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Review
. 2015 Dec;19(12):744-756.
doi: 10.1016/j.tics.2015.09.009. Epub 2015 Oct 19.

How Schizophrenia Develops: Cognitive and Brain Mechanisms Underlying Onset of Psychosis

Tyrone D Cannon  1
Affiliations
Review

How Schizophrenia Develops: Cognitive and Brain Mechanisms Underlying Onset of Psychosis

Tyrone D Cannon. Trends Cogn Sci. 2015 Dec.

Abstract

Identifying cognitive and neural mechanisms involved in the development of schizophrenia requires longitudinal observation of individuals prior to onset. Here recent studies of prodromal individuals who progress to full psychosis are briefly reviewed in relation to models of schizophrenia pathophysiology. Together, this body of work suggests that disruption in brain connectivity, driven primarily by a progressive reduction in dendritic spines on cortical pyramidal neurons, may represent a key triggering mechanism. The earliest disruptions appear to be in circuits involved in referencing experiences according to time, place, and agency, which may result in a failure to recognize particular cognitions as self-generated or to constrain interpretations of the meaning of events based on prior experiences, providing the scaffolding for faulty reality testing.

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Figures

Figure 1
Figure 1
Developmental trajectories of cortical synaptic connectivity, including a number of trajectories (blue) in which connectivity is reduced below a hypothetical threshold sufficient for expression of psychotic symptoms.
Figure 2
Figure 2
(Left) Cortical surface maps showing regions in which converters to psychosis had significantly greater progressive loss of gray matter thickness compared with non-converters and controls [22]; (Right) Cortical surface maps showing regions in which higher levels of unusual thought content at baseline predicted a steeper rate of gray matter thinning among converters [47].
Figure 3
Figure 3
Schematic of neurodevelopmental changes resulting in disruptions in excitation-inhibition balance. Reprinted by permission from Macmillan Publishers Ltd: Nature [103], copyright 2010.
Figure 4
Figure 4
Circuit model of neuronal changes relevant to models of schizophrenia. Excitatory activity of cortical pyramidal neurons (light blue) is thought to be reduced in schizophrenia, most likely due to NMDA receptor hypofunction. Because of interactions with inhibitory, GABAergic interneurons (green), decreased excitatory input to neurons in the mesencephalon would lead to increased dopamine activity in the striatum and decreased dopamine activity in the cortex (yellow). Reprinted by permission from the American Society of Clinical Investigation: Journal of Clinical Investigation [63], copyright 2009.
Figure I
Figure I
Descriptive model of the onset and course of psychotic symptoms among individuals who develop a prodromal risk syndrome. Approximately one-third of prodomal patients progress to full psychosis (red line), one-third maintain stable levels of sub-threshold symptoms (blue line), and one-third remit the prodromal symptoms (green line). Reprinted by permission from Macmillan Publishers Ltd: Nature Disease Primers [102], copyright 2015.
Figure II
Figure II
Hypothetical trajectories of indicators across illness phases. Different cognitive and neural mechanisms may be stably deviant in CHR cases from the pre- to post-onset phase (in which case they could be necessary, but not sufficient, for symptom onset) or may deteriorate during this period (in which case, they could represent a sufficient cause for symptom formation).
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