In this study, we investigated gamma-range cortical oscillatory power during preparatory cognitive control processing in first-episode schizophrenia patients. As hypothesized, the patient group was impaired in mounting a gamma oscillatory response to high-control demands and in task performance. These impairments were also observed in a patient subgroup that was similar in clinical severity to the treated patient subgroup, but free of concurrent antipsychotic medication treatment. Furthermore, these gamma power deficits were not coincident with changes in theta oscillatory power. These findings extend the literature to date, which has primarily emphasized deficits in various measures of evoked gamma oscillations in response to relatively simple information-processing demands, and primarily in chronic patients with a long history of antipsychotic medication exposure.
Gamma oscillatory deficits have been observed in schizophrenia under a wide range of experimental conditions, including in the resting state (Yeragani et al, 2006
), elicited by TMS (Ferrarelli et al, 2008
), with relatively simple perceptual task demands (Spencer et al, 2003
; Spencer et al, 2004
; Spencer et al, 2008a
), in relation to motor responses (Ford et al, 2008
), and with more complex cognitive demands (Cho et al, 2006
), including this study. Taken together, these findings suggest that cortical oscillatory dysfunction may be a general feature of this illness. Other measures of gamma phenomenology that are impaired in schizophrenia include measures of synchrony and phase-locking to environmental stimuli, which suggest that the temporal dynamics of stimulus-related oscillatory activity may be altered. The present measure of gamma power indicates that schizophrenia is characterized by an impaired PFC capacity for establishing dynamic neuronal assemblies, to represent information in the absence of a stimulus in order to guide task-relevant behavior. We found evidence that delay-period gamma power is also impaired to some degree even in a (green cued) task condition that does not have significant control demands. Nevertheless, these gamma deficits did not account for control-related gamma, which was manifest even after controlling for low-control gamma in this patient sample.
Cognitive control is a PFC-dependent process, which is consistently impaired in schizophrenia, appearing at the outset of overt psychotic illness (Barch et al, 2001
), and which may be specific to schizophrenia over other psychotic disorders (MacDonald et al, 2005
). It is associated with other classically defined executive functions (Cohen et al, 1999
; Minzenberg et al, 2009
), which strongly predict functional outcome in this illness (Green, 1996
). Because gamma oscillations are related to BOLD signal change measured by fMRI (Logothetis et al, 2001
; Mukamel et al, 2005
), the presently observed gamma deficits may form the basis of these other well-established neuroimaging measures of PFC dysfunction in schizophrenia. There is now an emerging empirical literature in schizophrenia demonstrating disturbances in GABAergic cortical interneurons (Gonzalez-Burgos and Lewis, 2008
), particularly fast-spiking, parvalbumin-positive interneurons, such as basket cells and chandelier cells, and associated decrements in cortical GABA levels (Yoon et al, 2010
). These interneurons are critical cellular elements that subserve a signal gating role to initiate and maintain high-frequency cortical oscillatory activity (Freund, 2003
). Therefore, gamma oscillatory deficits may represent the link between altered molecular/cellular processes and the deficits in complex cognition that appears ubiquitous in schizophrenia.
Interestingly, we also found that theta power is intact during preparatory cognitive control processes in this sample, in both medicated and unmedicated first-episode patients. The anterior cingulate cortex (ACC) can exhibit theta rhythms (Onton et al, 2005
), exhibits altered BOLD signal change in association with disturbed performance monitoring in schizophrenia (Carter et al, 2001
; Kerns et al, 2005
; Snitz et al, 2005
), and there is preliminary evidence for impaired theta power in association with error monitoring during N-Back performance in schizophrenia (Schmiedt et al, 2005
). Nevertheless, the cue-probe delay period of the present task is more directly dependent on the lateral PFC (where the rule, or context, is represented), than the ACC. The present evidence suggests that gamma deficits during lateral PFC-dependent cognitive processes are not merely a function of altered theta power. However, it remains unknown whether schizophrenia is characterized by a disturbed modulation of gamma oscillatory activity by theta phase, which could in principle arise from altered theta timing. Because theta oscillations are most powerfully driven (in the hippocampus at least) by activity at the dendrites of primary cells (Buzsaki, 2002
), the present results are again most consistent with a perisomatic locus of pathology in local PFC circuitry, which is where basket cells and chandelier cells exert their influence on high-frequency cortical oscillations (Freund, 2003
Several other central neurotransmitter system have been implicated in schizophrenia, including glutamate, serotonin, catecholamines, acetylcholine and others. These systems also have a role in the initiation and/or modulation of high-frequency cortical oscillations (Whittington et al, 2000
), and therefore the present findings do not clearly favor one model of pathophysiology over competing models. Recent preliminary evidence does indicate that GABA-A receptor-specific pharmacological agents may remediate these control-related gamma deficits in stable chronic schizophrenia patients (Lewis et al, 2008
), suggesting that the GABA system is one excellent candidate for targeting the neural basis of cognitive dysfunction in schizophrenia. Cortical GABAergic interneurons also mediate some major catecholamine modulatory effects as well (Bacci et al, 2005
), suggesting that procatecholamine agents may also exert part of their efficacy for PFC function through cortical interneurons.
Nonetheless, the issues of pharmacological and anatomical specificity in gamma oscillations, and how these might point toward the pathophysiology of schizophrenia, are important questions that remain unresolved. It seems likely that a ubiquitous basis for high-frequency cortical oscillations is found in the local interaction of GABAergic interneurons and glutamatergic principal cells (Whittington et al, 2000
). These interactions are strongly influenced by ascending thalamocortical projections, with additional modulatory influences conferred by ascending monoaminergic and cholinergic systems. The anatomic sites of oscillatory activity, and thus the profile of associated modulatory systems' influence, may result primarily from the distinct identity of the cortical ensemble that is engaged by a particular cognitive process. In the present case, this would be the dorsal frontoparietal network, and the various other cortical/subcortical areas that participate in cognitive control. These are targets for each of the ascending subcortical systems indicated above, leaving open the possibility of factors arising in one or more of many different (and interacting) systems contributing to gamma dysfunction in schizophrenia.
It also remains unknown whether these gamma deficits predate the overt manifestation of psychotic illness, or evolve over the course of illness in schizophrenia, and whether clinical remission is accompanied by normalization of this dysfunction. From another perspective, it is unknown to what degree this neural disturbance may represent a good candidate endophenotype for the illness (eg, whether it is found in non-affected biological relatives or independent of clinical status), as a useful phenotype to link to genetic alterations. A related issue is the nosological specificity of gamma dysfunction, which has yet to be fully addressed by comparing gamma phenomena in schizophrenia with that in other major mental disorders. Furthermore, the precise neurochemical systems implicated in this dysfunction in schizophrenia remain to be tested (as alluded to above), and changes in cortical oscillatory activity may ultimately be an expression of multiple interacting neurotransmitter systems, which may serve as concurrent targets of heterogeneous pharmacological agents (Roth et al, 2004
). Addressing these unresolved research questions will help to better understand the implications of gamma oscillatory dysfunction in schizophrenia.