Oxford Centre for Computational Neuroscience

Professor Edmund T. Rolls

Discoveries on the brain bases of mental disorders

Cerebral Cortex

Emotion and Decision-Making Explained

The Noisy Brain

Overview: Rolls has made discoveries about the brain bases of mental disorders that have their foundations in his interests in emotion and in computational neuroscience (B16). Rolls and colleagues have discovered that depression can be related in part to increased connectivity and sensitivity of the non-reward related lateral orbitofrontal cortex and decreased connectivity and sensitivity of the reward-related medial orbitofrontal cortex (626, B13, B16). Rolls and colleagues have related the symptoms of schizophrenia to altered stability of cortical attractor networks (631), in turn related in part to reduced forward relative to backward connectivity in the cerebral cortex (602). These approaches have been extended to the memory changes in normal aging (540), to autism (541, 609), to obsessive-compulsive disorder (449), and to the emotional changes that follow brain damage in humans (641).


A non-reward attractor theory of depression, in which the lateral orbitofrontal cortex attractor network system for non-reward maintains its activity for too long; and the medial orbitofrontal cortex reward system is less responsive (559, 572, 579, 626, B12, B13, B14, B16). The theory is supported by a model of the computation of non-reward in the orbitofrontal cortex (562). An introduction to the theory is available as a lecture.

The lateral orbitofrontal cortex and adjoining inferior frontal gyrus (615) in depression has increased functional connectivity (564, 591, B14, 626, B16) with the precuneus (where the self is represented, and which may contribute to the low self-esteem in depression) (592); with the angular gyrus (involved in language, and which may contribute by a long loop attractor to the negative rumination in depression); and with the temporal lobe cortex (which may contribute to the sad interpretation of faces and events)  (564). Effective or directed connectivity from the medial orbitofrontal cortex to the lateral orbitofrontal cortex is increased in depression, and given that the activity in these areas is reciprocally related, this may release the lateral orbitofrontal cortex into high activity, which was found in the analysis (583).

Rolls' theory of depression (559, 626, B13, B14, B16) is also supported by increased functional connectivity of the non-reward-related lateral orbitofrontal cortex (615, 626) with the posterior cingulate cortex (588) which provides a dorsal route into the hippocampal memory system (584), and decreased functional connectivity of the reward-related medial orbitofrontal cortex with the parahippocampal gyrus (564) which provides a ventral route into the hippocampal memory system, with both effects enhancing sad and reducing happy memories in depression (615, 626, B16).

A pregenual / subcallosal subdivision of the anterior cingulate cortex normally with high connectivity to the medial orbitofrontal cortex reward system has increased functional connectivity with the lateral orbitofrontal cortex non-reward system in depression. This may provide a mechanism for more non-reward information to be transmitted to the reward-related part of the anterior cingulate cortex, contributing to depression (596).

The amygdala has reduced functional connectivity in depression (590).

The importance of the orbitofrontal cortex, a key brain area for emotion, in depression (626) is supported by an activation study in the monetary incentive delay task (623). This shows that the sensitivity of the lateral orbitofrontal cortex to non-reward (not receiving an expected reward, a contingency that can produce sadness) is higher in adolescents with a high severity of depressive symptoms. Further, the medial orbitofrontal cortex is less sensitive to reward in those with a high severity of depressive symptoms (623). This provides further key evidence relevant to the theory of depression  (559, 626, B13, B14, B16).

An overview of the brain mechanisms of depression, and how this fits in with understanding of the brain mechanisms of emotion (626), is provided in The Brain, Emotion, and Depression (B13). This approach to depression has implications for treating depression both psychologically and medically  (559, B13, B14, B16).

Depression, and behavioural and depressive problems are associated in children with sleep problems and with  lower volumes of  brain regions such as the prefrontal cortex, orbitofrontal cortex, and anterior cingulate cortex (616). Lower volumes of these brain regions are also associated with behavioural and depressive problems in children of mothers with prolonged nausea and vomiting in pregnancy (622), in children of young mothers (642), and in children in families with family problems (636). Childhood trauma is associated with mental health and cognitive problems in adults, and the association is mediated by functional connectivity of the orbitofrontal cortex, prefrontal cortex, and temporal cortical areas (651).


A theory of schizophrenia in which reduced glutamate functionality in the prefrontal cortex destabilizes attractor networks  producing cognitive impairments in attention, and exceutive function;  and in which reduced glutamate function in the orbitofrontal cortex leads to the negative symptoms. Increased activity in medial temporal lobe networks overstabilizes attractor networks there leading to the positive symptoms including hallucinations and delusions. (450, 490, 496, 503, 602, B12, 631, B16).

The discovery in a sample of 2,567 patients with schizophrenia that the main variation between individuals is in the negative symptoms, using the PANSS (580). This has implications for stratified treatment.

In first-episode patients with schizophrenia the main changes in functional connectivity involve the inferior frontal gyrus; and become established in thalamic connectivity in the chronic state (563). The temporal variability of functional connectivity is increased in schizophrenia, is related to lower functional connectivity, and may underlie the thought disorders (629). Increased functional connectivity of the precuneus and posterior cingulate cortex is related to volition (thought control), and is not treated by neuroleptic drugs (538).

In schizophrenia, we provide evidence that goes beyond the disconnectivity hypothesis, by showing in a large sample of people with schizophrenia that whereas the effective connectivity in the strong or forward direction is reduced, the effective connectivity in the weak or backward direction is not (602). This may tend to result in over-emphasis on the internal world, with relative disconnection from the reality of the external world (B16).


A middle temporal gyrus / superior temporal sulcus (STS) region involved in face expression processing and theory of mind has reduced cortical functional connectivity with the ventromedial prefrontal cortex which is implicated in emotion and social communication. The precuneus,  which is implicated in spatial functions including of oneself, has reduced functional connectivity. These two types of functionality, face expression-related, and of one’s self and the environment, are important components of the computations involved in theory of mind, whether of oneself or of others, and the reduced connectivity within and between these regions is proposed to make a key contribution to the symptoms of autism (541, 570, 609).

Obsessive-Compulsive Disorder

A theory that hyperglutamergia in the prefrontal and premotor cortices in OCD overstablizes attractor networks in these regions (449, B14, B16).

Effects of damage to the human orbitofrontal cortex

Impairments in the rapid reversal of associations between stimuli and reward value in patients with selective lesions of the orbitofrontal cortex and related areas and their relation to emotional changes (188, 203, 331, 354, B14, 641). Also, impairments in impulsivity (353, 362, 394). These discoveries were inspired by the discoveries on neuronal activity in the orbitofrontal cortex, and are relevant to understanding the changes in patients with frontal lobe damage and in patients with borderline personality disorder (B16).

A recent discovery is of the effective connectivity of the  human orbitofrontal cortex, vmPFC and anterior cingulate cortex, which shows how reward value and emotion can reach the hippocampal memory system to become incorporated in episodic memory (649, 657, B16). This also shows how these cortical regions have connectivity with the septum and basal forebrain cholinergic systems, providing a mechanism that may contribute to the memory impairments produced by damage to the orbitofrontal cortex / vmPFC and/or anterior cingulate cortex in humans (649, 657). 


The medial orbitofrontal cortex reward system has high functional connectivity in those who tend to drink alcohol and who are sensation-seekers and impulsive; and the lateral orbitofrontal cortex non-reward system has low functional connectivity in  those who tend to smoke, and are impulsive for a different reason (599). The medial orbitofrontal is also activated by amphetamine (367). These discoveries underline the different neural bases for different types of addiction (B14).

Normal Aging

A theory of how reduced stability of cortical attractor networks can account for some of the memory and cognitive symptoms of normal aging, with implications for treatment (540, 613, B16).

Hypertension and impaired memory

Even moderate hypertension is associated with reduced hippocampal functional connectivity and impaired memory (625).

Brain, cognitive, and psychiatric differences associated with development

We have discovered a constellation of somewhat similar functional and structural differences of the brain (e.g. of the orbitofrontal cortex, anterior cingulate cortex, and hippocampus) that are associated with lower cognitive performance and with mental health symptoms including depression. The factors associated with these differences includechildhood traumatic events ( 651), the family environment (636), low age of the mother (642), prolonged nausea and vomiting in pregnancy (622), and low sleep duration (616).