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Neuropsychiatric Abnormalities: A New Vista From Studies on Fundamental Properties of Neural Communication

Neuropsychiatric Abnormalities: A New Vista From Studies on Fundamental Properties of Neural Communication

In recent years, a number of researchers have suggested schizophrenia be viewed as a disorder of brain connectivity (e.g., Andreasen, 2000; Crow, 1998; Friston and Frith, 1995; Selemon and Goldman-Rakic, 1999). This view is intuitively appealing, as schizophrenia was conceptualized by Bleuler (1950) as a "splitting of the psychic functions" in which aspects of thought and personality were disintegrated.

In this article, we will review recent research on neural circuit function in schizophrenia using γ-band (30 Hz to 100 Hz) oscillations in the electroencephalogram as a probe. It should be appreciated that the neural circuits discussed here are not the "macro" circuits or major fiber tracts, but rather they are the elementary neural circuits of a neuron projecting to other regions and its interaction with inhibitory neurons.

Neural Synchrony in the Gamma Band

The nature of neural coding has been the subject of intense research in neuroscience since the publication of Gray et al.'s (1989) classic paper. These researchers suggested that synchronous neuronal firing might serve as a mechanism whereby individual stimulus features could be bound together into coherent representations of complex objects. An important corollary finding was that neural synchrony was often accompanied by high-frequency oscillations in the γ band, often near 40 Hz (Eckhorn et al., 1988; Gray and Singer, 1989).

Since these initial reports, evidence for neural synchrony in the γ band has been found not just in perception but in diverse processes such as working memory (Pesaran et al., 2002), selective attention (Fries et al., 2001) and motor control (Schoffelen et al., 2005). Current views propose that neural synchrony is a general mechanism for dynamically linking together cells coding related pieces of information into assemblies (Singer, 1999).

Neural synchrony cannot be directly studied noninvasively, so it is inferred from particular patterns of neural activity measured in the scalp-recorded EEG. A growing number of studies have provided evidence of neural synchrony in humans (Tallon-Baudry and Bertrand, 1999; Varela et al., 2001). Evidence for γ-band neural synchrony has been reported in perception, attention and working memory tasks, among others.

Neural Circuitry Abnormalities in Schizophrenia

Research into the neural mechanisms of synchrony has demonstrated that inhibitory interneurons are critical elements in the synchronization of networks of neurons (Whittington and Traub, 2003). Pyramidal cells drive oscillations among inhibitory interneurons, which in turn modulate the firing rates of pyramidal cells, leading to a synchronized γ-band oscillation in the whole network.

A possible link between neural synchrony and schizophrenia has been suggested by postmortem studies of the brains of people with schizophrenia. These studies have found abnormalities in the morphology and distribution of certain types of neurons in schizophrenia, particularly inhibitory interneurons (Benes and Berretta, 2001; Lewis et al., 2005).

A number of neural circuitry models have postulated a deficit in recurrent inhibition, either from a loss of interneurons, a blockade of the excitatory input onto interneurons or an abnormality of modulation of interneurons. All of these models may produce abnormalities in γ oscillations.

There is considerable evidence that excitatory neurotransmission via N-methyl-D-aspartate (NMDA) receptors is abnormal in schizophrenia (Tsai and Coyle, 2002), and one possibility is that schizophrenic abnormalities of the NMDA-mediated glutamate projections from pyramidal cells to inhibitory interneurons (Woo et al., 2004) can impair oscillations, as shown in vitro (Grunze et al., 1996). A reduction in the excitatory input to inhibitory interneurons will reduce their recurrent inhibition of pyramidal cells, thus disrupting the generation of γ-band oscillations (Figure 1).

Chandelier cells are a class of interneurons that may be especially relevant to γ-band synchrony. These cells provide inhibitory input to the axon initial segment of pyramidal cells, so they are in an excellent position to control the timing of pyramidal cell firing and, hence, neural synchrony. In individuals with schizophrenia, recent studies have found abnormalities in the connections that chandelier cells make onto pyramidal cells (Lewis et al., 2005). In sum, there is considerable evidence that γ-band EEG oscillations might be sensitive to neural circuit abnormalities in schizophrenia.

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