Dysconnection in schizophrenia: from abnormal synaptic plasticity to failures of self-monitoring.
Over the last 2 decades, a large number of neurophysiological and neuroimaging studies of patients with schizophrenia have furnished in vivo evidence for dysconnectivity, ie, abnormal functional integration of brain processes. While the evidence for dysconnectivity in schizophrenia is strong, its etiology, pathophysiological mechanisms, and significance for clinical symptoms are unclear. First, dysconnectivity could result from aberrant wiring of connections during development, from aberrant synaptic plasticity, or from both. Second, it is not clear how schizophrenic symptoms can be understood mechanistically as a consequence of dysconnectivity. Third, if dysconnectivity is the primary pathophysiology, and not just an epiphenomenon, then it should provide a mechanistic explanation for known empirical facts about schizophrenia. This article addresses these 3 issues in the framework of the dysconnection hypothesis. This theory postulates that the core pathology in schizophrenia resides in aberrant N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic plasticity due to abnormal regulation of NMDARs by neuromodulatory transmitters like dopamine, serotonin, or acetylcholine. We argue that this neurobiological mechanism can explain failures of self-monitoring, leading to a mechanistic explanation for first-rank symptoms as pathognomonic features of schizophrenia, and may provide a basis for future diagnostic classifications with physiologically defined patient subgroups. Finally, we test the explanatory power of our theory against a list of empirical facts about schizophrenia.
Stephan
Klaas E
KE
k.stephan@fil.ion.ucl.ac.uk
Friston
Karl J
KJ
Frith
Chris D
CD
D000109:Acetylcholine / Q000378:metabolism; D001364:Awareness / Q000502:physiology*; D001921:Brain / Q000503:physiopathology*; D003702:Delusions / Q000503:physiopathology / Q000523:psychology; D004298:Dopamine / Q000378:metabolism; D004569:Electroencephalography; D006212:Hallucinations / Q000503:physiopathology / Q000523:psychology; D006801:Humans; D008279:Magnetic Resonance Imaging; D015225:Magnetoencephalography; D009415:Nerve Net / Q000503:physiopathology; D009473:Neuronal Plasticity / Q000502:physiology*; D011936:Reality Testing; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D012559:Schizophrenia / Q000503:physiopathology*; D012565:Schizophrenic Psychology; D012701:Serotonin / Q000378:metabolism; D013569:Synapses / Q000502:physiology*
D016194:Receptors, N-Methyl-D-Aspartate; D012701:Serotonin; D000109:Acetylcholine; D004298:Dopamine