Inhibition of Gamma Oscillations as a Neurophysiological Endophenotype of Schizophrenia

Abstract Background The pathophysiology of schizophrenia (SCZ) has not been fully elucidated. Studies have demonstrated that SCZ patients have impairments in the dorsolateral prefrontal cortex (DLPFC). Two findings have been shown in the DLPFC: deficits in GABAergic inhibitiory neurotransmission and abnormal inhibition of cortical oscillations. Thus, we aimed to assess frontal inhibition as a potential endophenotype of SCZ. Objectives The first objective was to quantitatively assess transcranial magnetic stimulation (TMS) motor cortex measures of inhibition and excitation in obsessive-compulsive disorder (OCD), major depressive disorder (MDD) and SCZ, as a meta-analysis. The second objective was to evaluate the inhibition of overall and gamma oscillations in the DLPFC and motor cortex using TMS and EEG in SCZ and OCD. The final objective was to evaluate the inhibition of overall and gamma oscillations in SCZ patients, OCD patients, and their unaffected first-degree relatives with TMS and EEG. Hypotheses First, we hypothesized that motor cortex inhibitory deficits would be a ubiquitous finding across OCD, MDD and SCZ patients. Second, we hypothesized that patients with SCZ would show deficits in overall and gamma inhibition in the DLPFC compared to healthy subjects and patients with OCD. Lastly, it was hypothesized that frontal inhibition in first-degree relatives of SCZ would be intermediate of healthy subjects and their related probands. Results The first study showed that motor inhibitory deficits were a ubiquitous finding across OCD, MDD, and SCZ. The second paper found that SCZ patients demonstrated inhibitory deficits in the DLPFC (overall and gamma inhibition), not observed in OCD patients. This was found to be independent of illness severity and medication. The final study demonstrated deficits in frontal inhibition in SCZ patients, which were significantly less than their unaffected first-degree relatives. No differences were found between first-degree relatives of SCZ and healthy controls. First-degree relatives were intermediate of their related probands and healthy controls. We did not show inhibition deficits in OCD patients and their first-degree relatives. Conclusions Frontal inhibition (measured via TMS and EEG) may be an essential neurophysiological process that is impaired in SCZ. Multi-site trials are needed to investigate inhibition as a potential endophenotype for SCZ.Ph.D

Characterizing long interval cortical inhibition over the time-frequency domain.

OBJECTIVE: Long-interval cortical inhibition (LICI) can be recorded from motor and non-motor regions of the cortex through combined transcranial magnetic stimulation (TMS) with electroencephalography (EEG). This study aimed to evaluate additional dimensions of LICI characteristics over an extended time-frequency and spatial domain. This was done by introducing two alternative measures of LICI signal amplitude: the Discrete Fourier Transform (DFT) and the Hilbert transform (HT). Both approaches estimate signal amplitude not taking into account the phase. In both cases LICI was measured as the difference between the unconditioned and conditioned activity evoked by the test pulse. Finally, we evaluated whether the topographical patterns of single and paired responses differed beyond the expected variations in amplitude. MATERIALS AND METHODS: LICI was delivered as single and paired pulses to the motor cortex (MC) and dorsolateral prefrontal cortex (DLPFC) in 33 healthy subjects with TMS-EEG. RESULTS: Significant differences (p<0.0001) between the unconditioned and conditioned evoked activity were found for both the DLPFC and MC using both methods (i.e., DFT and HT) after correcting for multiple comparisons in the time-frequency domain. The influence of inhibition was found to be significantly larger in space and time than previously considered. Single and paired conditions differ in intensity, but also in their topographic pattern (i.e., the specific spatiotemporal configuration of active sources). CONCLUSION: Similar results were found by both DFT and HT. The effect of inhibition across the cortex was also found to be complex and extended. In particular, it was found that LICI may be measured with high sensitivity in areas that were relatively distant from the stimulation site, which may have important practical applications. The analysis presented in this study overcomes some limitations of previous studies and could serve as a key reference for future studies examining TMS-indices of inhibition/excitation in healthy and diseased states

Strength of inhibition by electrode.

<p>Each value consists of the sum of all t-scores of LICI (DFT and HT), values within the major cluster of inhibition in the TF-map for each electrode within each specific condition (method and area of stimulation). These plots do not necessarily reflect the intensity of LICI at any specific time windows and, in this sense, are not directly comparable to previously published topographic maps of LICI.</p

Statistical significance of each sample in the TF-maps of LICI^DFT for DLPFC corresponding to each specific electrode.

<p>Statistical significance of each sample in the TF-maps of LICI^DFT for DLPFC corresponding to each specific electrode.</p

Time course of the LICI^HT for the evoked activity averaged across all channels for 12 frequencies, from 3.91 to 47.9 Hz (bold line).

<p>The gray area depicts confidence intervals calculated as percentiles from the histograms produced by 1,000 random permutations of U- and C-conditions, dark grey (95%) (p<0.05) and light grey (99%) (p<0.01). The thin line corresponds to the mean value across all permutations.</p

Significance levels of the differential response in pattern between the conditioned and unconditioned response.

<p>These plots are derived from the HT analysis.</p

Statistical significance of each sample in the TF-maps of LICI^HT for MC corresponding to each specific electrode.

<p>Statistical significance of each sample in the TF-maps of LICI^HT for MC corresponding to each specific electrode.</p

Time course of the LICI^DFT for the evoked activity averaged across all channels for 12 frequencies, from 3.91 to 47.9 Hz (bold line).

<p>The gray area depicts confidence intervals calculated as percentiles from the histograms produced by 1,000 random permutations of U- and C-conditions, dark grey (95%) (p<0.05) and light grey (99%) (p<0.01). The thin line corresponds to the mean value across all permutations.</p

Average TF-maps (LICI^DFT and LICI^HT) across channels and subjects.

<p>Each map was originally computed from the average trial (evoked response). The stimulation was applied over the DLPFC. The bottom panels show the statistical significance of the corresponding top graph at various levels of alpha: 0.001, 0.01, and 0.05.</p