Reduced grid-like theta modulation in schizophrenia

Abstract

The hippocampal formation has been implicated in the pathophysiology of schizophrenia, with patients showing impairments in spatial and relational cognition, structural changes in entorhinal cortex and reduced theta coherence with medial prefrontal cortex. Both the entorhinal cortex and medial prefrontal cortex exhibit a 6-fold (or 'hexadirectional') modulation of neural activity during virtual navigation that is indicative of grid cell populations and associated with accurate spatial navigation. Here, we examined whether these grid-like patterns are disrupted in schizophrenia. We asked 17 participants with diagnoses of schizophrenia and 23 controls (matched for age, sex and IQ) to perform a virtual reality spatial navigation task during magnetoencephalography. The control group showed stronger 4-10 Hz theta power during movement onset, as well as hexadirectional modulation of theta band oscillatory activity in the right entorhinal cortex whose directional stability across trials correlated with navigational accuracy. This hexadirectional modulation was absent in schizophrenia patients, with a significant difference between groups. These results suggest that impairments in spatial and relational cognition associated with schizophrenia may arise from disrupted grid firing patterns in entorhinal cortex.

Keywords: entorhinal cortex; grid cells; schizophrenia; spatial memory.

Figure 1

Spatial memory task. (A) Schematic. Participants navigate through the environment and make responses using a button box. During encoding, they are asked to remember the locations of four objects (one object being visible in each trial). During retrieval, a fixation cross on a grey screen is followed by an image of one object (cue period). The participants are then asked to navigate from a random start location to the retrieved location of that object and make a response. During navigation, the object image remains visible in the top left corner of the screen. Following a response, the object appears in its correct location to provide feedback. The next trial begins when the participants collide with the object. (B) Performance, quantified as the inverse of the average distance between remembered and actual object locations, for controls and patients. Each red line indicates the median, box edges the 25th and 75th percentiles, whiskers extend to the most extreme data points not considered to be outliers (defined as values more than 1.5 times above or below the 75th and 25th percentiles, respectively), and outliers are plotted individually. Spatial memory accuracy was significantly higher in the control group.

Figure 2

Movement-related 4–10 Hz theta power increases in controls and patients. (A) Power spectra showing normalized power during movement onset epochs (i.e. [−0.5 0.5] s around the onset of ≥1 s translational movements that were preceded by ≥1 s immobility), baseline corrected by average power during stationary periods (i.e. [0 1] s around the onset of ≥2 s periods of immobility) for controls and patients (shading indicates standard error). The grey bar delineates the 4–10 Hz theta band. (B) Time–frequency spectrograms showing normalized power during movement onset, baseline corrected by average power during stationary periods. Controls show a marked increase in theta power beginning ∼0.5 s prior to movement onset that is reduced in patients. (C) Scalp plots of normalized 4–10 Hz theta power during movement onset epochs, baseline corrected by average theta power during stationary periods for controls, patients, and for the contrast between groups. Highlighted channels show significant positive power differences at a threshold of P < 0.01 (uncorrected).

Figure 3

Modulation of oscillatory power by movement direction in right entorhinal cortex. (A) Regions showing significant hexadirectional modulation of 4–10 Hz theta power at the whole brain level. Only one cluster in right entorhinal cortex (peak at [18–22–44], Z = 4.05) passes our significance threshold of P < 0.05 FWE corrected (image shown at P < 0.005 uncorrected, for display purposes). (B) Image of the anatomically defined right entorhinal cortex region of interest. (C) Strength of hexadirectional theta modulation inside the region of interest for controls and patients, with 19/23 controls (82.6%) and 8/17 patients (47.1%) showing a positive beta coefficient. (D) Difference in theta power between on versus off axis movement inside the region of interest for controls and patients, with 19/23 controls (82.6%) and 7/17 patients (41.2%) showing greater on versus off axis theta power. (E) Difference in the percentage of movement samples that occurred during on versus off axis movement for controls and patients. (F) Theta modulation by 4–8-fold movement direction inside the region of interest for controls. (G) Strength of hexadirectional modulation of delta (2–4 Hz), theta (4–10 Hz), alpha (12–20 Hz), beta (20–35 Hz) and gamma (40–70 Hz) frequency bands inside the region of interest for controls. (H) Correlation between performance, quantified as the inverse of the average distance between remembered and actual object locations, and grid (in)stability across task blocks for controls. Each red line indicates the median, box edges the 25th and 75th percentiles, whiskers extend to the most extreme data points not considered to be outliers (defined as values more than 1.5 times above or below the 75th and 25th percentiles, respectively) and outliers are plotted individually.