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, 44 (6), 367-383

Inefficient Neural System Stabilization: A Theory of Spontaneous Resolutions and Recurrent Relapses in Psychosis

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Inefficient Neural System Stabilization: A Theory of Spontaneous Resolutions and Recurrent Relapses in Psychosis

Lena Palaniyappan. J Psychiatry Neurosci.

Abstract

A striking feature of psychosis is its heterogeneity. Presentations of psychosis vary from transient symptoms with no functional consequence in the general population to a tenacious illness at the other extreme, with a wide range of variable trajectories in between. Even among patients with schizophrenia, who are diagnosed on the basis of persistent deterioration, marked variation is seen in response to treatment, frequency of relapses and degree of eventual recovery. Existing theoretical accounts of psychosis focus almost exclusively on how symptoms are initially formed, with much less emphasis on explaining their variable course. In this review, I present an account that links several existing notions of the biology of psychosis with the variant clinical trajectories. My aim is to incorporate perspectives of systems neuroscience in a staging framework to explain the individual variations in illness course that follow the onset of psychosis.

Conflict of interest statement

L. Palaniyappan reports personal fees from Janssen Canada, Otsuka Canada, SPMM Course Limited, UK, and the Canadian Psychiatric Association; book royalties from Oxford University Press; investigator-initiated educational grants from Sunovion, Janssen Canada and Otsuka Canada; and travel support from Boehringer Ingelheim and Magstim Limited, outside the submitted work. In the last 3 years, L. Palaniyappan and/or his spouse have held shares in Shire Pharmaceuticals and GlaxoSmithKline in their pension funds for values less than US$10 000.

Figures

Fig. 1
Fig. 1
Illustration to reflect the balance between physiologic outputs of a neural unit (i.e., neuronal firing “activity”) and the social influence on the component unit (“connectivity”). If neuronal firing is excessive, the balance tilts, leading to engagement of homeostatic mechanisms that reduce the connectivity and restore the balance. Conversely, if synaptic strength/number (connectivity) is reduced, this triggers a compensatory increase in neuronal firing. This neural system stabilization helps to maintain topological homeostasis, likely characterized by a narrow range of “tuned states” of the brain connectome.
Fig. 2
Fig. 2
Anomalous associations and psychotic experiences. (A) Learning associations between 2 time-variable signals require tight temporal coordination (Hebbian window), shown as a narrow interval between the activation of pre- and postsynaptic neurons in the first illustration. This window can be prolonged in hyperdopaminergic states, as shown in the lower panel. (B) Anomalous bursts of presynaptic activity can lead to inadvertent Hebbian associations. (C) Failure of habituation may lead to prolonged states of evoked activity, increasing the probability of Hebbian associations.
Fig. 3
Fig. 3
Stabilization lag in a psychotic episode. Psychotic episodes can occur after repetitive or massive doses of inducing agents through mechanisms shown in Figure 2, leading to a temporary overload of neural system stabilization. Provided that the cellular/topological system stabilization apparatus (homeostatic) is intact, these episodes can resolve fully.
Fig. 4
Fig. 4
Stabilization shift in psychotic disorders. In those who have a predilection for aberrant functional plasticity, synaptic gains from associations accumulate over time, leading to runaway excitation in the neural network. The occurrence of this event may be brought forward by exposure to inducing agents, as indicated in Figure 3. In the absence of an intact neural system stabilization process, this results in a hyperconnected state for resting-state brain networks, with inefficient over-recruitment of task-processing regions. Subtle information-processing deficits that accompanied the predilection for aberrant functional plasticity now become more pronounced; the step change coincides with the first psychotic episode. The neural system stabilization mechanism now shifts from inefficient functional plasticity to a robust dependence on structural plasticity (i.e., spine reduction). fMRI = functional MRI.
Fig. 5
Fig. 5
Hub de-escalation in psychotic disorders. (A) Rich-club hubs of the human connectome (anterior cingulate cortex, insula, lateral prefrontal cortex, superior temporal gyrus and hippocampal regions) have inherently high activity levels and higher topological proximity to any given brain region. (B) As a result, the pathways to and from these nodes are most likely to be the sites of dendritic spine reduction occurring in response to anomalous hyperconnectivity. (C) With time, this leads to “deescalation” of hubs (red-dotted circles), increased demands on remaining hubs (overloading effect, shown with a red halo) and emergence of peripheral hubs (yellow nodes). While this helps with restoration of sparse connectivity, it comes at the cost of increased segregation of functional modules (nodes with a thunderbolt sign less well connected to other hubs) and prolonged transit time in the network.
Fig. 6
Fig. 6
Saturation of system stabilization. Hub de-escalation results in a suboptimally retuned system that is prone to runaway excitation, even with milder doses of psychosis-inducing triggers. Recurrent relapses exhaust the structural plasticity through dendritic spine elimination, leading to a state of homeostatic occlusion. This is associated with a treatment-resistant state, in which interventions that act primarily by enhancing functional plasticity are no longer effective.
Fig. 7
Fig. 7
Neural system stabilization and grades of psychosis. The degree of impairment in the homeostatic process of topological neural system stabilization determines whether an episode of psychosis resolves fully, relapses repeatedly or fails to respond to currently prescribed interventions.

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