High-frequency oscillations and the neurobiology of schizophrenia

Abstract

Neural oscillations at low- and high-frequency ranges are a fundamental feature of large-scale networks. Recent evidence has indicated that schizophrenia is associated with abnormal amplitude and synchrony of oscillatory activity, in particular, at high (beta/gamma) frequencies. These abnormalities are observed during task-related and spontaneous neuronal activity which may be important for understanding the pathophysiology of the syndrome. In this paper, we shall review the current evidence for impaired beta/gamma-band oscillations and their involvement in cognitive functions and certain symptoms of the disorder. In the first part, we will provide an update on neural oscillations during normal brain functions and discuss underlying mechanisms. This will be followed by a review of studies that have examined high-frequency oscillatory activity in schizophrenia and discuss evidence that relates abnormalities of oscillatory activity to disturbed excitatory/inhibitory (E/I) balance. Finally, we shall identify critical issues for future research in this area.

Keywords: cognition; gamma; neurobiology; oscillations; schizophrenia; synchrony.

Figure 1.. Mechanisms underlying the generation of gamma oscillations and synchrony, a) A neocortical circuit involved in the generation of gammaband oscillations. Generation of synchronized neural activity in neocortical circuits is dependent on negative feedback inhibition of pyramidal cells by GABA (γ-aminobutyric acid)-ergic interneurons that express the Ca2+-binding protein parvalbumin. These receive glutamate receptormediated feedforward excitatory inputs, which makes them susceptible to changes in glutamatergic drive. Transient excitation of parvalbumin-expressing interneurons leads to a depolarization of many interneurons, which are themselves reciprocally interconnected through gap junctions and chemical GABAergic synapses. Electrical synapses are important for the synchronization of network activity because they rapidly propagate activity. Conversely, mutual inhibition through chemical synapses is a crucial determinant of the network frequency, as the duration of inhibitory postsynaptic potentials determines the dominant oscillation frequency. The resulting rhythmic inhibitory postsynaptic potentials can synchronize the firing of a large population of pyramidal neurons as the axon of an individual GABAergic neuron makes multiple postsynaptic contacts onto several pyramidal cells. This phasic inhibition leads to the synchronization of spiking activity that can be recovered with a cross-correlogram. A local field potential (LFP) recorded with an extracellular electrode reflects the average of the transmembrane currents that fluctuate at gamma-band frequency. Its extracranial counterpart can be reflected in electroencephalography (EEG) or magnetoencephalography (MEG) signals, b) Cortico-cortical connections mediate long-distance synchronization. The relationship between the integrity of the corpus callosum and interhemispheric synchronization of gamma-band oscillations in the cat visual cortex is illustrated. Recording electrodes were placed in the vicinity of the border of areas 17 and 18 of the right (RH) and left (LH) cortical hemispheres during stimulation with a light bar. In the bottom panels are cross-correlograms between responses from different recording sites in the LH and RH that indicate the degree of interhemispheric synchronization. When the corpus callosum was intact (left-hand panel), strong interhemispheric synchronization occurred with no phase lag between the LH and RH recording sites. Sectioning of the corpus callosum (right-hand panel) abolished interhemispheric synchronization while leaving synchronization within hemispheres intact. These data show that synchronization can occur over long distances with high precision and is crucially dependent on the integrity of cortico-cortical connections. Adapted from ref 36: Uhlhaas PJ, singer W. Abnormal neural oscillations and synchrony in schizophrenia. Nat Rev Neurosci. 2010; 11:100-113. Copyright © Nature Publishing Group 2010

Figure 2.. High-frequency oscillations in schizophrenia patients. a) TMS-elicited high-frequency oscillations in controls and SCZ patients: single-pulse transcranial magnetic stimulation over 4 cortical areas was associated with peak frequencies between 20 and 30 Hz in controls with prefrontal oscillations showing the highest peak frequency. In SCZ patients, the frequency of prefrontal oscillatory activity was strongly reduced. The individual natural frequency values of healthy control subjects and patients with schizophrenia are shown for 4 cortical areas. Horizontal lines indicate mean natural frequency values of each group for each cortical area. * P≤.05; † ≤.001 . The frequency of prefrontal cortex oscillations was inversely related to the level of positive symptoms on the Positive and Negative Syndrome Scale (PANSS) (A) as well as to the reaction time of correct responses on a word memory task (B) in patients with schizophrenia. Adapted from ref 48: Ferrarelli F, Sarasso S, Guller Y, et al. Reduced natural oscillatory frequency of frontal thalamocortical circuits in schizophrenia. Arch Gen Psychiatry. 2012:69:766-774. Copyright © American Medical Association 2012 b) High-frequency oscillations during perceptual organization in SCZ. Left panel: Time-frequency representations and topographies of gammaband spectral power of magnetoen-data in response to Mooney faces for controls (top) and chronic SCZ patients (bottom). The gamma-band signal is expressed as relative power change in the post-stimulus time window compared with baseline, averaged across all channels. The topographies (middle panels) display the results for a nonparametric ANOVA indicating the main effects of group for both low (top) and high (bottom) gamma-band oscillations at the sensor level. Red colors indicate increased activity in controls while blue color suggests increased gamma-band power in schizophrenia patients relative to controls. The topographies depict corrected t-values and the channels that form a statistically significant cluster are indicated (*, P < 0.001 ; x, P< 0.05). Right panel: Correlation between high gamma-band power and disorganization. The scatter-plot shows the relationship between high (60 to 120 Hz) gamma-band power in the 50- to 350-ms time window over positive channels and the disorganization component of the positive and negative syndrome scale. Adapted from ref 41: Grutzner G, Wibral M, Sun S, et al. Deficits in high-frequency (> 60 Hz) gamma oscillations during visual processing in schizophrenia. Front Hum Neurosci. In press. Copyright © Frontiers Research Foundation