Healthy co-twins of patients with affective disorders show reduced risk-related activation of the insula during a monetary gambling task

Macoveanu J, Miskowiak KW, Kessing LV, Siebner HR, Vinberg M

J Psychiatry Neuroscience (in press)


Background: Healthy first-degree relatives to patients with affective disorders are at increased risk for affective disorders and express discrete structural and functional abnormalities in the brain reward system. However, the value-based decision-making is not well understood in these at-risk individuals.

Methods: We investigated healthy monozygotic (n = 30) and dizygotic (n = 37) twins with or without a co-twin history of affective disorders (high-risk and low-risk groups, respectively) using functional MRI while performing a gambling task. We assessed group differences in activity related to gambling risk over the entire brain.

Results: Neural activity in anterior insula and ventral striatum increased linearly with the amount of gambling risk in the entire cohort. Individual neuroticism scores were positively correlated with the neural response in ventral striatum to increasing gambling risk and negatively correlated with individual risk-taking behavior. Compared with low-risk twins, the high-risk twins showed a bilateral reduction of risk-related activity in the middle insula extending into temporal cortex with increasing gambling risk. Post-hoc analyses revealed that this effect was strongest in dizygotic twins.

Limitations: The higher average age of the twin cohort (49.2 years) may indicate an increased resilience to affective disorders. The size of the monozygotic high-risk group was relatively small (n=13).

Conclusion: The reduced processing of risk magnitude in the middle insula may indicate a deficient integration of exteroceptive information related to risk-related cues with interoceptive states in individuals at familial risk for affective disorders. Impaired risk processing might contribute to increased vulnerability to affective disorders.

‘Hot’ cognition in major depressive disorder: a systematic review

Miskowiak KW, Carvalho AF

CNS Neurol Disord Drug Targets. 2014;13(10):1787-803.


Major depressive disorder (MDD) is associated with significant cognitive dysfunction in both ‘hot’ (i.e. emotion-laden) and ‘cold’ (non-emotional) domains. Here we review evidence pertaining to ‘hot’ cognitive changes in MDD. This systematic review searched the PubMed and PsycInfo computerized databases in May 2014 augmented by hand searches of reference lists. We included original articles in which MDD participants (or their healthy first-degree relatives) and a healthy control group were compared on standard measures of emotional processing or reward/ punishment processing as well as systematic reviews and meta-analyses. A total of 116 articles met the inclusion criteria of which 97 were original studies. Negative biases in perception, attention and memory for emotional information, and aberrant reward/punishment processing occur in MDD. Imbalanced responses to negative stimuli in a fronto-limbic network with hyper-activity in limbic and ventral prefrontal regions paired with hypo-activity of dorsal prefrontal regions subserve these abnormalities. A cross-talk of ‘hot’ and ‘cold’ cognition disturbances in MDD occurs. Disturbances in ‘hot cognition’ may also contribute to the perpetuation of negative emotional states in MDD. Limited success in the identification of susceptibility genes in MDD has led to great research interest in identifying vulnerability biomarkers or endophenotypes. Emerging evidence points to the persistence of ‘hot’ cognition dysfunction during remission and to subtle ‘hot’ cognition deficits in healthy relatives of patients with MDD. Taken together, these findings suggest that abnormalities in ‘hot’ cognition may constitute a candidate neurocognitive endophenotype for depression.

Different neural and cognitive response to emotional faces in healthy monozygotic twins at risk of depression

Miskowiak KW, Glerup L, Vestbo C, Harmer CJ, Reinecke A, Macoveanu J, Siebner HR, Kessing LV, Vinberg M

Psychol Med. 2015 May;45(7):1447-58.


BACKGROUND: Negative cognitive bias and aberrant neural processing of emotional faces are trait-marks of depression. Yet it is unclear whether these changes constitute an endophenotype for depression and are also present in healthy individuals with hereditary risk for depression.

METHOD: Thirty healthy, never-depressed monozygotic (MZ) twins with a co-twin history of depression (high risk group: n = 13) or without co-twin history of depression (low-risk group: n = 17) were enrolled in a functional magnetic resonance imaging (fMRI) study. During fMRI, participants viewed fearful and happy faces while performing a gender discrimination task. After the scan, they were given a faces dot-probe task, a facial expression recognition task and questionnaires assessing mood, personality traits and coping strategies.

RESULTS: High-risk twins showed increased neural response to happy and fearful faces in dorsal anterior cingulate cortex (ACC), dorsomedial prefrontal cortex (dmPFC), pre-supplementary motor area and occipito-parietal regions compared to low-risk twins. They also displayed stronger negative coupling between amygdala and pregenual ACC, dmPFC and temporo-parietal regions during emotional face processing. These task-related changes in neural responses in high-risk twins were accompanied by impaired gender discrimination performance during face processing. They also displayed increased attention vigilance for fearful faces and were slower at recognizing facial expressions relative to low-risk controls. These effects occurred in the absence of differences between groups in mood, subjective state or coping.

CONCLUSIONS: Different neural response and functional connectivity within fronto-limbic and occipito-parietal regions during emotional face processing and enhanced fear vigilance may be key endophenotypes for depression

Acute antidepressant drug administration and autobiographical memory recall: a functional magnetic resonance imaging study

Papadatou-Pastou M1, Miskowiak KW, Williams JM, Harmer CJ, Reinecke A

Exp Clin Psychopharmacol. 2012 Oct;20(5):364-72.


Antidepressants affect memory and neural responses to emotionally valenced stimuli in healthy volunteers. However, it is unclear whether this extends to autobiographical memory for personally experienced events. The current study investigated the effects of acute administration of the antidepressant reboxetine on emotional autobiographical retrieval in healthy volunteers (14 men, 10 women). Functional magnetic resonance imaging was used in a double-blind between-groups investigation with reboxetine (4 mg) and placebo. Consistent with previous reports using lab-based stimuli, neural activation in the processing of positive versus negative memories was reduced following reboxetine compared with placebo in the left frontal lobe (extending into the insula) and the right superior temporal gyrus. This was paired with increased memory speed in volunteers given reboxetine versus placebo. The effect of reboxetine on emotional memory extends to recall of personally experienced events. Such effects may be relevant to the cognitive improvements found with recovery from depression and with the mechanism of action of contemporary antidepressant drugs.

Single dose antidepressant administration modulates the neural processing of self-referent personality trait words

Miskowiak K, Papadatou-Pastou M, Cowen PJ, Goodwin GM, Norbury R, Harmer CJ

Neuroimage. 2007 Sep 1;37(3):904-11.


Drugs which inhibit the re-uptake of monoamines in the brain are effective in the treatment of depression; however, the neuropsychological mechanisms which lead to the resolution of depressive symptomatology are unclear. Behavioral studies in healthy volunteers suggest that acute administration of the selective norepinephrine reuptake inhibitor reboxetine modulates emotional processing. The current study therefore explored the neural basis of this effect. A single dose of reboxetine (4 mg) or placebo was administered to 24 healthy volunteers in a double-blind between-group design. Neural responses during categorisation and recognition of self-referent personality trait words were assessed using event-related functional Magnetic Resonance Imaging (fMRI). Reboxetine had no effect on neuronal response during self-referent categorisation of positive or negative personality trait words. However, in a subsequent memory test, reboxetine reduced neuronal activation in a fronto-parietal network during correct recognition of positive target words vs. matched distractors. This was combined with increased speed to recognize positive vs. negative words compared to control subjects and suggests facilitated memory for positive self-referent material. These results support the hypothesis that antidepressants have early effects on the neural processing of emotional material which may be important in their therapeutic actions.

Erythropoietin improves mood and modulates the cognitive and neural processing of emotion 3 days post administration.

Erythropoietin improves mood and modulates the cognitive and neural processing of emotion 3 days post administration.

Miskowiak K, Inkster B, Selvaraj S, Wise R, Goodwin GM, Harmer CJ.


Neuropsychopharmacology. 2008 Feb;33(3):611-8.


Erythropoietin (Epo) has neuroprotective and neurotrophic effects and is a promising candidate for treatment of neurodegenerative and psychiatric disorder. Recently, we demonstrated that Epo modulates memory-relevant hippocampal response and fear processing in human models of antidepressant drug action 1 week post-administration, and improves self-reported mood for 3 days immediately following administration. The present study explored the effects of Epo (40 000 IU) vs saline on self-reported mood and on neural and cognitive function in healthy volunteers 3 days post-administration to test the reliability of the rapid mood improvement and its neuropsychological basis. Neuronal responses during the processing of happy and fearful faces were investigated using functional magnetic resonance imaging (fMRI); facial expression recognition performance was assessed after the fMRI scan. Daily ratings of mood were obtained for 3 days after Epo/saline administration. During faces processing Epo enhanced activation in the left amygdala and right precuneus to happy and fearful expressions. This was paired with improved recognition of all facial expressions, in particular of low intensity happiness and fear. This is similar to behavioral effects observed with acute administration of serotonergic antidepressants. Consistent with our previous finding, Epo improved self-reported mood for all 3 days post-administration. Together, these results suggest that characterization of the effects of Epo in a clinically depressed group is warranted.

Erythropoietin reduces neural and cognitive processing of fear in human models of antidepressant drug action.

Miskowiak K, O’Sullivan U, Harmer CJ.


Biological Psychiatry. 2007 Dec 1;62(11):1244-50.


BACKGROUND: Erythropoietin (Epo) has neuroprotective and neurotrophic effects in animal models and affects cognitive and associated neural responses in humans. These effects have highlighted Epo as a candidate for treatment of psychiatric disease including schizophrenia and depression. The current study aimed to explore the effects of Epo on neural and behavioral measures of emotional processing relevant for depression and the effects of conventional antidepressant medication. METHODS: In the present study, we used functional magnetic resonance imaging to explore the effects of Epo (40,000 IU) versus saline on the neural processing of happy and fearful faces in 23 healthy volunteers. Facial expression recognition was assessed outside the scanner. RESULTS: One week after administration, Epo reduced neural response to fearful versus neutral faces in the occipito-parietal cortex consistent with reduced attention to fear. Erythropoietin additionally reduced recognition of fearful facial expressions without affecting recognition of other emotional expressions. These actions occurred in the absence of changes in hematological parameters. CONCLUSIONS: The present study demonstrates that Epo directly modulates brain responses to emotional information in humans in a manner consistent with the actions of conventional antidepressants. The characterization of the effects of Epo in a clinically depressed group is therefore warranted.