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.
References
1. Andreasen NC (2000), Schizophrenia: the fundamental questions. Brain Res Brain Res Rev 31(2-3):106-112.
2. Benes FM, Berretta S (2001), GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology 25(1):1-27.
3. Bleuler E (1950), Dementia Praecox. New York: International Universities Press.
4. Crow TJ (1998), Schizophrenia as a transcallosal misconnection syndrome. Schizophr Res 30(2): 111-114.
5. Eckhorn R, Bauer R, Jordan W et al. (1988), Coherent oscillations: a mechanism of feature linking in the visual cortex? Multiple electrode and correlation analyses in the cat. Biol Cybern 60(2):121-130.
6. Friston KJ, Frith CD (1995), Schizophrenia: a disconnection syndrome? Clin Neurosci 3(2):89-97.
7. Fries P, Reynolds JH, Rorie AE, Desimone R (2001), Modulation of oscillatory neuronal synchronization by selective visual attention. Science 291(5508):1560-1563 [see comment].
8. Gray CM, Konig P, Engel AK, Singer W (1989), Oscillatory responses in cat visual cortex exhibit inter-columnar synchronization which reflects global stimulus properties. Nature 338(6213): 334-337.
9. Gray CM, Singer W (1989), Stimulus-specific neuronal oscillations in orientation columns of cat visual cortex. Proc Natl Acad Sci U S A 86(5):1698-1702.
10. Grunze HC, Rainnie DG, Hasselmo ME et al. (1996), NMDA-dependent modulation of CA1 local circuit inhibition. J Neurosci 16(6):2034-2043.
11. Kopell N, Ermentrout GB, Whittington MA, Traub RD (2000), Gamma rhythms and beta rhythms have different synchronization properties. Proc Natl Acad Sci U S A 97(4):1867-1872.
12. Kubicki M, Park H, Westin CF et al. (2005), DTI and MTR abnormalities in schizophrenia: analysis of white matter integrity. Neuroimage 26(4):1109-1118.
13. Kwon JS, O'Donnell BF, Wallenstein GV et al. (1999), Gamma frequency-range abnormalities to auditory stimulation in schizophrenia. Arch Gen Psychiatry 56(11):1001-1005 [see comment].
14. Lewis DA, Hashimoto T, Volk DW (2005), Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 6(4):312-324.
15. Pesaran B, Pezaris JS, Sahani M et al. (2002), Temporal structure in neuronal activity during working memory in macaque parietal cortex. Nat Neurosci 5(8):805-811.
16. Schoffelen JM, Oostenveld R, Fries P (2005), Neuronal coherence as a mechanism of effective corticospinal interaction. Science 308(5718):111-113.
17. Selemon LD, Goldman-Rakic PS (1999), The reduced neuropil hypothesis: a circuit based model of schizophrenia. Biol Psychiatry 45(1):17-25 [see comment].
18. Singer W (1999), Neuronal synchrony: a versatile code for the definition of relations? Neuron 24(1):49-65, 111-125.
19. Silverstein SM, Kovacs I, Corry R, Valone C (2000), Perceptual organization, the disorganization syndrome, and context processing in chronic schizophrenia. Schizophr Res 43(1):11-20.
20. Silverstein SM, Wilkniss SM (2004), At issue: the future of cognitive rehabilitation of schizophrenia. Schizophr Bull 30(4):679-692.
21. Spencer KM, Nestor PG, Niznikiewicz MA et al. (2003), Abnormal neural synchrony in schizophrenia. J Neurosci 23(19):7407-7411.
22. Spencer KM, Nestor PG, Perlmutter R et al. (2004), Neural synchrony indexes disordered perception and cognition in schizophrenia. Proc Natl Acad Sci U S A 101(49):17288-17293 [see comment].
23. Tallon-Baudry C, Bertrand O (1999), Oscillatory gamma activity in humans and its role in object representation. Trends Cogn Sci 3(4):151-162.
24. Tsai G, Coyle JT (2002), Glutamatergic mechanisms in schizophrenia. Annu Rev Pharmacol Toxicol 42:165-179.
25. Uhlhaas PJ, Silverstein SM, Phillips WA, Lovell PG (2004), Evidence for impaired visual context processing in schizotypy with thought disorder. Schizophr Res 68(2-3):249-260.
26. Varela FJ, Lachaux JP, Rodriguez E, Martinerie J (2001), The brainweb: phase synchronization and large-scale integration. Nat Rev Neurosci 2(4):229-239.
27. Whittington MA, Traub RD (2003), Interneuron diversity series: inhibitory interneurons and network oscillations in vitro. Trends Neurosci 26(12):676-682.
28. Woo TU, Walsh JP, Benes FM (2004), Density of glutamic acid decarboxylase 67 messenger RNA-containing neurons that express the N-methyl-D-aspartate receptor subunit NR2A in the anterior cingulate cortex in schizophrenia and bipolar disorder. Arch Gen Psychiatry 61(7):649-657.