to as a primary negative symptom core-the causes of which are still undiscovered. I believe that in many cases the ‘causes’ can be located within the subjective human brain in interaction with its world and self.
The current research findings in schizophrenia being revealed by newer techniques such as MTI and DTI, I believe, are congruent with stress-induced neural plasticity. These findings also fit with the neuroimaging research in outcome studies in schizophrenia.
Neuroimaging in Schizophrenia
Schröder, Bottmer and Pantel (2002) reviewed at least 30 longitudinal neuroimaging studies on structural cerebral changes in schizophrenia involving CT and MRI scans. Besides the early identification of ventriculomegaly in schizophrenia in 1927 (pneuencephalography) by Jacobi and Winkler, these researchers noted: “In addition, decreased volumes of the frontal and temporal lobes, the medial temporal substructures [e.g., hippocampus] and thalamic nuclei, and the cerebellum were also frequently described” (p.83). Schröder and colleagues presented evidence suggesting that cortical volume changes are dynamic and reversible (which fits with my neural-stress hypothesis). This runs counter to current neurodevelopmental and neurodegenerative models.
These studies demonstrated significant reversibility of ventriculomegaly and reduced cortical volume (perhaps the primary reductions are in the neuropil-which are potentially reversible) in good-outcome patients. The current neuroreductive (neurodevelopmental and neurodegenerative) models would be hard pressed to explain these data.Schröder et al (2002) concluded :”...the presently available neuroimaging studies do not convincingly support the hypothesis that schizophrenia is generally associated with a global cerebral tissue loss” (p.93).
Brian Koehler PhD
New York University
New York NY 10003
212.533.5687
brian_koehler@psychoanalysis.net
