MEG auditory evoked fields suggest altered structural/functional asymmetry in primary but not secondary auditory cortex in bipolar disorder

The relationship between schizophrenia and bipolar disorder has been a topic of considerable long-term interest, with viewpoints ranging from considering them the same basic disorder with variable phenotypic expression to entirely separate disorders. Kraepelin initially suggested a dichotomy between cognitive (e.g., schizophreniform) and affective (e.g., bipolar) disorders (1), but later authors have generally preferred a continuum model, with bipolar disorder and schizophrenia on opposite poles of a dimensional continuum. Proponents of this view have included Menninger (2) and more recently Crow (3), who have suggested that the psychoses are not a group of different disorders, but rather may reflect the variable expression of a single gene. Kendler and colleagues (4), however, examining the genetic data from the Roscommon Family Study, have stated, “These results suggest a relatively complex typology of psychotic syndromes consistent neither with a unitary model nor with a Kraepelinian dichotomy.” Our understanding is compromised by the relative dearth of common pathophysiological measures characterizing these disorders. One physiological metric that has been noted by investigators in several laboratories to characterize patients with schizophrenia has been evidence of anomalous left-right asymmetry of auditory evoked field (EF) sources generated in both the primary auditory (AI) and the secondary auditory (AII) cortex, suggestive of cortical disorganization as well as anomalous left-right brain asymmetry at the level of the superior temporal gyrus (STG). Initial reports of anomalous asymmetry of magnetic auditory EFs involved recordings of the major auditory EF component, occurring about 100 ms post stimulus receipt and termed the M100. This component is generated primarily in AII on the lateral aspect of Heschl’s gyrus and anterior bank of the temporal planum (5-9). In 1989, the M100 was reported to demonstrate anomalous asymmetry in subjects with schizophrenia based on recordings with a single-channel gradiometer, with M100 source locations exhibiting less interhemispheric lateralization, and localized generally somewhat further anteriorly in the left hemisphere compared to nonschizophrenic control subjects (10). Subsequent reports from investigators in Finland (11) and Germany (12-15), as well as North America (10, 16, 17), also described anomalous, usually decreased lateralization of the M100, suggesting that it is a robust finding. Addressing the issue of whether the anomalous lateralization reflected altered localization of Heschl’s gyri in schizophrenia, Rojas et al. (18) compared M100 functional lateralization to Heschl’s gyri structural lateralization in schizophrenia by computing the centroid of Heschl’s gyri in both hemispheres [obtained from magnetic resonance imaging (MRI) images]. This study found that both groups exhibited right anterior to left asymmetry, and demonstrated no statistically significant differences. The implication was that individuals with schizophrenia displayed cortical disorganization such that the functions subserving M100 generation were displaced compared to nonschizophrenic subjects. Teale and colleagues provided data supporting the concept that the M100 was likely a composite component incorporating two subcomponents with latencies of approximately 75 (M100a) and 100 (M100b) ms (19), both of which were shown to exhibit abnormal asymmetry in schizophrenia (20). This abnormal functional location and asymmetry of auditory EF sources with evidence of normal structural location of Heschl’s gyri again supported the concept of cortical reorganization in the AII cortex in schizophrenia. To date however, lateralization of the magnetoencephalography (MEG) M100 components generated in AII have not been described in patients with bipolar disorder, nor have estimates of lateralization of Heschl’s gyri centroids been published in bipolar patients. Subsequent studies utilized paradigms designed specifically to activate the AI cortex. Auditory stimulation at 40 Hz produces a steady state response (SSR) whose source generators are thought to be restricted to the AI cortex on the medial aspect of Heschl’s gyri (5, 21-23). There is some individual as well as interhemispheric variability of absolute location of auditory koniocortex with respect to Heschl’s gyrus; while primarily restricted to Heschl’s, there may be some koniocortex on the anterior temporal planum immediately adjacent to the postero-medial aspect of Heschl’s (24). The SSR response represents the driving of the AI cortex at a resonant frequency in the gamma band range. This early AI component demonstrates abnormal (decreased) laterality in patients with schizophrenia compared to controls compatible with a developmental disturbance of cerebral asymmetry (25), but again, such measures have not been previously reported in bipolar subjects. The present study was undertaken for the purpose of investigating, in patients with bipolar disorder, the source location of those auditory EF components previously found to demonstrate anomalous asymmetry in schizophrenia, including the SSR generated in the AI cortex, and the M100a and M100b components generated in the AII cortex. We also computed the centroids of the medial aspect of Heschl’s gyri in these bipolar subjects to allow correlation of function (SSR source location) with the structural location of the purported source generators (medial Heschl’s gyri). We believe such data will contribute to our improved understanding of the relationship between affective and schizophreniform illness on the basis of objective physiological measurements. Since the SSR and M100 components are generated by fundamentally different experimental design and data-processing methods, the methods and results of the M100 and SSR experiments will be reported separately, as will the methods and results for anatomical determination of medial Heschl’s gyri centroids.