Sex differences in the emotional brain

In this issue, Schienle et al. use brain imaging to examine emotion-related activation differences between men and women. Are those differences related to the way the sexes feel emotions? Are they hardwired? In this commentary, we briefly review sex differences in feeling, perception of emotionally evocative cues, and expression of emotions, and we discuss how they may be related to sex differences in the emotional brain.     

Amygdala recruitment in schizophrenia in response to aversive emotional material: a meta-analysis of neuroimaging studies

Emotional dysfunction has long been established as a critical clinical feature of schizophrenia. In the past decade, there has been extensive work examining the potential contribution of abnormal amygdala activation to this dysfunction in patients with schizophrenia. A number of studies have demonstrated under-recruitment of the amygdala in response to emotional stimuli, while others have shown intact recruitment of this region. To date, there have been few attempts to synthesize this literature using quantitative criteria or to use a formal meta-analytic approach to examine which variables may moderate the magnitude of between-group differences in amygdala activation in response to aversive emotional stimuli. We conducted a meta-analysis of amygdala activation in patients with schizophrenia, using a bootstrapping approach to investigate: (a) evidence for amygdala under-recruitment in schizophrenia and (b) variables that may moderate the magnitude of between-group differences in amygdala activation. We demonstrate that patients with schizophrenia show statistically significant, but modest, under-recruitment of bilateral amygdala (mean effect size = -0.20 SD). However, present findings indicate that this under-recruitment is dependent on the use of a neutral vs emotion interaction contrast and is not apparent if amygdala activation by patients and controls is evaluated in a negative emotional condition only.     

Predictors of amygdala activation during the processing of emotional stimuli: a meta-analysis of 385 PET and fMRI studies

Although amygdala activity has been purported to be modulated by affective and non-affective factors, considerable controversy remains on its precise functional nature. We conducted a meta-analysis of 385 functional neuroimaging studies of emotional processing, examining the effects of experimental characteristics on the probability of detecting amygdala activity. All emotional stimuli were associated with higher probability of amygdala activity than neutral stimuli. Comparable effects were observed for most negative and positive emotions, however there was a higher probability of activation for fear and disgust relative to happiness. The level of attentional processing affected amygdala activity, as passive processing was associated with a higher probability of activation than active task instructions. Gustatory-olfactory and visual stimulus modalities increased the probability of activation relative to internal stimuli. Aversive learning increased the probability of amygdala activation as well. There was some evidence of hemispheric specialization with a relative left-lateralization for stimuli containing language and a relative right-lateralization for masked stimuli. Methodological variables, such as type of analysis and magnet strength, were also independent predictors of amygdala activation.     

The role of the amygdala in emotional processing: a quantitative meta-analysis of functional neuroimaging studies

Functional neuroimaging studies have provided strong support for a critical role of the amygdala in emotional processing. However, several controversies remain in terms of whether different factors—such as sex, valence and stimulus type—have an effect on the magnitude and lateralization of amygdala responses. To address these issues, we conducted a meta-analysis of functional neuroimaging studies of visual emotional perception that reported amygdala activation. Critically, unlike previous neuroimaging meta-analyses, we took into account the magnitude (effect size) and reliability (variance) associated with each of the activations. Our results confirm that the amygdala responds to both positive and negative stimuli, with a preference for faces depicting emotional expressions. We did not find evidence for amygdala lateralization as a function of sex or valence. Instead, our findings provide strong support for a functional dissociation between left and right amygdala in terms of temporal dynamics. Taken together, results from this meta-analysis shed new light on several of the models proposed in the literature regarding the neural basis of emotional processing.     

Sex steroids and connectivity in the human brain: a review of neuroimaging studies

Our brain operates by the way of interconnected networks. Connections between brain regions have been extensively studied at a functional and structural level, and impaired connectivity has been postulated as an important pathophysiological mechanism underlying several neuropsychiatric disorders. Yet the neurobiological mechanisms contributing to the development of functional and structural brain connections remain to be poorly understood. Interestingly, animal research has convincingly shown that sex steroid hormones (estrogens, progesterone and testosterone) are critically involved in myelination, forming the basis of white matter connectivity in the central nervous system. To get insights, we reviewed studies into the relation between sex steroid hormones, white matter and functional connectivity in the human brain, measured with neuroimaging. Results suggest that sex hormones organize structural connections, and activate the brain areas they connect. These processes could underlie a better integration of structural and functional communication between brain regions with age. Specifically, ovarian hormones (estradiol and progesterone) may enhance both cortico-cortical and subcortico-cortical functional connectivity, whereas androgens (testosterone) may decrease subcortico-cortical functional connectivity but increase functional connectivity between subcortical brain areas. Therefore, when examining healthy brain development and aging or when investigating possible biological mechanisms of 'brain connectivity' diseases, the contribution of sex steroids should not be ignored.     

The brain network for deductive reasoning: a quantitative meta-analysis of 28 neuroimaging studies

Over the course of the past decade, contradictory claims have been made regarding the neural bases of deductive reasoning. Researchers have been puzzled by apparent inconsistencies in the literature. Some have even questioned the effectiveness of the methodology used to study the neural bases of deductive reasoning. However, the idea that neuroimaging findings are inconsistent is not based on any quantitative evidence. Here, we report the results of a quantitative meta-analysis of 28 neuroimaging studies of deductive reasoning published between 1997 and 2010, combining 382 participants. Consistent areas of activations across studies were identified using the multilevel kernel density analysis method. We found that results from neuroimaging studies are more consistent than what has been previously assumed. Overall, studies consistently report activations in specific regions of a left fronto-parietal system, as well as in the left BG. This brain system can be decomposed into three subsystems that are specific to particular types of deductive arguments: relational, categorical, and propositional. These dissociations explain inconstancies in the literature. However, they are incompatible with the notion that deductive reasoning is supported by a single cognitive system relying either on visuospatial or rule-based mechanisms. Our findings provide critical insight into the cognitive organization of deductive reasoning and need to be accounted for by cognitive theories.     

The Ultimatum Game and the brain: A meta-analysis of neuroimaging studies

Social decision-making tasks involve psychological processes key to effective functioning in a complex, social world. The Ultimatum Game (UG) is a widely studied social decision-making task, which models responses to fairness. A number of neuroimaging studies have investigated the UG to identify neural correlates of unfairness and decisions to reject versus accept an offer. We present the first quantitative summary of neuroimaging studies in social decision-making with a meta-analysis of 11 fMRI studies of the UG, including data from 282 participants. Effect-Size Signed Differential Mapping was used to estimate effect sizes from statistical parametric maps and reported peak information before meta-analysing them. Consistent activations were seen in the anterior insula, anterior cingulate cortex (ACC), supplementary motor area (SMA) and cerebellum in response to unfair offers. Robust activations in the ACC, SMA and putamen were seen when deciding to reject rather than accept UG offers. These are consistent with models of motivational conflict during the UG decision-making process, a response to norm violations, with a possible role for the reward system.     

Neuroticism and the brain: A quantitative meta-analysis of neuroimaging studies investigating emotion processing

Neuroticism is a robust personality trait that constitutes a risk factor for mood disorders. Neuroimaging findings related to neuroticism have been inconsistent across studies and hardly integrated in order to construct a model of the underlying neural correlates of neuroticism. The aim of the current meta-analysis was to provide a quantitative summary of the literature, using a parametric coordinate-based meta-analysis (PCM) approach. Data were pooled for emotion processing tasks investigating the contrasts (negative > neutral) and (positive > neutral) to identify brain regions that are consistently associated with neuroticism across studies. Significant negative and positive correlations with neuroticism were found only for the contrast (negative > neutral) after multiple comparisons correction. Differences in brain activation were found to be associated with neuroticism during fear learning, anticipation of aversive stimuli and the processing and regulation of emotion. The relationship between neuroticism and these three psychological processes and their corresponding neural correlates is discussed. Furthermore, the meta-analytic findings are incorporated into a general model of emotion processing in neuroticism.     

Conscious perception of emotional stimuli: brain mechanisms

Emotional stimuli are thought to gain rapid and privileged access to processing resources in the brain. The structures involved in this enhanced access are thought to support subconscious, reflexive processes. Whether these pathways contribute to the phenomenological experience of emotional visual awareness (i.e., conscious perception) is unclear. In this review, it is argued that subcortical networks associated with the rapid detection of emotionally salient stimuli also play a key role in shaping awareness. This proposal is based on the idea that awareness of visual stimuli should be considered along a continuum, having intermediate levels, rather than as an all-or-none construct. It is also argued that awareness of emotional stimuli requires less input from frontoparietal structures that are often considered crucial for visual awareness. Evidence is also presented that implicates a region of the medial prefrontal cortex, involved in emotion regulation, in modulating amygdala output to determine awareness of emotional visual stimuli; when emotional stimuli are present, the conscious perception of alternative stimuli requires greater regulatory influences from cortical structures. Thus, emotional stimuli are privileged not only for neuronal representation and impact on subconscious processes, but also for awareness, allowing humans to deal flexibly rather than merely reflexively to biologically significant stimuli.     

Mapping vulnerability to bipolar disorder: a systematic review and meta-analysis of neuroimaging studies

Background

Although early interventions in individuals with bipolar disorder may reduce the associated personal and economic burden, the neurobiologic markers of enhanced risk are unknown.

Methods

Neuroimaging studies involving individuals at enhanced genetic risk for bipolar disorder (HR) were included in a systematic review. We then performed a region of interest (ROI) analysis and a whole-brain meta-analysis combined with a formal effect-sizes meta-analysis in a subset of studies.

Results

There were 37 studies included in our systematic review. The overall sample for the systematic review included 1258 controls and 996 HR individuals. No significant differences were detected between HR individuals and controls in the selected ROIs: striatum, amygdala, hippocampus, pituitary and frontal lobe. The HR group showed increased grey matter volume compared with patients with established bipolar disorder. The HR individuals showed increased neural response in the left superior frontal gyrus, medial frontal gyrus and left insula compared with controls, independent from the functional magnetic resonance imaging task used. There were no publication biases. Sensitivity analysis confirmed the robustness of these results.

Limitations

As the included studies were cross-sectional, it remains to be determined whether the observed neurofunctional and structural alterations represent risk factors that can be clinically used in preventive interventions for prodromal bipolar disorder.

Conclusion

Accumulating structural and functional imaging evidence supports the existence of neurobiologic trait abnormalities in individuals at genetic risk for bipolar disorder at various scales of investigation.     

Sex differences in bipolar disorder: a review of neuroimaging findings and new evidence

Jogia J, Dima D, Frangou S. Sex differences in bipolar disorder: a review of neuroimaging findings and new evidence.
Bipolar Disord 2012: 14: 461–471. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objectives: The sex of an individual is known to modulate the clinical presentation of bipolar disorder (BD), but little is known as to whether there are significant sex‐by‐diagnosis interactions on the brain structural and functional correlates of BD. Methods: We conducted a literature review of magnetic resonance imaging (MRI) studies in BD, published between January 1990 and December 2010, reporting on the effects of sex and diagnosis. In the absence of any functional MRI (fMRI) studies, this review was supplemented by original data analyses focusing on sex‐by‐diagnosis interactions on patterns of brain activation obtained during tasks of working memory, incentive decision‐making, and facial affect processing. Results: We found no support for a sex‐by‐diagnosis interaction in global gray or white matter volume. Evidence regarding regional volumetric measures is limited, but points to complex interactions between sex and diagnosis with developmental and temperamental factors within limbic and prefrontal regions. Sex‐by‐diagnosis interactions were noted in the pattern of activation within the basal ganglia during incentive decision‐making and within ventral prefrontal regions during facial affect processing. Conclusions: Potential sex‐by‐diagnosis interactions influencing the brain structural and functional correlates of disease expression in BD have received limited attention. Our data suggest that the sex of an individual modulates structure and function within subcortical and cortical regions implicated in disease expression.     

Social brain dysfunctions in schizophrenia: a review of neuroimaging studies

Several studies have indicated that schizophrenic patients show impaired performance in various aspects of social cognition, including theory of mind, emotion processing, and agency judgments. Neuroimaging studies that have compared patients and healthy subjects during such mental activity indicate an abnormal hemodynamic response in the medial prefrontal cortex, the prefrontal cortex, the amygdala, the inferior parietal lobe, i.e., a set of regions known to be critically involved in social cognition. This paper addresses a number of issues raised by schizophrenia research into theory of mind, emotion perception and self-agency with regards to the neural systems that mediate social cognition. In healthy subjects, typical brain patterns are associated with theory of mind, emotion perception and self-agency; some activated clusters overlap, while others are distinct. For instance, activations in the paracingulate gyrus are almost systematically associated with theory of mind tasks, while the amygdala is mainly involved in emotion perception tasks. Additional foci are frequently found activated during those tasks: superior temporal sulcus, inferior frontal area. Moreover, the inferior parietal lobe is thought to contribute to agency judgments. In the light of the data on brain abnormalities and neurochemical dysfunctions in schizophrenia, we discuss the interaction of social cognitive dysfunction with the supposed information processing abnormalities caused by dopamine dysregulation.     

The social evaluation of faces: a meta-analysis of functional neuroimaging studies

Neuroscience research on the social evaluation of faces has accumulated over the last decade, yielding divergent results. We used a meta-analytic technique, multi-level kernel density analysis (MKDA), to analyze 29 neuroimaging studies on face evaluation. Across negative face evaluations, we observed the most consistent activations in bilateral amygdala. Across positive face evaluations, we observed the most consistent activations in medial prefrontal cortex, pregenual anterior cingulate cortex (pgACC), medial orbitofrontal cortex (mOFC), left caudate and nucleus accumbens (NAcc). Based on additional analyses comparing linear and non-linear responses, we propose a ventral/dorsal dissociation within the amygdala, wherein separate populations of neurons code for face valence and intensity, respectively. Finally, we argue that some of the differences between studies are attributable to differences in the typicality of face stimuli. Specifically, extremely attractive faces are more likely to elicit responses in NAcc/caudate and mOFC.     

Sex differences in brain activation to anticipated and experienced pain in the medial prefrontal cortex

Previous studies on sex differences in neural responses to noxious stimuli yielded mixed results. Both increased and decreased brain activation in several brain areas in women as compared to men has been reported. The current event-related functional magnetic resonance imaging study used a parametric design with different levels of the intensity of electrical stimulation in order to investigate sex differences in brain activation during pain processing. Four intensity levels, which were determined individually according to subjective ratings, ranging from stimulation below the stimulus detection threshold to moderately painful stimuli, were applied. Females experienced mild and moderate pain at lower stimulus intensity than males. Pronounced sex differences in brain activation were found in response to stimulation below the detection threshold and for the most intense pain stimuli in the medial prefrontal cortex (MPFC). Under both the conditions, women showed stronger activation in a region of the pregenual MPFC, which has been implicated in introspective, self-focused information processing. The results suggest that women, as compared to men, show increased self-related attention during anticipation of pain and in response to intense pain.     

N-back working memory paradigm: a meta-analysis of normative functional neuroimaging studies

One of the most popular experimental paradigms for functional neuroimaging studies of working memory has been the n-back task, in which subjects are asked to monitor the identity or location of a series of verbal or nonverbal stimuli and to indicate when the currently presented stimulus is the same as the one presented n trials previously. We conducted a quantitative meta-analysis of 668 sets of activation coordinates in Talairach space reported in 24 primary studies of n-back task variants manipulating process (location vs. identity monitoring) and content (verbal or nonverbal) of working memory. We found the following cortical regions were activated robustly (voxelwise false discovery rate = 1%): lateral premotor cortex; dorsal cingulate and medial premotor cortex; dorsolateral and ventrolateral prefrontal cortex; frontal poles; and medial and lateral posterior parietal cortex. Subsidiary meta-analyses based on appropriate subsets of the primary data demonstrated broadly similar activation patterns for identity monitoring of verbal stimuli and both location and identity monitoring of nonverbal stimuli. There was also some evidence for distinct frontoparietal activation patterns in response to different task variants. The functional specializations of each of the major cortical components in the generic large-scale frontoparietal system are discussed. We conclude that quantitative meta-analysis can be a powerful tool for combining results of multiple primary studies reported in Talairach space. Here, it provides evidence both for broadly consistent activation of frontal and parietal cortical regions by various versions of the n-back working memory paradigm, and for process- and content-specific frontoparietal activation by working memory.     

Sex differences in emotional reactivity to daily life stress in psychosis

BACKGROUND: The expression of schizophrenia has been reported to differ between the sexes. The current study investigates whether these sex differences in clinical expression are reflected in one underlying mechanism that may be causally related to psychosis, namely increases in stress sensitivity in daily life. METHOD: Forty-two participants (22 men, 20 women) with Research Diagnostic Criteria-defined psychotic disorder in a state of clinical remission were studied with the Experience Sampling Method (a structured diary technique assessing current context and mood in daily life) to assess (1) appraised subjective stress related to daily events and activities and (2) emotional reactivity conceptualized as changes in both negative affect and positive affect in relation to the subjective stress. Data were collected from January 1997 to May 1999. RESULTS: Multilevel regression analyses revealed that women reported a significantly (p < .05) increased emotional reactivity to daily life stress compared with men, reflected in both an increase in negative affect and a decrease in positive affect. CONCLUSION: These results suggest that gender differences may not be limited to the characteristics of psychosis but may also be reflected in underlying etiologic mechanisms. Furthermore, these results might strengthen the hypothesis that women are more susceptible than men to a schizoaffective expression of schizophrenia.