These new findings on coupled theta and gamma rhythms in schizophrenia patients are fascinating. Increases in theta power were seen that correlated with deficits in verbal learning, but were not accompanied by increases in gamma power or disturbances in cross-frequency interactions between theta phase and gamma amplitude. Our currently limited knowledge of the origins of theta-gamma cross-frequency interactions does not provide a clear hypothesis of how theta amplitude could increase without corresponding increases in gamma amplitude. More studies of theta-gamma patterns in animal models and computational models are needed to uncover the mechanisms of theta-gamma cross-frequency coupling.

The new study also found that schizophrenia patients exhibited reduced gamma phase locking to auditory stimuli, while theta phase-locking remained intact. Again, there is no obvious explanation for this finding. Future studies of stimulus-induced gamma oscillations in animal models, combined with computational models of gamma, are likely to yield insights about why gamma phase...  Read more

These new findings on coupled theta and gamma rhythms in schizophrenia patients are fascinating. Increases in theta power were seen that correlated with deficits in verbal learning, but were not accompanied by increases in gamma power or disturbances in cross-frequency interactions between theta phase and gamma amplitude. Our currently limited knowledge of the origins of theta-gamma cross-frequency interactions does not provide a clear hypothesis of how theta amplitude could increase without corresponding increases in gamma amplitude. More studies of theta-gamma patterns in animal models and computational models are needed to uncover the mechanisms of theta-gamma cross-frequency coupling.

The new study also found that schizophrenia patients exhibited reduced gamma phase locking to auditory stimuli, while theta phase-locking remained intact. Again, there is no obvious explanation for this finding. Future studies of stimulus-induced gamma oscillations in animal models, combined with computational models of gamma, are likely to yield insights about why gamma phase locking is disrupted in schizophrenia.

The recent study by Kirihara et al. adds important information to our knowledge base about the relationship between brain oscillations and schizophrenia. It is increasingly appreciated that abnormal brain oscillations may play a role in schizophrenia (Lewis et al., 2005; Sohal, 2012). However, the precise nature of these abnormalities and their relationships to specific aspects of schizophrenia remain unclear. Three findings from this study address these questions. First, consistent with previous findings (Boutros et al., 2008), this study found increased power in the theta range. Theta power does not vary much during the period of auditory stimulation, so this seems to reflect an increase in baseline theta oscillations. Moreover, in patients, increased theta power correlates with worse cognitive performance.

Second, phase locking near 40 Hz, induced by 40 Hz auditory stimulation, is reduced in patients with schizophrenia. This is...  Read more

The recent study by Kirihara et al. adds important information to our knowledge base about the relationship between brain oscillations and schizophrenia. It is increasingly appreciated that abnormal brain oscillations may play a role in schizophrenia (Lewis et al., 2005; Sohal, 2012). However, the precise nature of these abnormalities and their relationships to specific aspects of schizophrenia remain unclear. Three findings from this study address these questions. First, consistent with previous findings (Boutros et al., 2008), this study found increased power in the theta range. Theta power does not vary much during the period of auditory stimulation, so this seems to reflect an increase in baseline theta oscillations. Moreover, in patients, increased theta power correlates with worse cognitive performance.

Second, phase locking near 40 Hz, induced by 40 Hz auditory stimulation, is reduced in patients with schizophrenia. This is consistent with numerous studies that have shown impaired gamma frequency synchronization in schizophrenia. At first, it might seem surprising that the amplitude of gamma oscillations was not decreased in patients with schizophrenia, but such observations typically occur in the context of tasks or stimulation which cause the amplitude of gamma oscillations to increase in healthy controls. Based on Fig. 2, this auditory stimulation paradigm did not elicit much of a change in the power of gamma oscillations, but it did cause gamma oscillations to synchronize with the timing of the stimulation. Thus, it is not surprising that measures of gamma synchrony were abnormal in patients with schizophrenia, whereas measures of gamma amplitude were not.

Third, this study did not uncover evidence for alterations in cross-frequency coupling between theta and gamma oscillations. Specifically, the amplitude of gamma oscillations are larger during some phases of ongoing theta oscillations, and this pattern was unaltered in patients with schizophrenia. Overall, these findings help to better define precisely what is (and what is not) abnormal about brain oscillations in schizophrenia. Brain oscillations have attracted a great deal of interest in schizophrenia because they represent a mechanism that could plausibly explain how some of the neuropathological abnormalities observed in schizophrenia (e.g., abnormalities in inhibitory interneurons) cause their behavioral or cognitive consequences. In this respect, the negative correlation between theta power and a measure of cognition observed in this study is important, because it suggests that increases in theta power either contribute to cognitive dysfunction, or are closely linked with the mechanisms that cause cognitive dysfunction. As the authors themselves note, an important future direction would be to explore cross-frequency coupling under conditions that more intensively engage specific neural circuits. Specifically, it would be interesting to repeat these measurements during a task or stimulation paradigm that induces a robust change in the amplitude of theta and gamma oscillations.

References:

Boutros NN, Arfken C, Galderisi S, Warrick J, Pratt G, Iacono W (2008): The status of spectral EEG abnormality as a diagnostic test for schizophrenia. Schizophr Res. 99:225-237. Abstract

Lewis DA, Hashimoto T, Volk DW (2005): Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci. 6:312-324. Abstract

Sohal VS (2012): Insights into cortical oscillations arising from optogenetic studies. Biol Psychiatry. 71:1039-1045. Abstract

Understanding the complex neural dynamics that underlie perceptual and higher-order cognitive operations is an important area of neuroscience. We wholeheartedly agree with the sentiments of Drs. Colgin and Sohal that much work is needed to continue to elaborate the pathways from genes-to-cells-to-circuits-to-behavior in healthy and neuropsychiatric patient populations, and we appreciate their thoughtful comments on our manuscript.

We hope that future studies of the assessment of oscillatory dynamics—including the interactions of oscillations that vary in amplitude, time, phase, and location—will be informative for the development of treatments that target the disabling clinical, cognitive, and psychosocial functional impairments of schizophrenia patients. Unfortunately, we have no available laboratory-based biomarkers that can be used to facilitate differential diagnosis, guide treatment decisions, or predict responses or outcomes. In a related study, we have compared many commonly studied neurophysiologic and neurocognitive biomarkers for use in genomic and...  Read more

Understanding the complex neural dynamics that underlie perceptual and higher-order cognitive operations is an important area of neuroscience. We wholeheartedly agree with the sentiments of Drs. Colgin and Sohal that much work is needed to continue to elaborate the pathways from genes-to-cells-to-circuits-to-behavior in healthy and neuropsychiatric patient populations, and we appreciate their thoughtful comments on our manuscript.

We hope that future studies of the assessment of oscillatory dynamics—including the interactions of oscillations that vary in amplitude, time, phase, and location—will be informative for the development of treatments that target the disabling clinical, cognitive, and psychosocial functional impairments of schizophrenia patients. Unfortunately, we have no available laboratory-based biomarkers that can be used to facilitate differential diagnosis, guide treatment decisions, or predict responses or outcomes. In a related study, we have compared many commonly studied neurophysiologic and neurocognitive biomarkers for use in genomic and clinical outcome studies of schizophrenia (Light et al., 2012). Although gamma and theta measures were not examined in our related study, these important oscillatory measures nevertheless seem to be promising probes of neural circuit functioning. Since oscillatory measures appear to have tight cross-species homology, they appear to offer promise for linking underlying cellular abnormalities with low-cost observations in scalp EEG and cognition, and, thus, bridge the vast “gene-to-phene” knowledge gap.

References:

Light, G.A., Swerdlow, N.R., Rissling, A.J., Radant, A., Sugar, C.A., Sprock, J., Pela, M., Geyer, M.A., Braff, D.L., 2012. Characterization of Neurophysiologic and Neurocognitive Biomarkers for Use in Genomic and Clinical Outcome Studies of Schizophrenia. PLoS One 7, e39434.