Tinnitus Correlates with Downregulation of Cortical Glutamate Decarboxylase 65 Expression But Not Auditory Cortical Map Reorganization.

Hearing loss is the biggest risk factor for tinnitus, and hearing-loss-related pathological changes in the auditory pathway have been hypothesized as the mechanism underlying tinnitus. However, due to the comorbidity of tinnitus and hearing loss, it has been difficult to differentiate between neural correlates of tinnitus and consequences of hearing loss. In this study, we dissociated tinnitus and hearing loss in FVB mice, which exhibit robust resistance to tinnitus following monaural noise-induced hearing loss. Furthermore, knock-down of glutamate decarboxylase 65 (GAD65) expression in auditory cortex (AI) by RNA interference gave rise to tinnitus in normal-hearing FVB mice. We found that tinnitus was significantly correlated with downregulation of GAD65 in the AI. By contrast, cortical map distortions, which have been hypothesized as a mechanism underlying tinnitus, were correlated with hearing loss but not tinnitus. Our findings suggest new strategies for the rehabilitation of tinnitus and other phantom sensation, such as phantom pain.SIGNIFICANCE STATEMENT Hearing loss is the biggest risk factor for tinnitus in humans. Most animal models of tinnitus also exhibit comorbid hearing loss, making it difficult to dissociate the mechanisms underlying tinnitus from mere consequences of hearing loss. Here we show that, although both C57BL/6 and FVB mice exhibited similar noise-induced hearing threshold increase, only C57BL/6, but not FVB, mice developed tinnitus following noise exposure. Although both strains showed frequency map reorganization following noise-induced hearing loss, only C57BL/6 mice had reduced glutamate decarboxylase 65 (GAD65) expression in the auditory cortex (AI). Knocking down GAD65 expression in the AI resulted in tinnitus in normal-hearing FVB mice. Our results suggest that reduced inhibitory neuronal function, but not sensory map reorganization, underlies noise-induced tinnitus.

Dopaminergic modulation of distracter-resistance and prefrontal delay period signal.

Dopamine has long been implicated in the online maintenance of information across short delays. Specifically, dopamine has been proposed to modulate the strength of working memory representations in the face of intervening distracters. This hypothesis has not been tested in humans. We fill this gap using pharmacological neuroimaging. Healthy young subjects were scanned after intake of the dopamine receptor agonist bromocriptine or placebo (in a within-subject, counterbalanced, and double-blind design). During scanning, subjects performed a delayed match-to-sample task with face stimuli. A face or scene distracter was presented during the delay period (between the cue and the probe). Bromocriptine altered distracter-resistance, such that it impaired performance after face relative to scene distraction. Individual differences in the drug effect on distracter-resistance correlated negatively with drug effects on delay period signal in the prefrontal cortex, as well as on functional connectivity between the prefrontal cortex and the fusiform face area. These results provide evidence for the hypothesis that dopaminergic modulation of the prefrontal cortex alters resistance of working memory representations to distraction. Moreover, we show that the effects of dopamine on the distracter-resistance of these representations are accompanied by modulation of the functional strength of connections between the prefrontal cortex and stimulus-specific posterior cortex.

An approach for identifying brainstem dopaminergic pathways using resting state functional MRI.

Here, we present an approach for identifying brainstem dopaminergic pathways using resting state functional MRI. In a group of healthy individuals, we searched for significant functional connectivity between dopamine-rich midbrain areas (substantia nigra; ventral tegmental area) and a striatal region (caudate) that was modulated by both a pharmacological challenge (the administration of the dopaminergic agonist bromocriptine) and a dopamine-sensitive cognitive trait (an individual's working memory capacity). A significant inverted-U shaped connectivity pattern was found in a subset of midbrain-striatal connections, demonstrating that resting state fMRI data is sufficiently powerful to identify brainstem neuromodulatory brain networks.

The influence of combined cognitive plus social-cognitive training on amygdala response during face emotion recognition in schizophrenia.

Both cognitive and social-cognitive deficits impact functional outcome in schizophrenia. Cognitive remediation studies indicate that targeted cognitive and/or social-cognitive training improves behavioral performance on trained skills. However, the neural effects of training in schizophrenia and their relation to behavioral gains are largely unknown. This study tested whether a 50-h intervention which included both cognitive and social-cognitive training would influence neural mechanisms that support social ccognition. Schizophrenia participants completed a computer-based intervention of either auditory-based cognitive training (AT) plus social-cognition training (SCT) (N=11) or non-specific computer games (CG) (N=11). Assessments included a functional magnetic resonance imaging (fMRI) task of facial emotion recognition, and behavioral measures of cognition, social cognition, and functional outcome. The fMRI results showed the predicted group-by-time interaction. Results were strongest for emotion recognition of happy, surprise and fear: relative to CG participants, AT+SCT participants showed a neural activity increase in bilateral amygdala, right putamen and right medial prefrontal cortex. Across all participants, pre-to-post intervention neural activity increase in these regions predicted behavioral improvement on an independent emotion perception measure (MSCEIT: Perceiving Emotions). Among AT+SCT participants alone, neural activity increase in right amygdala predicted behavioral improvement in emotion perception. The findings indicate that combined cognition and social-cognition training improves neural systems that support social-cognition skills.

Neural activity during emotion recognition after combined cognitive plus social cognitive training in schizophrenia.

Cognitive remediation training has been shown to improve both cognitive and social cognitive deficits in people with schizophrenia, but the mechanisms that support this behavioral improvement are largely unknown. One hypothesis is that intensive behavioral training in cognition and/or social cognition restores the underlying neural mechanisms that support targeted skills. However, there is little research on the neural effects of cognitive remediation training. This study investigated whether a 50 h (10-week) remediation intervention which included both cognitive and social cognitive training would influence neural function in regions that support social cognition. Twenty-two stable, outpatient schizophrenia participants were randomized to a treatment condition consisting of auditory-based cognitive training (AT) [Brain Fitness Program/auditory module ~60 min/day] plus social cognition training (SCT) which was focused on emotion recognition [~5-15 min per day] or a placebo condition of non-specific computer games (CG) for an equal amount of time. Pre and post intervention assessments included an fMRI task of positive and negative facial emotion recognition, and standard behavioral assessments of cognition, emotion processing, and functional outcome. There were no significant intervention-related improvements in general cognition or functional outcome. fMRI results showed the predicted group-by-time interaction. Specifically, in comparison to CG, AT+SCT participants had a greater pre-to-post intervention increase in postcentral gyrus activity during emotion recognition of both positive and negative emotions. Furthermore, among all participants, the increase in postcentral gyrus activity predicted behavioral improvement on a standardized test of emotion processing (MSCEIT: Perceiving Emotions). Results indicate that combined cognition and social cognition training impacts neural mechanisms that support social cognition skills.

Individual differences in neural responses to social rejection: the joint effect of self-esteem and attentional control.

Individuals with low self-esteem have been found to react more negatively to signs of interpersonal rejection than those with high self-esteem. However, previous research has found that individual differences in attentional control can attenuate negative reactions to social rejection among vulnerable, low self-esteem individuals. The current fMRI study sought to elucidate the neurobiological substrate of this buffering effect. We hypothesized and found that while looking at scenes of social rejection (vs negative scenes) low self-esteem high attentional control individuals engaged the rostral anterior cingulate cortex (rACC), an area of the brain associated with emotional control, more than their low self-esteem low attentional control peers. Furthermore, we found that low self-esteem high attentional control individuals evaluated social rejection as less arousing and less rejecting in a separate behavioral task. Importantly, activation in the rACC fully mediated the relationship between the interaction of self-esteem and attentional control and emotional evaluations, suggesting that the rACC activation underlies the buffering effects of attentional control. Results are discussed in terms of individual differences in emotional vulnerability and protection and by highlighting the role of rACC in emotion regulation.

Neural activity to a partner's facial expression predicts self-regulation after conflict.

BACKGROUND: Failure to self-regulate after an interpersonal conflict can result in persistent negative mood and maladaptive behaviors. Research indicates that lateral prefrontal cortex (LPFC) activity is related to emotion regulation in response to laboratory-based affective challenges, such as viewing emotional pictures. This suggests that compromised LPFC function may be a risk factor for mood and behavior problems after an interpersonal conflict. However, it remains unclear whether LPFC activity to a laboratory-based affective challenge predicts self-regulation in real life. METHODS: We investigated whether LPFC activity to a laboratory-based affective challenge (negative facial expressions of a partner) predicts self-regulation after a real-life affective challenge (interpersonal conflict). During a functional magnetic resonance imaging scan, healthy, adult participants in committed relationships (n = 27) viewed positive, negative, and neutral facial expressions of their partners. In a three-week online daily diary, participants reported conflict occurrence, level of negative mood, rumination, and substance use. RESULTS: LPFC activity in response to the laboratory-based affective challenge predicted self-regulation after an interpersonal conflict in daily life. When there was no interpersonal conflict, LPFC activity was not related to mood or behavior the next day. However, when an interpersonal conflict did occur, ventral LPFC (VLPFC) activity predicted mood and behavior the next day, such that lower VLPFC activity was related to higher levels of negative mood, rumination, and substance use. CONCLUSIONS: Low LPFC function may be a vulnerability and high LPFC function may be a protective factor for the development of mood and behavior problems after an interpersonal stressor.

Striatal dopamine predicts outcome-specific reversal learning and its sensitivity to dopaminergic drug administration.

Individual variability in reward-based learning has been ascribed to quantitative variation in baseline levels of striatal dopamine. However, direct evidence for this pervasive hypothesis has hitherto been unavailable. We demonstrate that individual differences in reward-based reversal learning reflect variation in baseline striatal dopamine synthesis capacity, as measured with neurochemical positron emission tomography. Subjects with high baseline dopamine synthesis in the striatum showed relatively better reversal learning from unexpected rewards than from unexpected punishments, whereas subjects with low baseline dopamine synthesis in the striatum showed the reverse pattern. In addition, baseline dopamine synthesis predicted the direction of dopaminergic drug effects. The D(2) receptor agonist bromocriptine improved reward-based relative to punishment-based reversal learning in subjects with low baseline dopamine synthesis capacity, while impairing it in subjects with high baseline dopamine synthesis capacity in the striatum. Finally, this pattern of drug effects was outcome-specific, and driven primarily by drug effects on punishment-, but not reward-based reversal learning. These data demonstrate that the effects of D(2) receptor stimulation on reversal learning in humans depend on task demands and baseline striatal dopamine synthesis capacity.

The influence of personality on neural mechanisms of observational fear and reward learning.

Fear and reward learning can occur through direct experience or observation. Both channels can enhance survival or create maladaptive behavior. We used fMRI to isolate neural mechanisms of observational fear and reward learning and investigate whether neural response varied according to individual differences in neuroticism and extraversion. Participants learned object-emotion associations by observing a woman respond with fearful (or neutral) and happy (or neutral) facial expressions to novel objects. The amygdala-hippocampal complex was active when learning the object-fear association, and the hippocampus was active when learning the object-happy association. After learning, objects were presented alone; amygdala activity was greater for the fear (vs. neutral) and happy (vs. neutral) associated object. Importantly, greater amygdala-hippocampal activity during fear (vs. neutral) learning predicted better recognition of learned objects on a subsequent memory test. Furthermore, personality modulated neural mechanisms of learning. Neuroticism positively correlated with neural activity in the amygdala and hippocampus during fear (vs. neutral) learning. Low extraversion/high introversion was related to faster behavioral predictions of the fearful and neutral expressions during fear learning. In addition, low extraversion/high introversion was related to greater amygdala activity during happy (vs. neutral) learning, happy (vs. neutral) object recognition, and faster reaction times for predicting happy and neutral expressions during reward learning. These findings suggest that neuroticism is associated with an increased sensitivity in the neural mechanism for fear learning which leads to enhanced encoding of fear associations, and that low extraversion/high introversion is related to enhanced conditionability for both fear and reward learning.

Working memory capacity predicts dopamine synthesis capacity in the human striatum.

Evidence from psychopharmacological research has revealed that dopamine receptor agents have opposite effects on cognitive function depending on baseline levels of working memory capacity. These contrasting effects have been interpreted to reflect differential baseline levels of dopamine. Here we demonstrate for the first time that working memory capacity as measured by listening span predicts dopamine synthesis capacity in the striatum, indicating that subjects with low working memory capacity have low DA synthesis capacity in the striatum, whereas subjects with high working memory capacity have high DA synthesis capacity in the striatum.