Jonathan P. Roiser

Cognitive impairment in depression: a systematic review and meta-analysis

BACKGROUND This review aimed to address the question of whether cognitive impairment should be considered a core feature of depression that may be a valuable target for treatment. METHOD We conducted a systematic review and meta-analysis of cognitive function, assessed with a single neuropsychological test battery, the Cambridge Neuropsychological Test Automated Battery (CANTAB), in patients with depression during symptomatic and remitted states. Inclusion of studies comparing patients remitted from depression and controls enabled us to investigate whether cognitive impairment persists beyond episodes of low mood in depression. RESULTS Our meta-analysis revealed significant moderate cognitive deficits in executive function, memory and attention in patients with depression relative to controls (Cohens d effect sizes ranging from -0.34 to -0.65). Significant moderate deficits in executive function and attention (Cohens d ranging from -0.52 to -0.61) and non-significant small/moderate deficits in memory (Cohens d ranging from -0.22 to -0.54) were found to persist in patients whose depressive symptoms had remitted, indicating that cognitive impairment occurs separately from episodes of low mood in depression. CONCLUSIONS Both low mood and cognitive impairment are associated with poor psychosocial functioning. Therefore, we argue that remediation of cognitive impairment and alleviation of depressive symptoms each play an important role in improving outcome for patients with depression. In conclusion, this systematic review and meta-analysis demonstrates that cognitive impairment represents a core feature of depression that cannot be considered an epiphenomenon that is entirely secondary to symptoms of low mood and that may be a valuable target for future interventions.

Reward and Punishment Processing in Depression

Depression is a complex and heterogeneous disorder whose cause is poorly understood. Theories on the mechanisms of the disease have often focused on either its neurobiology or its cognitive and behavioral manifestations. Recently, studies exploring how depressed patients process reward and punishment have linked these two facets together. It has been suggested that individuals with a dysfunction in a specialized network of brain regions are unable to exploit affective information to guide behavior. Deficits in this ability might predispose such individuals to develop depression, whereas subsequent restoration of this ability--whether through pharmacological or behavioral treatments--might enable recovery from the disorder. Here we review behavioral, neuroimaging, and computational findings relevant to this hypothesis. There is good evidence that depressed patients exhibit abnormal behavioral responses to rewards and punishments and that these tendencies correspond to aberrant function in frontostriatal systems modulated by the monoamine systems. Furthermore, computational studies have generated testable predictions for how these neural signaling and neurochemical abnormalities might contribute to the symptoms of depression. Combining these approaches--as well as molecular and behavioral work in animals--provides great promise for furthering our understanding of this common and debilitating disease.

Atomoxetine Modulates Right Inferior Frontal Activation During Inhibitory Control: A Pharmacological Functional Magnetic Resonance Imaging Study

BACKGROUND Atomoxetine, a selective noradrenaline reuptake inhibitor (SNRI) licensed for the treatment of attention-deficit/hyperactivity disorder (ADHD), has been shown to improve response inhibition in animals, healthy volunteers, and adult patients. However, the mechanisms by which atomoxetine improves inhibitory control have yet to be determined. METHODS The effects of atomoxetine (40 mg) were measured with a stop-signal functional magnetic resonance imaging (fMRI) paradigm in 19 healthy volunteers, in a within-subject, double-blind, placebo-controlled design. RESULTS Atomoxetine improved inhibitory control and increased activation in the right inferior frontal gyrus when volunteers attempted to inhibit their responses (irrespective of success). Plasma levels of drug correlated significantly with right inferior frontal gyrus activation only during successful inhibition. CONCLUSIONS These results show that atomoxetine exerts its beneficial effects on inhibitory control via modulation of right inferior frontal function, with implications for understanding and treating inhibitory dysfunction of ADHD and other disorders.

Dopamine, serotonin and impulsivity.

Impulsive people have a strong urge to act without thinking. It is sometimes regarded as a positive trait but rash impulsiveness is also widely present in clinical disorders such as attention deficit hyperactivity disorder (ADHD), drug dependence, mania, and antisocial behaviour. Contemporary research has begun to make major inroads into unravelling the brain mechanisms underlying impulsive behaviour with a prominent focus on the limbic cortico-striatal systems. With this progress has come the understanding that impulsivity is a multi-faceted behavioural trait involving neurally and psychologically diverse elements. We discuss the significance of this heterogeneity for clinical disorders expressing impulsive behaviour and the pivotal contribution made by the brain dopamine and serotonin systems in the aetiology and treatment of behavioural syndromes expressing impulsive symptoms.

Striatal Prediction Error Modulates Cortical Coupling

Both perceptual inference and motor responses are shaped by learned probabilities. For example, stimulus-induced responses in sensory cortices and preparatory activity in premotor cortex reflect how (un)expected a stimulus is. This is in accordance with predictive coding accounts of brain function, which posit a fundamental role of prediction errors for learning and adaptive behavior. We used functional magnetic resonance imaging and recent advances in computational modeling to investigate how (failures of) learned predictions about visual stimuli influence subsequent motor responses. Healthy volunteers discriminated visual stimuli that were differentially predicted by auditory cues. Critically, the predictive strengths of cues varied over time, requiring subjects to continuously update estimates of stimulus probabilities. This online inference, modeled using a hierarchical Bayesian learner, was reflected behaviorally: speed and accuracy of motor responses increased significantly with predictability of the stimuli. We used nonlinear dynamic causal modeling to demonstrate that striatal prediction errors are used to tune functional coupling in cortical networks during learning. Specifically, the degree of striatal trial-by-trial prediction error activity controls the efficacy of visuomotor connections and thus the influence of surprising stimuli on premotor activity. This finding substantially advances our understanding of striatal function and provides direct empirical evidence for formal learning theories that posit a central role for prediction error-dependent plasticity.

Cognitive Mechanisms of Treatment in Depression

Cognitive abnormalities are a core feature of depression, and biases toward negatively toned emotional information are common, but are they a cause or a consequence of depressive symptoms? Here, we propose a ‘cognitive neuropsychological’ model of depression, suggesting that negative information processing biases have a central causal role in the development of symptoms of depression, and that treatments exert their beneficial effects by abolishing these biases. We review the evidence pertaining to this model: briefly with respect to currently depressed patients, and in more detail with respect to individuals at risk for depression and the effects of antidepressant treatments. As well as being present in currently depressed individuals, negative biases are detectable in those vulnerable for depression due to neuroticism, genetic risk, or previous depressive illness. Recent evidence provides strong support for the notion that both antidepressant drugs and psychological therapies modify negative biases, providing a common mechanism for understanding treatments for depression. Intriguingly, it may even be possible to predict which patients will benefit most from which treatments on the basis of neural responses to negative stimuli. However, further research is required to ascertain whether negative processing biases will be useful in predicting, detecting, and treating depression, and hence in preventing a chronic, relapsing course of illness.

Chronic cocaine but not chronic amphetamine use is associated with perseverative responding in humans

RationaleChronic drug use has been associated with increased impulsivity and maladaptive behaviour, but the underlying mechanisms of this impairment remain unclear. We investigated the ability to adapt behaviour according to changes in reward contingencies, using a probabilistic reversal-learning task, in chronic drug users and controls.Materials and methodsFive groups were compared: chronic amphetamine users (n = 30); chronic cocaine users (n = 27); chronic opiate users (n = 42); former drug users of psychostimulants and opiates (n = 26); and healthy non-drug-taking control volunteers (n = 25). Participants had to make a forced choice between two alternative stimuli on each trial to acquire a stimulus–reward association on the basis of degraded feedback and subsequently to reverse their responses when the reward contingencies changed.ResultsChronic cocaine users demonstrated little behavioural change in response to the change in reward contingencies, as reflected by perseverative responding to the previously rewarded stimulus. Perseverative responding was observed in cocaine users regardless of whether they completed the reversal stage successfully. Task performance in chronic users of amphetamines and opiates, as well as in former drug users, was not measurably impaired.ConclusionOur findings provide convincing evidence for response perseveration in cocaine users during probabilistic reversal-learning. Pharmacological differences between amphetamine and cocaine, in particular their respective effects on the 5-HT system, may account for the divergent task performance between the two psychostimulant user groups. The inability to reverse responses according to changes in reinforcement contingencies may underlie the maladaptive behaviour patterns observed in chronic cocaine users but not in chronic users of amphetamines or opiates.

A Genetically Mediated Bias in Decision Making Driven by Failure of Amygdala Control

Genetic variation at the serotonin transporter-linked polymorphic region (5-HTTLPR) is associated with altered amygdala reactivity and lack of prefrontal regulatory control. Similar regions mediate decision-making biases driven by contextual cues and ambiguity, for example the “framing effect.” We hypothesized that individuals hemozygous for the short (s) allele at the 5-HTTLPR would be more susceptible to framing. Participants, selected as homozygous for either the long (la) or s allele, performed a decision-making task where they made choices between receiving an amount of money for certain and taking a gamble. A strong bias was evident toward choosing the certain option when the option was phrased in terms of gains and toward gambling when the decision was phrased in terms of losses (the frame effect). Critically, this bias was significantly greater in the ss group compared with the lala group. In simultaneously acquired functional magnetic resonance imaging data, the ss group showed greater amygdala during choices made in accord, compared with those made counter to the frame, an effect not seen in the lala group. These differences were also mirrored by differences in anterior cingulate–amygdala coupling between the genotype groups during decision making. Specifically, lala participants showed increased coupling during choices made counter to, relative to those made in accord with, the frame, with no such effect evident in ss participants. These data suggest that genetically mediated differences in prefrontal–amygdala interactions underpin interindividual differences in economic decision making.

Encoding of Marginal Utility across Time in the Human Brain

Marginal utility theory prescribes the relationship between the objective property of the magnitude of rewards and their subjective value. Despite its pervasive influence, however, there is remarkably little direct empirical evidence for such a theory of value, let alone of its neurobiological basis. We show that human preferences in an intertemporal choice task are best described by a model that integrates marginally diminishing utility with temporal discounting. Using functional magnetic resonance imaging, we show that activity in the dorsal striatum encodes both the marginal utility of rewards, over and above that which can be described by their magnitude alone, and the discounting associated with increasing time. In addition, our data show that dorsal striatum may be involved in integrating subjective valuation systems inherent to time and magnitude, thereby providing an overall metric of value used to guide choice behavior. Furthermore, during choice, we show that anterior cingulate activity correlates with the degree of difficulty associated with dissonance between value and time. Our data support an integrative architecture for decision making, revealing the neural representation of distinct subcomponents of value that may contribute to impulsivity and decisiveness.

Do patients with schizophrenia exhibit aberrant salience

Background It has been suggested that some psychotic symptoms reflect ‘aberrant salience’, related to dysfunctional reward learning. To test this hypothesis we investigated whether patients with schizophrenia showed impaired learning of task-relevant stimulus–reinforcement associations in the presence of distracting task-irrelevant cues. Method We tested 20 medicated patients with schizophrenia and 17 controls on a reaction time game, the Salience Attribution Test. In this game, participants made a speeded response to earn money in the presence of conditioned stimuli (CSs). Each CS comprised two visual dimensions, colour and form. Probability of reinforcement varied over one of these dimensions (task-relevant), but not the other (task-irrelevant). Measures of adaptive and aberrant motivational salience were calculated on the basis of latency and subjective reinforcement probability rating differences over the task-relevant and task-irrelevant dimensions respectively. Results Participants rated reinforcement significantly more likely and responded significantly faster on high-probability-reinforced relative to low-probability-reinforced trials, representing adaptive motivational salience. Patients exhibited reduced adaptive salience relative to controls, but the two groups did not differ in terms of aberrant salience. Patients with delusions exhibited significantly greater aberrant salience than those without delusions, and aberrant salience also correlated with negative symptoms. In the controls, aberrant salience correlated significantly with ‘introvertive anhedonia’ schizotypy. Conclusions These data support the hypothesis that aberrant salience is related to the presence of delusions in medicated patients with schizophrenia, but are also suggestive of a link with negative symptoms. The relationship between aberrant salience and psychotic symptoms warrants further investigation in unmedicated patients.