Gamma Oscillatory Power is Impaired During Cognitive Control Independent of Medication Status in First-Episode Schizophrenia

Abstract

Schizophrenia is characterized by impaired cognitive control associated with prefrontal cortex dysfunction, but the underlying pathophysioloical mechanisms remain unknown. Higher cognitive processes are associated with cortical oscillations in the gamma range, which are also impaired in chronic schizophrenia. We tested whether cognitive control-related gamma deficits are observed in firstepisode patients, and whether they are associated with antipsychotic medication exposure. Fifty-three first-episode schizophrenia patients (21 without antipsychotic medication treatment) and 29 healthy control subjects underwent electroencephalography (EEG) during performance of a preparatory cognitive control task (preparing to overcome prepotency or POP task). The first-episode schizophrenia patient group was impaired (relative to the control group) on task performance and on delay-period gamma power at each of the three subgroups of frontal electrodes. The unmedicated patient subgroup was similarly impaired compared with controls, and was not different on these measures compared with the medicated patient subgroup. In contrast, delay-period theta power was not impaired in the full patient group nor in the unmedicated patient subgroup. Impaired cognitive control-related gamma cortical oscillatory activity is present at the first psychotic episode in schizophrenia, and is independent of medication status. This suggests that altered local circuit function supporting high-frequency oscillatory activity in prefrontal cortex ensembles may serve as the pathophysiological substrate of cognitive control deficits in schizophrenia.

A Novel α5GABAAR-Positive Allosteric Modulator Reverses Hyperactivation of the Dopamine System in the MAM Model of Schizophrenia

“…The loss of PV corresponds with a pathological alteration in oscillatory activity with broad consequences on network dynamics between brain regions. Gamma oscillations in the HPC require GABA A receptor activity (Whittington et al, 1995), and there is a loss of evoked gamma oscillatory activity, both in MAM rats and in humans, in regions showing PV neuron decreases (Gonzalez-Burgos et al, 2010;Lodge et al, 2009;Minzenberg et al, 2010).…”

Dysconnectivity, large-scale networks and neuronal dynamics in schizophrenia

“…Evidence suggests that induced gamma-band activity is reduced during a wide range of cognitive and perceptual paradigms, including working memory, executive control and perceptual processing in both chronic and unmedicated patient populations, suggesting a generalized circuit dysfunction in schizophrenia [31,32]. Finally, reduced auditory evoked 7 activity has been demonstrated in first-degree relatives of patients with schizophrenia as well as in unaffected, monozygotic twins with a high degree of heritability [33,34], suggesting the neural synchrony parameters are endophenotypes.…”

Acute phencyclidine administration induces c-Fos-immunoreactivity in interneurons in cortical and subcortical regions

“…Thus PV cells play a central role in coordinating the activity of excitatory pyramidal cells and GABAergic interneurons governing the synchronisation of cortical gamma-oscillations (Gonzalez-Burgos and Lewis, 2012), and it has been shown that the induction of gamma-oscillations is dependent on NMDARs expressed in PV interneurons (Sohal et al 2009;Carlén et al 2012). Although the mPFC contains the PV neurons generating and regulating gamma-oscillations and is probably the site important in schizophrenia patients (Beasley and Reynolds, 1997;Danos et al 1998;Zhang and Reynolds 2002;Cho et al 2006;Uhlhaas and Singer 2010;Minzenberg et al 2009Minzenberg et al , 2010) and animal models (Cochran et al 2003;McKibben et al 2010;Thomsen et al 2010), we found no PCPinduced c-Fos-IR in PV-IR cells in the mPFC areas. Consistently, a previous study found no increase in c-Fos mRNA in GABAergic neurons in the mPFC (Santana et al 2011).…”

“…This increase in PFC activity has been observed to be followed by a delayed depression of activity over a 24 hours period followed (Gao et al 1993(Gao et al , 1998, which may be relevant to the decrease in PFC activity 5 seen in schizophrenia patients. Furthermore, PFC synchronous gamma-oscillations important for cognitive function are impaired in schizophrenia (Cho et al 2006;Uhlhaas and Singer, 2010;Minzenberg et al 2009Minzenberg et al , 2010Gonzalez-Burgos and Lewis, 2012). Importantly, those neurons mediating the psychotomimetic actions of non-competitive NMDAR antagonists are still unknown.…”