Spatiotemporal Alterations in Working Memory-Related Beta Band Neuromagnetic Activity of Patients With Schizophrenia On and Off Antipsychotic Medication: Investigation With MEG

Abstract

Background and hypothesis: We used the uniquely high combined spatial and temporal resolution of magnetoencephalography to characterize working memory (WM)-related modulation of beta band activity in neuroleptic-free patients with schizophrenia in comparison to a large sample of performance-matched healthy controls. We also tested for effects of antipsychotic medication on identified differences in these same patients.

Study design: Inpatients with schizophrenia (n = 21) or psychotic disorder not otherwise specified (n = 4) completed N-back and control tasks during magnetoencephalography while on placebo and during antipsychotic medication treatment, in a blinded, randomized, counterbalanced manner. Healthy, performance-matched controls (N = 100) completed the same tasks. WM-related neural activation was estimated as beta band (14-30 Hz) desynchronization throughout the brain in successive 400 ms time windows. Voxel-wise statistical comparisons were performed between controls and patients while off-medication at each time window. Significant clusters resulting from this between-groups analysis were then used as regions-of-interest, the activations of which were compared between on- and off-medication conditions in patients.

Study results: Controls showed beta-band desynchronization (activation) of a fronto-parietal network immediately preceding correct button press responses-the time associated with WM updating and task execution. Altered activation in medication-free patients occurred largely during this time, in prefrontal, parietal, and visual cortices. Medication altered patients' neural responses such that the activation time courses in these regions-of-interest more closely resembled those of controls.

Conclusions: These findings demonstrate that WM-related beta band alterations in schizophrenia are time-specific and associated with neural systems targeted by antipsychotic medications. Future studies may investigate this association by examining its potential neurochemical basis.

Trial registration: ClinicalTrials.gov NCT00001247 NCT00001921 NCT00004571.

Keywords: cognition; prefrontal cortex; psychosis.

Fig. 1.

Behavioral performance variables for healthy controls and patients while on and off medication. *Note that response times for 2-back are shorter than for 0-back because for 2-back the response to a stimulus is known beforehand (from the trial that occurred two stimuli prior), whereas for the 0-back subjects cannot prepare the response ahead of time. Error bars indicate standard deviations.

Fig. 2.

Regional localization and time course of WM-related modulations of beta desynchronization. Patients (top), controls (middle) (threshold at 90%ile), and the difference between them (P < .005 uncorrected, for visualization) in a slice through the dorsolateral prefrontal cortex. Right hemisphere is shown on the right. Blue in top two rows indicate greater beta band activation, or desynchronization, (ie, less power in 2-back compared to 0-back); orange indicates opposite. Blue in bottom row indicates greater WM-related beta band activation (desynchronization) in patients compared to controls; orange indicates greater WM-related beta activation (desynchronization) in controls compared to patients.

Fig. 3.

Regional localization and time courses of beta band activation for six regions that showed diagnosis and medication-related alterations. Brain sections on the right of each panel indicate contrasts between unmedicated patients and controls at the time at which the circled cluster has most significant group difference (A. Right lingual gyrus; B. Left middle occipital gyrus; C. Right DLPFC; D. Left DLPFC; E. Left DLPFC; F. Left cerebellum). Orange indicates reduced WM-related beta activation in patients compared with controls; blue indicate greater WM-related activation in patients. Graphs on the left indicate time series of WM activation for the cluster whose peak is indicated on right, for controls (green), patients during medicated condition (blue), and unmedicated condition (red). The gray shaded region indicates the interval of the time window from which the contrast image is generated, with the vertical dotted line indicating the center of the time window. Color shaded regions indicate standard errors. Asterisks indicate significance of unmedicated vs medicated comparison (* = P < .05; ** = P < .01; *** = P < .001). Images of the diamond-shaped cue and hand indicate of the average relative timing of the stimuli and button press responses, respectively.