Scientific Understanding of Consciousness
Consciousness as an Emergent Property of Thalamocortical Activity

Oscillations and Schizophrenia



Nature Volume: 468, Pages: 194–202: (11 November 2010)

From maps to mechanisms through neuroimaging of schizophrenia

Andreas Meyer-Lindenberg

Central Institute of Mental Health, University of Heidelberg/Medical Faculty Mannheim, J5, 68159 Mannheim, Germany


Functional and structural brain imaging has identified neural and neurotransmitter systems involved in schizophrenia and their link to cognitive and behavioural disturbances such as psychosis. Mapping such abnormalities in patients, however, cannot fully capture the strong neurodevelopmental component of schizophrenia that pre-dates manifest illness. A recent strategy to address this issue has been to focus on mechanisms of disease risk. Imaging genetics techniques have made it possible to define neural systems that mediate heritable risk linked to candidate and genome-wide-supported common variants, and mechanisms for environmental risk and gene–environment interactions are emerging. Characterizing the neural risk architecture of schizophrenia provides a translational research strategy for future treatments.

Oscillations and schizophrenia

Oscillations are important organizers of brain activity, plasticity and connectivity. They can be measured using electroencephalography (EEG) or magnetoencephalography (MEG). Oscillations in the gamma range are important for synchronized activity within local cortical networks. Essential for the generation of local gamma activity are parvalbumin-containing GABAergic interneurons under glutamatergic stimulation. Cognition requires that the results of local computations are globally integrated. Neural oscillations in the low (especially theta) ranges are critical for long-range connectivity because they engage larger areas and effectively modulate fast local oscillations, such as gamma oscillations. In hippocampus, highly synchronized theta frequency oscillations are observed which have been proposed to serve as a temporal organizer for cortex. This has recently been demonstrated in mouse104, where hippocampal theta oscillations drive cortically generated gamma oscillations through phase locking. Importantly, NMDA (N-methyl-D-aspartate) antagonism can influence both local and long-range synchronization because NMDA receptors in superficial layers of cortex, themain recipients of long cortical connections, control local processing. Dopaminemodulates these oscillations. In the prefrontal cortex in schizophrenia patients, reductions in the gamma and theta band have been observed at rest and during stimulus processing. Aspects of these features seem to be present in firstdegree relatives of patients with schizophrenia, indicating a role in the risk architecture.

Temporal coordination of oscillatory activity is critical for experience-dependent plasticity and therefore in the maturation of cortical networks. For spike-timing-dependent plasticity to occur, a window of the order of tenths of amillisecond for the co-occurrence of pre- and postsynaptic spiking has been proposed, which can be achieved through co-stimulation of cortical neurons over the thetacycle of the hippocampus. This opens the possibility that aberrant oscillations during critical periods can have an enduring effect on the shaping of cortical circuits beyond their immediate impact on local processing. Compromising both long-range coupling (through white matter tract maldevelopment or lesions) and local processing (for example, in interneurons) could have enduring effects on synaptic plasticity. Dopamine could have a modulating role in this process because intactmesocortical dopaminergic input is necessary for long-term potentiation to occur at hippocampal–prefrontal cortex synapses, reflecting dopamine-D2-receptor-mediated dopaminergic control over NMDA-receptor-dependent synaptic plasticity in prefrontal cortex, indicative of a ‘gating function’ of dopamine D2 receptors. A further link to the neurodevelopmental hypothesis is provided by the observation that long-range synchronization of the theta and gamma band undergoes profound changes during adolescence, when cortical–cortical connectivity continues to mature through myelinization of long-range tracks. This indicates that the reduction of transmission delays between brain regions during adolescence, especially between hippocampus and prefrontal cortex, enables the kind of precise temporal coordination that is important for activity-dependent shaping of prefrontal circuits. Importantly, this emergence of long-range connectivity has been linked to maturation of cortical grey matter, indicating a causal sequence. Speculatively, in the context of the interaction of hippocampus and prefrontal cortex, a sequence of events seems credible in which hippocampal dysfunction leads to abnormal shaping of neurocortical circuits as soon as hippocampal–prefrontal connections become sufficiently stable during late adolescence. This deficit could even become progressive if experience-dependent plasticity continues throughout adult life.

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