Birth of the blues: emotional sound processing in infants exposed to prenatal maternal depression.

BACKGROUND: Offspring exposed to prenatal maternal depression (PMD) are vulnerable to depression across their lifespan. The underlying cause(s) for this elevated intergenerational risk is most likely complex. However, depression is underpinned by a dysfunctional frontal-limbic network, associated with core information processing biases (e.g. attending more to sad stimuli). Aberrations in this network might mediate transmission of this vulnerability in infants exposed to PMD. In this study, we aimed to explore the association between foetal exposure to PMD and frontal-limbic network function in infancy, hypothesising that, in response to emotional sounds, infants exposed to PMD would exhibit atypical activity in these regions, relative to those not exposed to PMD. METHOD: We employed a novel functional magnetic resonance imaging sequence to compare brain function, whilst listening to emotional sounds, in 78 full-term infants (3-6 months of age) born to mothers with and without a diagnosis of PMD. RESULTS: After exclusion of 19 datasets due to infants waking up, or moving excessively, we report between-group brain activity differences, between 29 infants exposed to PMD and 29 infants not exposed to PMD, occurring in temporal, striatal, amygdala/parahippocampal and frontal regions (p < 0.005). The offspring exposed to PMD exhibited a relative increase in activation to sad sounds and reduced (or unchanged) activation to happy sounds in frontal-limbic clusters. CONCLUSIONS: Findings of a differential response to positive and negative valanced sounds by 3-6 months of age may have significant implications for our understanding of neural mechanisms that underpin the increased risk for later-life depression in this population.

Normalization of mediotemporal and prefrontal activity, and mediotemporal-striatal connectivity, may underlie antipsychotic effects of cannabidiol in psychosis.

BACKGROUND: Recent evidence suggests that cannabidiol (CBD), a non-intoxicating ingredient present in cannabis extract, has an antipsychotic effect in people with established psychosis. However, the effect of CBD on the neurocognitive mechanisms underlying psychosis is unknown. METHODS: Patients with established psychosis on standard antipsychotic treatment were studied on separate days at least one week apart, to investigate the effects of a single dose of orally administered CBD (600 mg) compared to a matched placebo (PLB), using a double-blind, randomized, PLB-controlled, repeated-measures, within-subject cross-over design. Three hours after taking the study drug participants were scanned using a block design functional magnetic resonance imaging (fMRI) paradigm, while performing a verbal paired associate learning task. Fifteen psychosis patients completed both study days, 13 completed both scanning sessions. Nineteen healthy controls (HC) were also scanned using the same fMRI paradigm under identical conditions, but without any drug administration. Effects of CBD on brain activation measured using the blood oxygen level-dependent hemodynamic response fMRI signal were studied in the mediotemporal, prefrontal, and striatal regions of interest. RESULTS: Compared to HC, psychosis patients under PLB had altered prefrontal activation during verbal encoding, as well as altered mediotemporal and prefrontal activation and greater mediotemporal-striatal functional connectivity during verbal recall. CBD attenuated dysfunction in these regions such that activation under its influence was intermediate between the PLB condition and HC. CBD also attenuated hippocampal-striatal functional connectivity and caused trend-level symptom reduction in psychosis patients. CONCLUSIONS: This suggests that normalization of mediotemporal and prefrontal dysfunction and mediotemporal-striatal functional connectivity may underlie the antipsychotic effects of CBD.

Neural and psychological maturation of decision-making in adolescence and young adulthood.

We examined the maturation of decision-making from early adolescence to mid-adulthood using fMRI of a variant of the Iowa gambling task. We have previously shown that performance in this task relies on sensitivity to accumulating negative outcomes in ventromedial PFC and dorsolateral PFC. Here, we further formalize outcome evaluation (as driven by prediction errors [PE], using a reinforcement learning model) and examine its development. Task performance improved significantly during adolescence, stabilizing in adulthood. Performance relied on greater impact of negative compared with positive PEs, the relative impact of which matured from adolescence into adulthood. Adolescents also showed increased exploratory behavior, expressed as a propensity to shift responding between options independently of outcome quality, whereas adults showed no systematic shifting patterns. The correlation between PE representation and improved performance strengthened with age for activation in ventral and dorsal PFC, ventral striatum, and temporal and parietal cortices. There was a medial-lateral distinction in the prefrontal substrates of effective PE utilization between adults and adolescents: Increased utilization of negative PEs, a hallmark of successful performance in the task, was associated with increased activation in ventromedial PFC in adults, but decreased activation in ventrolateral PFC and striatum in adolescents. These results suggest that adults and adolescents engage qualitatively distinct neural and psychological processes during decision-making, the development of which is not exclusively dependent on reward-processing maturation.

Neuroticism influences brain activity during the experience of visceral pain.

BACKGROUND & AIMS: One particularly important individual dynamic known to influence the experience of pain is neuroticism, of which little is known about in visceral pain research. Our aim was to study the relationship between neuroticism, psychophysiologic response, and brain processing of visceral pain. METHODS: Thirty-one healthy volunteers (15 male; age range, 22-38 years) participated in the study. The Eysenck Personality Questionnaire was used to assess neuroticism. Skin conductance level, pain ratings, and functional magnetic resonance imaging data were acquired during anticipation of pain and painful esophageal distention. The effect of neuroticism was assessed using correlation analysis. RESULTS: There was a wide spread of neuroticism scores (range, 0-22) but no influence of neuroticism on skin conductance level and pain tolerance or pain ratings. However, a positive correlation between brain activity and neuroticism during anticipation was found in regions associated with emotional and cognitive pain processing, including the parahippocampus, insula, thalamus, and anterior cingulate cortex. These regions showed a negative correlation with neuroticism during pain (P < .001). CONCLUSIONS: This study provides novel data suggesting higher neuroticism is associated with engagement of brain regions responsible for emotional and cognitive appraisal during anticipation of pain but reduced activity in these regions during pain. This may reflect a maladaptive mechanism in those with higher neuroticism that promotes overarousal during anticipation and avoidance coping during pain.

Maturation of limbic corticostriatal activation and connectivity associated with developmental changes in temporal discounting.

Temporal discounting (TD) matures with age, alongside other markers of increased impulse control, and coherent, self-regulated behaviour. Discounting paradigms quantify the ability to refrain from preference of immediate rewards, in favour of delayed, larger rewards. As such, they measure temporal foresight and the ability to delay gratification, functions that develop slowly into adulthood. We investigated the neural maturation that accompanies the previously observed age-related behavioural changes in discounting, from early adolescence into mid-adulthood. We used functional magnetic resonance imaging of a hypothetical discounting task with monetary rewards delayed in the week to year range. We show that age-related reductions in choice impulsivity were associated with changes in activation in ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), ventral striatum (VS), insula, inferior temporal gyrus, and posterior parietal cortex. Limbic frontostriatal activation changes were specifically associated with age-dependent reductions in impulsive choice, as part of a more extensive network of brain areas showing age-related changes in activation, including dorsolateral PFC, inferior parietal cortex, and subcortical areas. The maturational pattern of functional connectivity included strengthening in activation coupling between ventromedial and dorsolateral PFC, parietal and insular cortices during selection of delayed alternatives, and between vmPFC and VS during selection of immediate alternatives. We conclude that maturational mechanisms within limbic frontostriatal circuitry underlie the observed post-pubertal reductions in impulsive choice with increasing age, and that this effect is dependent on increased activation coherence within a network of areas associated with discounting behaviour and inter-temporal decision-making.

Right ventromedial and dorsolateral prefrontal cortices mediate adaptive decisions under ambiguity by integrating choice utility and outcome evaluation.

The Iowa gambling task (IGT) is one of the most influential behavioral paradigms in reward-related decision making and has been, most notably, associated with ventromedial prefrontal cortex function. However, performance in the IGT relies on a complex set of cognitive subprocesses, in particular integrating information about the outcome of choices into a continuously updated decision strategy under ambiguous conditions. The complexity of the task has made it difficult for neuroimaging studies to disentangle the underlying neurocognitive processes. In this study, we used functional magnetic resonance imaging in combination with a novel adaptation of the task, which allowed us to examine separately activation associated with the moment of decision or the evaluation of decision outcomes. Importantly, using whole-brain regression analyses with individual performance, in combination with the choice/outcome history of individual subjects, we aimed to identify the neural overlap between areas that are involved in the evaluation of outcomes and in the progressive discrimination of the relative value of available choice options, thus mapping the two fundamental cognitive processes that lead to adaptive decision making. We show that activation in right ventromedial and dorsolateral prefrontal cortex was predictive of adaptive performance, in both discriminating disadvantageous from advantageous decisions and confirming negative decision outcomes. We propose that these two prefrontal areas mediate shifting away from disadvantageous choices through their sensitivity to accumulating negative outcomes. These findings provide functional evidence of the underlying processes by which these prefrontal subregions drive adaptive choice in the task, namely through contingency-sensitive outcome evaluation.

Negative mood affects brain processing of visceral sensation.

BACKGROUND & AIMS: A link between negative emotional state and abnormal visceral sensation has been frequently reported. However, the influence of negative emotion on brain processing of painful visceral sensations has not been investigated. We used functional magnetic resonance imaging (fMRI) and negative emotional stimuli to investigate the effects of negative emotion on brain processing of esophageal sensation. METHODS: Twelve healthy male volunteers (age range, 21-32 years) participated in the study. Negative emotion was induced using emotionally valent music. fMRI images were acquired during 2 experimental runs; throughout these, volunteers received randomized nonpainful and painful distentions to the esophagus during neutral and negative emotion. Subjective perception of each stimulus was acquired, as were mood ratings. RESULTS: Sadness ratings increased significantly following negative mood induction (P < .01). There was no significant effect of emotion on subjective perception of painful and nonpainful stimulation (P > .05). Following painful stimulation, brain activity increased in the right hemisphere during negative emotion and was localized to the anterior cingulate cortex (ACC; BA24/32), anterior insula, and inferior frontal gyrus. Following nonpainful stimulation during negative emotion, brain activity increased in the right anterior insula and ACC (BA24 and 32). CONCLUSIONS: This study provides new information about the influence of negative affect on central processing of visceral pain. Evidence of right hemispheric dominance during negative emotion indicates this hemisphere is predominately associated with sympathetic activity (arousal, negative affect) and that the right insula and right ACC are integral to subjective awareness of emotion through interoception.

Sex-dependent age modulation of frontostriatal and temporo-parietal activation during cognitive control.

Developmental functional imaging studies of cognitive control show progressive age-related increase in task-relevant fronto-striatal activation in male development from childhood to adulthood. Little is known, however, about how gender affects this functional development. In this study, we used event related functional magnetic resonance imaging to examine effects of sex, age, and their interaction on brain activation during attentional switching and interference inhibition, in 63 male and female adolescents and adults, aged 13 to 38. Linear age correlations were observed across all subjects in task-specific frontal, striatal and temporo-parietal activation. Gender analysis revealed increased activation in females relative to males in fronto-striatal areas during the Switch task, and laterality effects in the Simon task, with females showing increased left inferior prefrontal and temporal activation, and males showing increased right inferior prefrontal and parietal activation. Increased prefrontal activation clusters in females and increased parietal activation clusters in males furthermore overlapped with clusters that were age-correlated across the whole group, potentially reflecting more mature prefrontal brain activation patterns for females, and more mature parietal activation patterns for males. Gender by age interactions further supported this dissociation, revealing exclusive female-specific age correlations in inferior and medial prefrontal brain regions during both tasks, and exclusive male-specific age correlations in superior parietal (Switch task) and temporal regions (Simon task). These findings show increased recruitment of age-correlated prefrontal activation in females, and of age-correlated parietal activation in males, during tasks of cognitive control. Gender differences in frontal and parietal recruitment may thus be related to gender differences in the neurofunctional maturation of these brain regions.

Effects of attention on visceral stimulus intensity encoding in the male human brain.

BACKGROUND & AIMS: Hypervigilance is considered important in pain perception in functional gastrointestinal disorders. Nonetheless, a comprehensive assessment of the influence of attention on brain processing of visceral sensation has not been performed. We investigated the effects of attention on esophageal pain perception and brain activity. METHODS: Twelve healthy male volunteers (age range, 21-32 years) underwent 4 functional magnetic resonance imaging scans incorporating 4 levels of esophageal stimulation (ES), ranging from nonpainful to painful, during which they completed a task aimed at distracting them from the esophageal stimulus. The volunteers were then scanned a fifth time, during painful stimulation without distraction. RESULTS: Following ES during distraction, there was a significant linear trend (P < .05) in which the intensity of cerebral activation in the primary somatosensory cortex (SI) (bilateral) and left mid-anterior cingulate cortex (ACC) increased with stimulation intensity. When pain was delivered during distraction, there was a significant reduction in pain ratings, accompanied by significant decreases (P < .05) in brain activity in the right ACC and right prefrontal cortex. There was no effect of distraction on SI activity (P < .05). CONCLUSIONS: Our results suggest that the SI is involved in processing sensory-discriminative aspects of visceral sensation. In contrast, activity in the mid-ACC suggests that this region is multifunctional because it appears to be involved in sensory and cognitive appraisal of visceral pain; the right prefrontal cortex seems to be involved in only cognitive responses to pain.

Conflicting emergences. Weak vs. strong emergence for the modelling of brain function.

The concept of "emergence" has become commonplace in the modelling of complex systems, both natural and man-made; a functional property" emerges" from a system when it cannot be readily explained by the properties of the system's sub-units. A bewildering array of adaptive and sophisticated behaviours can be observed from large ensembles of elementary agents such as ant colonies, bird flocks or by the interactions of elementary material units such as molecules or weather elements. Ultimately, emergence has been adopted as the ontological support of a number of attempts to model brain function. This manuscript aims to clarify the ontology of emergence and delve into its many facets, particularly into its "strong" and "weak" versions that underpin two different approaches to the modelling of behaviour. The first group of models is here represented by the "free energy" principle of brain function and the "integrated information theory" of consciousness. The second group is instead represented by computational models such as oscillatory networks that use mathematical scalable representations to generate emergent behaviours and are then able to bridge neurobiology with higher mental functions. Drawing on the epistemological literature, we observe that due to their loose mechanistic links with the underlying biology, models based on strong forms of emergence are at risk of metaphysical implausibility. This, in practical terms, translates into the over determination that occurs when the proposed model becomes only one of a large set of possible explanations for the observable phenomena. On the other hand, computational models that start from biologically plausible elementary units, hence are weakly emergent, are not limited by ontological faults and, if scalable and able to realistically simulate the hierarchies of brain output, represent a powerful vehicle for future neuroscientific research programmes.

Reversibility of the effects of acute ovarian hormone suppression on verbal memory and prefrontal function in pre-menopausal women.

BACKGROUND: Whilst acute loss of ovarian function is associated with memory deficits, the biological basis of this is poorly understood. We have previously reported that acute loss of function during Gonadotropin Hormone Releasing Hormone agonists (GnRHa) treatment is associated with impaired verbal memory and a disruption of corresponding left inferior frontal gyrus (LIFG) during the encoding stage. In the current study, we provide a critical extension to this work by determining whether this memory deficit is reversible following normalization of ovarian function. To do this we carried out a further imaging study using the same verbal memory recognition task after cessation of GnRHa-induced ovarian suppression. METHOD: We used event-related fMRI to study verbal episodic memory performance and brain activation at the LIFG in 13 healthy pre-menopausal women pre-, during, and post-acute ovarian hormone suppression using GnRHa. RESULTS: Following resolution of acute GnRHa-induced ovarian suppression, verbal recognition scores returned to their initial levels and this restoration was associated with a restored level of left frontal activation during successful encoding of words. CONCLUSIONS: Our findings suggest that the memory deficits associated with acute ovarian suppression are reversed following resolution of normal ovarian function and are associated with reversible attenuation of LIFG activation during encoding. These findings lend further support to the hypothesis that memory difficulties reported by some women following acute ovarian hormone withdrawal are reversible and may have a clear neurobiological basis.

A study of visuospatial working memory pre- and post-Gonadotropin Hormone Releasing Hormone agonists (GnRHa) in young women.

Gonadotropin Hormone Releasing Hormone agonists (GnRHa) produce an acute decline in ovarian hormone production leading to a 'pseudo' menopause. This is therapeutically useful in the management of a variety of gynaecological conditions but also serves as a powerful model to study the effects of ovarian hormones on cognition. Animal and human behavioral studies report that memory is particularly sensitive to the effects ovarian hormone suppression (e.g. post GnRHa). Further, it has recently been reported that ovariectomy in young women increases the risk of cognitive impairment in later life. However, the underlying brain networks and/or stages of memory processing that might be modulated by acute ovarian hormone suppression remain poorly understood. We used event-related fMRI to examine the effect of GnRHa on visual working memory (VWM). Neuroimaging outcomes from 17 pre-menopausal healthy women were assessed at baseline and 8 weeks after GnRHa treatment. Seventeen matched wait-listed volunteers served as the control group and were assessed at similar intervals during the late follicular phase of the menstrual cycle. We report GnRHa was associated with attenuation of left parahippocampal (BA 35) and middle temporal gyri (BA 21 ,22, 39) activation, with a significant group-by-time interaction at left precuneus (BA 7) and posterior cingulate cortex (PCC) (BA 31) at encoding, and with cerebellar activation at recognition in the context of unimpaired behavioral responses. Our study suggests that acute ovarian hormone withdrawal following GnRHa, and perhaps at other times, (e.g. following surgical menopause and postpartum) alters the neural circuitry underlying performance of VWM.

Modulation of acute effects of delta-9-tetrahydrocannabinol on psychotomimetic effects, cognition and brain function by previous cannabis exposure.

Cannabis use has been associated with psychosis and cognitive dysfunction. Some evidence suggests that the acute behavioral and neurocognitive effects of the main active ingredient in cannabis, (-)-trans-Δ9-tetrahydrocannabinol (∆9-THC), might be modulated by previous cannabis exposure. However, this has not been investigated either using a control group of non-users, or following abstinence in modest cannabis users, who represent the majority of recreational users. Twenty-four healthy men participated in a double-blind, randomized, placebo-controlled, repeated-measures, within-subject, ∆9-THC challenge study. Compared to non-users (N=12; <5 lifetime cannabis joints smoked), abstinent modest cannabis users (N=12; 24.5±9 lifetime cannabis joints smoked) showed worse performance and stronger right hemispheric activation during cognitive processing, independent of the acute challenge (all P≤0.047). Acute ∆9-THC administration produced transient anxiety and psychotomimetic symptoms (all P≤0.02), the latter being greater in non-users compared to users (P=0.040). Non-users under placebo (control group) activated specific brain areas to perform the tasks, while deactivating others. An opposite pattern was found under acute (∆9-THC challenge in non-users) as well as residual (cannabis users under placebo) effect of ∆9-THC. Under ∆9-THC, cannabis users showed brain activity patterns intermediate between those in non-users under placebo (control group), and non-users under ∆9-THC (acute effect) and cannabis users under placebo (residual effect). In non-users, the more severe the ∆9-THC-induced psychotomimetic symptoms and cognitive impairments, the more pronounced was the neurophysiological alteration (all P≤0.036). Previous modest cannabis use blunts the acute behavioral and neurophysiological effects of ∆9-THC, which are more marked in people who have never used cannabis.

Previous cannabis exposure modulates the acute effects of delta-9-tetrahydrocannabinol on attentional salience and fear processing.

Cannabis can induce transient psychotic and anxiety symptoms and long-lasting disorders. The acute psychoactive effects of its main active ingredient, (-)-trans-Δ9-tetrahydrocannabinol (Δ9-THC), may be modulated by previous cannabis exposure. Secondary data analyses tested whether modest previous cannabis exposure modulated the acute effects of Δ9-THC on attentional salience and emotional processing and their neurophysiological substrates. Twenty-four healthy men participated in a double-blind, randomized, placebo-controlled, repeated-measures, within-subject, Δ9-THC challenge study using fMRI. Compared with nonusers (NUs; n = 12; <5 lifetime cannabis joints smoked), abstinent-modest cannabis users (CUs; n = 12; 24.5 ± 9 lifetime cannabis joints smoked) showed less efficient attentional salience processing and recruited different/additional brain areas to process attentional salient and emotional stimuli (all ps ≤ .01). The Δ9-THC challenge disrupted attentional salience and emotional-processing-related brain activity and induced transient anxiety and psychotic symptoms (all ps ≤ .02). However, Δ9-THC-induced psychotic symptoms and attentional salience behavioral impairment were more pronounced in NUs compared with CUs (all ps ≤ .04). Also, NUs under Δ9-THC shifted toward recruitment of other brain areas to perform the tasks. Conversely, CUs were less affected by the acute challenge in an exposure-dependent manner, showing a neurophysiological pattern similar to that of NUs under placebo. Only in NUs, Δ9-THC-induced psychotic symptom and cognitive impairment severity was associated with a more pronounced neurophysiological alteration (all ps ≤ .048). In conclusion, CUs displayed residual effects of cannabis exposure but more blunted responses to the acute symptomatic, behavioral, and neurophysiological effects of Δ9-THC, which were more marked in NUs. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Gonadotropin hormone releasing hormone agonists alter prefrontal function during verbal encoding in young women.

Gonadotropin hormone releasing hormone agonists (GnRHa) are commonly used in clinical practice to suppress gonadal hormone production in the management of various gynaecological conditions and as a treatment for advanced breast and prostate cancer. Animal and human behavioural studies suggest that GnRHa may also have significant effects on memory. However, despite the widespread use of GnRHa, the underlying brain networks and/or stages of memory processing that might be modulated by GnRHa remain poorly understood. We used event-related functional magnetic resonance imaging to examine the effect of GnRHa on verbal encoding and retrieval. Neuroimaging outcomes from 15 premenopausal healthy women were assessed at baseline and 8 weeks after Gonadotrophin Releasing Hormone analogue (GnRHa) treatment. Fifteen matched wait-listed volunteers served as the control group and were assessed at similar intervals during the late follicular phase of the menstrual cycle. GnRHa was associated with changes in brain response during memory encoding but not retrieval. Specifically, GnRHa administration led to a change in the typical pattern of prefrontal activation during successful encoding, with decreased activation in left prefrontal cortex, anterior cingulate, and medial frontal gyrus. Our study suggests that the memory difficulties reported by some women following GnRHa, and possibly at other times of acute ovarian hormone withdrawal (e.g. following surgical menopause and postpartum), may have a clear neurobiological basis; one that manifest during encoding of words and that is evident in decreased activation in prefrontal regions known to sub-serve deep processing of to-be-learned words.

Task-specific hypoactivation in prefrontal and temporoparietal brain regions during motor inhibition and task switching in medication-naive children and adolescents with attention deficit hyperactivity disorder.

OBJECTIVE: A relatively small number of functional imaging studies of attention deficit hyperactivity disorder (ADHD) have shown abnormal prefrontal and striatal brain activation during tasks of motor response inhibition. However, the potential confound of previous medication exposure has not yet been addressed, and no functional imaging study exists to date on medication-naive children and adolescents with ADHD. The aim of this study was to investigate the neural substrates of a range of motor and cognitive inhibitory functions in a relatively large group of children and adolescents with ADHD who had never previously been exposed to medication. METHOD: Nineteen boys with ADHD and 27 healthy age- and IQ-matched boys underwent functional MRI to compare brain activation during performance of tasks that assessed motor response inhibition (go/no go task), cognitive interference inhibition (motor Stroop task), and cognitive flexibility (switch task). RESULTS: Boys with ADHD showed decreased activation in the left rostral mesial frontal cortex during the go/no go task and decreased activation in the bilateral prefrontal and temporal lobes and right parietal lobe during the switch task. No significant group differences were observed during motor Stroop task performance. CONCLUSION: Abnormal brain activation was observed in medication-naive children and adolescents with ADHD during tasks involving motor inhibition and task switching, suggesting that hypoactivation in this patient group is unrelated to long-term stimulant exposure. Furthermore, functional abnormalities are task-specific and extend from frontostriatal to parietal and temporal cortices.

The neural correlates of anhedonia in major depressive disorder.

BACKGROUND: Anhedonia is a relative lack of pleasure in response to formerly rewarding stimuli. It is an important diagnostic feature of major depressive disorder (MDD), and predicts antidepressant efficacy. Understanding its neurobiological basis may help to target new treatments and predict treatment outcomes. Using a novel paradigm, we aimed to explore the correlations between anhedonia severity and magnitude of neural responses to happy and sad stimuli in regions previously implicated in studies of human reward processing and depressive anhedonia. METHODS: Neural responses to happy and sad emotional stimuli (autobiographical prompts and mood congruent facial expressions) were measured using blood oxygen level dependent (BOLD) functional magnetic resonance imaging in twelve MDD individuals with varying degrees of anhedonia. RESULTS: In response to happy stimuli, anhedonia, but not depression severity per se, was positively and negatively correlated with ventromedial prefrontal cortex (VMPFC) and amygdala/ventral striatal activity, respectively. State anxiety independently contributed to a VMPFC-subcortical dissociation of response to happy (but not sad) stimuli, which was similar, but different, to anhedonia. CONCLUSIONS: These findings suggest that anhedonia and state anxiety are associated with dysfunction within neural systems underlying the response to, and assessment of, the rewarding potential of emotive stimuli in MDD, and highlight the importance of employing a symptom-dimension-based approach in the examination of the neurobiology of depression.

A double dissociation of ventromedial prefrontal cortical responses to sad and happy stimuli in depressed and healthy individuals.

BACKGROUND: The ventromedial prefrontal cortex (VMPFC) is a region implicated in the assessment of the rewarding potential of stimuli and may be dysfunctional in major depressive disorder (MDD). The few studies examining prefrontal cortical responses to emotive stimuli in MDD have indicated increased VMPFC responses to pleasant images but decreased responses to sad mood provocation when compared with healthy individuals. We wished to corroborate these results by examining neural responses to personally relevant happy and sad stimuli in MDD and healthy individuals within the same paradigm. METHODS: Neural responses to happy and sad emotional stimuli (autobiographical memory prompts and congruent facial expressions) were measured using blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) in MDD (n = 12) and healthy (n = 12) individuals. RESULTS: Increased and decreased responses in VMPFC were observed in MDD and healthy individuals, respectively, to happy stimuli, whereas the pattern was reversed for MDD and healthy individual responses to sad stimuli. These findings were not explained by medication effects in depressed individuals. CONCLUSIONS: These findings indicate a double dissociation of the pattern of VMPFC response to happy and sad stimuli in depressed and healthy individuals and suggest abnormal reward processing in MDD.

Cannabinoid modulation of functional connectivity within regions processing attentional salience.

There is now considerable evidence to support the hypothesis that psychotic symptoms are the result of abnormal salience attribution, and that the attribution of salience is largely mediated through the prefrontal cortex, the striatum, and the hippocampus. Although these areas show differential activation under the influence of delta-9-tetrahydrocannabinol (delta-9-THC) and cannabidiol (CBD), the two major derivatives of cannabis sativa, little is known about the effects of these cannabinoids on the functional connectivity between these regions. We investigated this in healthy occasional cannabis users by employing event-related functional magnetic resonance imaging (fMRI) following oral administration of delta-9-THC, CBD, or a placebo capsule. Employing a seed cluster-based functional connectivity analysis that involved using the average time series from each seed cluster for a whole-brain correlational analysis, we investigated the effect of drug condition on functional connectivity between the seed clusters and the rest of the brain during an oddball salience processing task. Relative to the placebo condition, delta-9-THC and CBD had opposite effects on the functional connectivity between the dorsal striatum, the prefrontal cortex, and the hippocampus. Delta-9-THC reduced fronto-striatal connectivity, which was related to its effect on task performance, whereas this connection was enhanced by CBD. Conversely, mediotemporal-prefrontal connectivity was enhanced by delta-9-THC and reduced by CBD. Our results suggest that the functional integration of brain regions involved in salience processing is differentially modulated by single doses of delta-9-THC and CBD and that this relates to the processing of salient stimuli.

Neurofunctional effects of methylphenidate and atomoxetine in boys with attention-deficit/hyperactivity disorder during time discrimination.

BACKGROUND: The catecholamine agonists methylphenidate and atomoxetine effectively treat attention-deficit/hyperactivity disorder (ADHD). Furthermore, dopamine agonists have shown to improve time estimation in ADHD, a core cognitive deficit. However, few have compared the effects of methylphenidate and atomoxetine on brain function in ADHD, and none during time estimation. Using single dose challenges, we investigated shared and drug-specific effects in ADHD adolescents on the neural substrates of time discrimination (TD). METHODS: Twenty ADHD adolescent male subjects were compared in a randomized double-blind cross-over design after single doses of methylphenidate, atomoxetine, and placebo in functional magnetic resonance imaging during TD. Normalization effects were assessed by comparing brain activation under each drug condition with that of 20 healthy age-matched control subjects. RESULTS: Relative to control subjects, patients under placebo showed TD deficits and reduced activation of ventrolateral prefrontal cortex (VLPFC)/insula, inferior frontal cortex, and supplementary motor area. Performance differences were normalized only by methylphenidate, relative to both atomoxetine and placebo. Both medications, however, significantly upregulated right VLPFC/insula activation within patients and normalized its underactivation in ADHD boys under placebo relative to control subjects. The supplementary motor area and inferior frontal cortex activation differences that were observed under placebo were reduced by methylphenidate and atomoxetine, respectively, but neither survived rigorous testing for normalization. CONCLUSIONS: While only methylphenidate had a drug-specific effect of improving TD performance deficits, both drugs significantly upregulated and normalized right VLPFC underactivation in ADHD boys under placebo relative to control subjects, suggesting shared effects of stimulants and nonstimulants on a key prefrontal dysfunction during timing.