A non-reward attractor theory of depression

Abstract

Neuroscience and Biobehavioral Reviews, in press (May 2016) \papers\Emotion\depression\depression16b.docx 2 SummaryA non-reward attractor theory of depression is proposed based on the operation of the lateral orbitofrontal cortex and supracallosal cingulate cortex. The orbitofrontal cortex contains error neurons that respond to non-reward for many seconds in an attractor state that maintains a memory of the nonreward. The human lateral orbitofrontal cortex is activated by non-reward during reward reversal, and by a signal to stop a response that is now incorrect. Damage to the human orbitofrontal cortex impairs reward reversal learning. Not receiving reward can produce depression. The theory proposed is that in depression, this lateral orbitofrontal cortex non-reward system is more easily triggered, and maintains its attractor-related firing for longer. This triggers negative cognitive states, which in turn have positive feedback top-down effects on the orbitofrontal cortex non-reward system. Treatments for depression, including ketamine, may act in part by quashing this attractor. The mania of bipolar disorder is hypothesized to be associated with oversensitivity and overactivity in the reciprocally related reward system in the medial orbitofrontal cortex and pregenual cingulate cortex.

Non-reward neural mechanisms in the orbitofrontal cortex

“…For these reasons, understanding the mechanisms that underlie non-reward is important not only for understanding normal human behavior and how it changes when rewards are not received, but also for understanding and potentially treating better some emotional and psychiatric disorders. Indeed, a prediction of the current model is that if there are non-reward attractors in the orbitofrontal cortex, and these are over-sensitive in depression, then treatments such as ketamine which by blocking NMDA receptors knock the network out of its attractor state, may in this way reduce depression, and there is already evidence consistent with this (Rolls 2016b, Carlson, Diazgranados, Nugent, Ibrahim, Luckenbaugh, Brutsche, Herscovitch, Manji, Zarate and Drevets 2013, Lally, Nugent, Luckenbaugh, Niciu, Roiser and Zarate 2015. Responses of an or bitofrontal cortex neuron that responded only when the monkey licked to a visual st imulus during reversal, expecting to obtain fruit juice reward, but actually obtained the taste of aversive saline because it was the first trial of reversal (trials 3, 6, and 13) .…”

“…The process is important in many emotions, which can be produced if an expected reward is not received or lost, with examples including sadness and anger (Rolls 2014). Consistent with this the psychiatric disorder of depression may arise when the non-reward system leading to sadness is too sensitive, or maintains its activity for too long (Rolls 2016b), or has increased functional connectivity (Cheng, Rolls, Qiu, Liu, Tang, Huang, Wang, Zhang, Lin, Zheng, Pu, Tsai, Yang, Lin, Wang, Xie and Feng 2016). Conversely, if the non-reward system is underactive or is damaged by lesions of the orbitofrontal cortex, the decreased sensitivity to non-reward may contribute to increased impulsivity Kischka 2004, Berlin, Rolls andIversen 2005), and even antisocial and psychopathic behavior (Rolls 2014).…”

The roles of the orbitofrontal cortex via the habenula in non-reward and depression, and in the responses of serotonin and dopamine neurons

“…This commentary draws out the implications of that theory of depression for understanding the functions of the habenula in depression, and the subcortical structures to which it projects including the serotonin (5-HT, 5-hydroxytryptamine) and dopamine systems. This commentary and extension of the theory (Rolls, 2016b) is timely in view of the current interest in the functions of the habenula in depression (Fakhoury, 2017;Loonen and Ivanova, 2015, 2016a, 2017.…”

“…The habenula also projects via the rostromedial tegmental nucleus to the dopaminecontaining neurons, and this, it is proposed, provides a route for reward prediction error signals and other reward-and punishment-related signals of cortical and striatal origin to influence the dopamine system. This paper is a brief commentary on the paper "A non-reward attractor theory of depression" that focused on orbitofrontal cortex non-reward attractor networks and their potential relevance to depression (Rolls, 2016b). This commentary draws out the implications of that theory of depression for understanding the functions of the habenula in depression, and the subcortical structures to which it projects including the serotonin (5-HT, 5-hydroxytryptamine) and dopamine systems.…”

“…One key point is that the neocortex with its highly developed local recurrent collateral excitatory connections between the pyramidal cells appears to allow ongoing firing to continue in attractor states, each one of which might represent a short-term memory, an expected value, a long-term memory, the result of a decision just taken, or the recent receipt of non-reward (Rolls, 2016a).…”