These findings suggest a decrease in the ability of auditory neural networks to support synchronous neural activity at 40 Hz, but not at lower frequencies, in schizophrenia. Since N
-aspartate (NMDA)–modulated GABAergic activity may play a critical role in gamma-frequency synchronization, these results may provide a neurophysiological link to cellular models of schizophrenia that posit NMDA dysregulation.11
An important role for NMDA receptors in the clinical manifestations of schizophrenia is supported by the finding that NMDA antagonists, such as phencyclidine hydrochloride, mimic the positive and negative symptoms of the disorder.22
has shown in the rat hippocampus in vitro that the NMDA receptor mediating recurrent collaterals of projection neurons onto GABAergic interneurons is some 10-fold more sensitive to blockade by NMDA receptor blockers than the NMDA receptor mediating excitatory (Schaffer collateral) input onto the projection neurons. The net result of NMDA blockade is thus reduced inhibition. Also, in postmortem studies in the temporal lobes of schizophrenic patients, Tsai and coworkers23
have demonstrated elevated concentrations of N
-acetyl-aspartyl-glutamate, a compound that in vitro has been demonstrated to block preferentially the NMDA receptor mediating excitatory input on inhibitory interneurons,12
and that thus may be an endogenous NMDA channel blocker.
Recent basic science investigations using in vitro24
and in vivo25
preparations suggest the critical involvement of excitatory drive on interneurons in the generation of synchronized gamma activity, or at least in the ability of networks to resonate in the gamma range. A reduction of this recurrent drive might result in lessened recurrent inhibition, and a lessened ability of the network to entrain faithfully to a gamma frequency, as shown in schizophrenic patients. Intrinsic abnormalities of GABAergic neurons, such as have been reported in postmortem tissue of schizophrenic patients, also might be a mechanism contributing to a failure of recurrent inhibition.26
Failure of gamma-range inhibition also has been reported to contribute to sensory gating deficits as measured by the P50 paradigm.13
Dysregulation in the circuits producing the gamma rhythm might interfere with transmission of transient or high temporal frequency information, and thus contribute to behavioral deficits noted for tasks that require rapid temporal integration, such as motion perception27
and backward masking.28
More speculatively, an inability to support 40-Hz oscillations could lead to abnormalities in perceptual and temporal binding, and consequently might play a role in the reality distortions and disordered trains of thought seen in schizophrenia. However, further investigations of driven and transient gamma activity will be required to establish this relationship.
There are important limitations in the interpretation of our study, which will require further investigation. First, the relationship between synchronized auditory gamma activity to specific anatomic regions remains controversial, as does whether the response is entirely evoked or reflects intrinsic resonance, as is suggested by our data (eg, Pantev et al3
; Picton et al7
; Bressler and Freeman29
; and Hari et al30
). Second, the roles of antipsychotics and anticholinergic medication and the EEG abnormalities reported herein remain to be clarified. Since these medications likely influence neurotransmission within glutamatergic circuits, studies with larger sample sizes, and including subjects not receiving medication, will be required for definitive clarification of these relationships. An evaluation of our data showed gamma power was not significantly correlated with chlorpromazine equivalent dosage of typical and atypical neuroleptics (Spearman ρ). There were no statistically significant group differences using Mann-Whitney tests in gamma power in a comparison of subjects receiving typical vs atypical neuroleptics or in a comparison of subjects receiving vs those not receiving anticholinergics. Third, the specificity of these abnormalities to schizophrenia has not been tested. Finally, the subjects in this study were chronically ill patients who were relatively refractory to treatment. It remains to be determined whether gamma-range abnormalities would be present in patients at the first episode of the illness, as well.