Neural correlates of specific and general Pavlovian-to-Instrumental Transfer within human amygdalar subregions: a high-resolution fMRI study.

It is widely held that the interaction between instrumental and Pavlovian conditioning induces powerful motivational biases. Pavlovian-Instrumental Transfer (PIT) is one of the key paradigms demonstrating this effect, which can further be decomposed into a general and specific component. Although these two forms of PIT have been studied at the level of amygdalar subregions in rodents, it is still unknown whether they involve different areas of the human amygdala. Using a high-resolution fMRI (hr-fMRI) protocol optimized for the amygdala in combination with a novel free operant task designed to elicit effects of both general and specific PIT, we demonstrate that a region of ventral amygdala within the boundaries of the basolateral complex and the ventrolateral putamen are involved in specific PIT, while a region of dorsal amygdala within the boundaries of the centromedial complex is involved in general PIT. These results add to a burgeoning literature indicating different functional contributions for these different amygdalar subregions in reward-processing and motivation.

Your goal is mine: unraveling mimetic desires in the human brain.

The spread of desires among individuals is widely believed to shape motivational drives in human populations. However, objective evidence for this phenomenon and insights into the underlying brain mechanisms are still lacking. Here we show that participants rated objects as more desirable once perceived as the goals of another agent's action. We then unravel the mechanisms underpinning such goal contagion, using functional neuroimaging. As expected, observing goal-directed actions activated a parietofrontal network known as the mirror neuron system (MNS), whereas subjective desirability ratings were represented in a ventral striatoprefrontal network known as the brain valuation system (BVS). Crucially, the induction of mimetic desires through action observation involved the modulation of BVS activity through MNS activity. Furthermore, MNS-BVS effective connectivity predicted individual susceptibility toward mimetic desires. We therefore suggest that MNS-BVS interaction represents a fundamental mechanism explaining how nonverbal behavior propagates desires without the need for explicit, intentional communication.

Differentiating hemispheric contributions to syntax and semantics in patients with left-hemisphere lesions.

Understanding the relationship between brain and cognition critically depends on data from brain-damaged patients since these provide major constraints on identifying the essential components of brain-behavior systems. Here we relate structural and functional fMRI data with behavioral data in 21 human patients with chronic left hemisphere (LH) lesions and a range of language impairments to investigate the controversial issue of the role of the hemispheres in different language functions. We address this issue within a dual neurocognitive model of spoken language comprehension in which core linguistic functions, e.g., syntax, depend critically upon an intact left frontotemporal system, whereas more general communicative abilities, e.g., semantics, are supported by a bilateral frontotemporal system and may recover from LH damage through normal or enhanced activity in the intact right hemisphere. The fMRI study used a word-monitoring task that differentiated syntactic and semantic aspects of sentence comprehension. We distinguished overlapping interactions between structure, neural activity, and performance using joint independent components analysis, identifying two structural-functional networks, each with a distinct relationship with performance. Syntactic performance correlated with tissue integrity and activity in a left frontotemporal network. Semantic performance correlated with activity in right superior/middle temporal gyri regardless of tissue integrity. Right temporal activity did not differ between patients and controls, suggesting that the semantic network is degenerately organized, with regions in both hemispheres able to perform similar computations. Our findings support the dual neurocognitive model of spoken language comprehension and emphasize the importance of linguistic specificity in investigations of language recovery in patients.

Priming of control: implicit contextual cuing of top-down attentional set.

Cognitive models have long distinguished between "automatic" associative processes that can be triggered in a bottom-up fashion, and "controlled" processes, where internal goals guide information processing in a deliberate, top-down manner. However, recent behavioral studies have cast doubt on the validity of this dichotomy, showing that implicit contextual cues can modulate performance in a way suggestive of an associative triggering of specific top-down control states. Here, we harnessed functional magnetic resonance imaging in humans to test whether these behavioral findings truly reflect online, bottom-up priming of top-down attentional control settings. Using a flanker interference task where stimulus location cued the likelihood of incongruent trials, we found that the behavioral phenomenon of implicit, context-specific improvements in interference resolution was mirrored in hemodynamic activity in the medial superior parietal lobule (mSPL), previously implicated in voluntary (as opposed to primed) attention shifts. Moreover, the mSPL displayed context-specific functional coupling with visual regions involved in processing the flanker stimuli, and the modulation of the latter was predictive of the behavioral effects. Finally, the implementation of this contextual control was "on the fly," that is, it was primed online by a switch to the context associated with high conflict. These results suggest that top-down control states can be bound into episodic event representations and can subsequently be primed by other features of those representations. Together, our findings illustrate a more intimate link between associative and controlled processing than is traditionally assumed, and place the neural substrate of that linkage in the posterior parietal cortex.

Gender modulates the APOE ε4 effect in healthy older adults: convergent evidence from functional brain connectivity and spinal fluid tau levels.

We examined whether the effect of the apolipoprotein E (APOE) genotype on functional brain connectivity is modulated by gender in healthy older human adults. Our results confirm significantly decreased connectivity in the default mode network in healthy older APOE ε4 carriers compared with ε3 homozygotes. More important, further testing revealed a significant interaction between APOE genotype and gender in the precuneus, a major default mode hub. Female ε4 carriers showed significantly reduced default mode connectivity compared with either female ε3 homozygotes or male ε4 carriers, whereas male ε4 carriers differed minimally from male ε3 homozygotes. An additional analysis in an independent sample of healthy elderly using an independent marker of Alzheimer's disease, i.e., spinal fluid levels of tau, provided corresponding evidence for this gender-by-APOE interaction. Together, these results converge with previous work showing a higher prevalence of the ε4 allele among women with Alzheimer's disease and, critically, demonstrate that this interaction between APOE genotype and gender is detectable in the preclinical period.

Sleep deprivation is associated with attenuated parametric valuation and control signals in the midbrain during value-based decision making.

Sleep deprivation (SD) has detrimental effects on cognition, but the affected psychological processes and underlying neural mechanisms are still essentially unclear. Here we combined functional magnetic resonance imaging and computational modeling to examine how SD alters neural representation of specific choice variables (subjective value and decision conflict) during reward-related decision making. Twenty-two human subjects underwent two functional neuroimaging sessions in counterbalanced order, once during rested wakefulness and once after 24 h of SD. Behaviorally, SD attenuated conflict-dependent slowing of response times, which was reflected in an attenuated conflict-induced decrease in drift rates in the drift diffusion model. Furthermore, SD increased overall choice stochasticity during risky choice. Model-based functional neuroimaging revealed attenuated parametric subjective value signals in the midbrain, parietal cortex, and ventromedial prefrontal cortex after SD. Conflict-related midbrain signals showed a similar downregulation. Findings are discussed with respect to changes in dopaminergic signaling associated with the sleep-deprived state.

Altered functional brain connectivity in a non-clinical sample of young adults with attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is characterized by symptoms of inattention and hyperactivity/impulsivity that often persist in adulthood. There is a growing consensus that ADHD is associated with abnormal function of diffuse brain networks, but such alterations remain poorly characterized. Using resting-state functional magnetic resonance imaging, we characterized multivariate (complex network measures), bivariate (network-based statistic), and univariate (regional homogeneity) properties of brain networks in a non-clinical, drug-naive sample of high-functioning young men and women with ADHD (nine males, seven females) and a group of matched healthy controls. Data from our sample allowed the isolation of intrinsic functional connectivity alterations specific to ADHD diagnosis and symptoms that are not related to developmental delays, general cognitive dysfunction, or history of medication use. Multivariate results suggested that frontal, temporal, and occipital cortices were abnormally connected locally as well as with the rest of the brain in individuals with ADHD. Results from the network-based statistic support and extend multivariate results by isolating two brain networks comprising regions between which inter-regional connectivity was significantly altered in the ADHD group; namely, a frontal amygdala-occipital network and a frontal temporal-occipital network. Brain behavior correlations further highlighted the key role of altered orbitofrontal-temporal and frontal-amygdala connectivity for symptoms of inattention and hyperactivity/impulsivity. All univariate properties were similar between groups. Taken together, results from this study show that the diagnosis and the two main symptom dimensions of ADHD are related to altered intrinsic connectivity in orbitofrontal-temporal-occipital and fronto-amygdala-occipital networks. Accordingly, our findings highlight the importance of extending the conceptualization of ADHD beyond segregated fronto-striatal alterations.

Improving visual perception through neurofeedback.

Perception depends on the interplay of ongoing spontaneous activity and stimulus-evoked activity in sensory cortices. This raises the possibility that training ongoing spontaneous activity alone might be sufficient for enhancing perceptual sensitivity. To test this, we trained human participants to control ongoing spontaneous activity in circumscribed regions of retinotopic visual cortex using real-time functional MRI-based neurofeedback. After training, we tested participants using a new and previously untrained visual detection task that was presented at the visual field location corresponding to the trained region of visual cortex. Perceptual sensitivity was significantly enhanced only when participants who had previously learned control over ongoing activity were now exercising control and only for that region of visual cortex. Our new approach allows us to non-invasively and non-pharmacologically manipulate regionally specific brain activity and thus provide "brain training" to deliver particular perceptual enhancements.

Striatal dopamine D2/D3 receptors mediate response inhibition and related activity in frontostriatal neural circuitry in humans.

Impulsive behavior is thought to reflect a traitlike characteristic that can have broad consequences for an individual's success and well-being, but its neurobiological basis remains elusive. Although striatal dopamine D2-like receptors have been linked with impulsive behavior and behavioral inhibition in rodents, a role for D2-like receptor function in frontostriatal circuits mediating inhibitory control in humans has not been shown. We investigated this role in a study of healthy research participants who underwent positron emission tomography with the D2/D3 dopamine receptor ligand [¹8F]fallypride and BOLD fMRI while they performed the Stop-signal Task, a test of response inhibition. Striatal dopamine D2/D3 receptor availability was negatively correlated with speed of response inhibition (stop-signal reaction time) and positively correlated with inhibition-related fMRI activation in frontostriatal neural circuitry. Correlations involving D2/D3 receptor availability were strongest in the dorsal regions (caudate and putamen) of the striatum, consistent with findings of animal studies relating dopamine receptors and response inhibition. The results suggest that striatal D2-like receptor function in humans plays a major role in the neural circuitry that mediates behavioral control, an ability that is essential for adaptive responding and is compromised in a variety of common neuropsychiatric disorders.

The relation between perception and brain activity in gaze-evoked tinnitus.

Tinnitus is a phantom sound percept that can be severely disabling. Its pathophysiology is poorly understood, partly due to the inability to objectively measure neural correlates of tinnitus. Gaze-evoked tinnitus (GET) is a rare form of tinnitus that may arise after vestibular schwannoma removal. Subjects typically describe tinnitus in the deaf ear on the side of the surgery that can be modulated by peripheral eye gaze. This phenomenon offers a unique opportunity to study the relation between tinnitus and brain activity. We used functional magnetic resonance imaging in humans to show that in normal-hearing control subjects, peripheral gaze results in inhibition of the auditory cortex, but no detectable response in the medial geniculate body (MGB) and inferior colliculus (IC). In patients with GET, peripheral gaze (1) reduced the cortical inhibition, (2) inhibited the MGB, and (3) activated the IC. Furthermore, increased tinnitus loudness is represented by increased activity in the cochlear nucleus (CN) and IC and reduced inhibition in the auditory cortex (AC). The increase of CN and IC activity with peripheral gaze is consistent with models of plastic reorganization in the brainstem following vestibular schwannoma removal. The activity decrease in the MGB and the reduced inhibition of the AC support a model that attributes tinnitus to a dysrhythmia of the thalamocortical loop, leading to hypometabolic theta activity in the MGB. Our data offer the first support of this loop hypothesis of tinnitus, independent of the initial experiments that led to its formulation.

Amygdala activation in maltreated children during pre-attentive emotional processing.

BACKGROUND: Childhood adversity is associated with significantly increased risk of psychiatric disorder. To date, functional magnetic resonance imaging (fMRI) studies of children have mainly focused on institutionalisation and investigated conscious processing of affect. AIMS: To investigate neural response to pre-attentively presented affect cues in a community sample of children with documented experiences of maltreatment in the home. METHOD: A masked dot-probe paradigm involving pre-attentive presentation of angry, happy and neutral facial expressions was employed. Eighteen maltreated children were compared with 23 carefully matched non-maltreated peers. RESULTS: Increased neural response was observed in the right amygdala for pre-attentively presented angry and happy faces in maltreated v. non-maltreated children. Level of amygdala activation was negatively associated with age at onset for several abuse subtypes. CONCLUSIONS: Maltreatment is associated with heightened neural response to positive and negative facial affect, even to stimuli outside awareness. This may represent a latent neural risk factor for future psychiatric disorder.

Dopamine transporter genotype predicts behavioural and neural measures of response inhibition.

The ability to inhibit unwanted actions is a heritable executive function that may confer risk to disorders such as attention deficit hyperactivity disorder (ADHD). Converging evidence from pharmacology and cognitive neuroscience suggests that response inhibition is instantiated within frontostriatal circuits of the brain with patterns of activity that are modulated by the catecholamines dopamine and noradrenaline. A total of 405 healthy adult participants performed the stop-signal task, a paradigmatic measure of response inhibition that yields an index of the latency of inhibition, termed the stop-signal reaction time (SSRT). Using this phenotype, we tested for genetic association, performing high-density single-nucleotide polymorphism mapping across the full range of autosomal catecholamine genes. Fifty participants also underwent functional magnetic resonance imaging to establish the impact of associated alleles on brain and behaviour. Allelic variation in polymorphisms of the dopamine transporter gene (SLC6A3: rs37020; rs460000) predicted individual differences in SSRT, after corrections for multiple comparisons. Furthermore, activity in frontal regions (anterior frontal, superior frontal and superior medial gyri) and caudate varied additively with the T-allele of rs37020. The influence of genetic variation in SLC6A3 on the development of frontostriatal inhibition networks may represent a key risk mechanism for disorders of behavioural inhibition.

Association between genetic variation in a region on chromosome 11 and schizophrenia in large samples from Europe.

Recent molecular studies have implicated common alleles of small to moderate effect and rare alleles with larger effect sizes in the genetic architecture of schizophrenia (SCZ). It is expected that the reliable detection of risk variants with very small effect sizes can only be achieved through the recruitment of very large samples of patients and controls (that is tens of thousands), or large, potentially more homogeneous samples that have been recruited from confined geographical areas using identical diagnostic criteria. Applying the latter strategy, we performed a genome-wide association study (GWAS) of 1169 clinically well characterized and ethnically homogeneous SCZ patients from a confined area of Western Europe (464 from Germany, 705 from The Netherlands) and 3714 ethnically matched controls (1272 and 2442, respectively). In a subsequent follow-up study of our top GWAS results, we included an additional 2569 SCZ patients and 4088 controls (from Germany, The Netherlands and Denmark). Genetic variation in a region on chromosome 11 that contains the candidate genes AMBRA1, DGKZ, CHRM4 and MDK was significantly associated with SCZ in the combined sample (n=11 540; P=3.89 × 10(-9), odds ratio (OR)=1.25). This finding was replicated in 23 206 independent samples of European ancestry (P=0.0029, OR=1.11). In a subsequent imaging genetics study, healthy carriers of the risk allele exhibited altered activation in the cingulate cortex during a cognitive control task. The area of interest is a critical interface between emotion regulation and cognition that is structurally and functionally abnormal in SCZ and bipolar disorder.

Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers.

Chronic cannabis (marijuana, hashish) smoking can result in dependence. Rodent studies show reversible downregulation of brain cannabinoid CB(1) (cannabinoid receptor type 1) receptors after chronic exposure to cannabis. However, whether downregulation occurs in humans who chronically smoke cannabis is unknown. Here we show, using positron emission tomography imaging, reversible and regionally selective downregulation of brain cannabinoid CB(1) receptors in human subjects who chronically smoke cannabis. Downregulation correlated with years of cannabis smoking and was selective to cortical brain regions. After ∼4 weeks of continuously monitored abstinence from cannabis on a secure research unit, CB(1) receptor density returned to normal levels. This is the first direct demonstration of cortical cannabinoid CB(1) receptor downregulation as a neuroadaptation that may promote cannabis dependence in human brain.

Impulsiveness and insula activation during reward anticipation are associated with genetic variants in GABRA2 in a family sample enriched for alcoholism.

Genetic factors, externalizing personality traits such as impulsivity, and brain processing of salient stimuli all can affect individual risk for alcoholism. One of very few confirmed genetic association findings differentiating alcoholics from non-alcoholics is with variants in the inhibitory γ-amino butyric acid α2 receptor subunit (GABRA2) gene. Here we report the association of two of these GABRA2 variants with measures of alcohol symptoms, impulsivity and with insula cortex activation during anticipation of reward or loss using functional magnetic resonance imaging (fMRI). In a sample of 173 families (449 subjects), 129 of whom had at least one member diagnosed with alcohol dependence or abuse, carriers for the G allele in two single-nucleotide polymorphisms (SNPs) and haplotypes were more likely to have alcohol dependence symptoms (rs279858, P=0.01; rs279826, P=0.05; haplotype, P=0.02) and higher NEO Personality Inventory-Revised (NEO-PI-R) Impulsiveness scores (rs279858, P=0.016; rs279826, P=0.012; haplotype, P=0.032) with a stronger effect in women (rs279858, P=0.011; rs279826, P=0.002; haplotype, P=0.006), all P-values are corrected for family history and age. A subset of offspring from these families (n=44, 20 females), genotyped for GABRA2, participated in an fMRI study using a monetary incentive delay task. Increased insula activation during reward (r(2)=0.4; P=0.026) and loss (r(2)=0.38; P=0.039) anticipation was correlated with NEO-PI-R Impulsiveness and further associated with the GG genotype for both SNPs (P's<0.04). Our results suggest that GABRA2 genetic variation is associated with Impulsiveness through variation of insula activity responses, here evidenced during anticipatory responses.

Short-term antidepressant administration reduces negative self-referential processing in the medial prefrontal cortex in subjects at risk for depression.

Depression has been associated with changes in responses within the medial prefrontal cortex (mPFC) during emotional information processing. Antidepressant drug treatment has been shown to modify neural responses in healthy volunteers early in treatment within similar circuitry. It is unclear, however, whether the same early effect occurs in depressed patients, before changes in mood. The current study therefore investigated the effects of 7-days administration of the selective serotonin-uptake inhibitor citalopram vs placebo in volunteers (n=29) at a high risk for the development of depression, using the personality phenotype of high neuroticism in a double-blind, between-groups design. On the last day of treatment, resting haemoperfusion and functional magnetic resonance imaging (MRI) data were acquired during a self-referential words categorisation task. A significant activation in a cluster of mPFC areas, including dorsal anterior cingulate and right orbitofrontal cortex was revealed, driven by decreased responses to the negative self-descriptors following citalopram compared with placebo, in the absence of any mood differences. These findings show a normalisation of neural abnormalities in- and at-risk population early in treatment, supporting the theory that antidepressants may indeed act by modifying specific neural dysfunctions correlated to negative cognitive biases.

Visual cortical activity reflects faster accumulation of information from cortically blind fields.

Brain responses (from functional magnetic resonance imaging) and components of information processing were investigated in nine cortically blind observers performing a global direction discrimination task. Three of these subjects had responses in perilesional cortex in response to blind field stimulation, whereas the others did not. We used the EZ-diffusion model of decision making to understand how cortically blind subjects make a perceptual decision on stimuli presented within their blind field. We found that these subjects had slower accumulation of information in their blind fields as compared with their good fields and to intact controls. Within cortically blind subjects, activity in perilesional tissue, V3A and hMT+ was associated with a faster accumulation of information for deciding direction of motion of stimuli presented in the blind field. This result suggests that the rate of information accumulation is a critical factor in the degree of impairment in cortical blindness and varies greatly among affected individuals. Retraining paradigms that seek to restore visual functions might benefit from focusing on increasing the rate of information accumulation.

Atypical activation during the Embedded Figures Task as a functional magnetic resonance imaging endophenotype of autism.

Atypical activation during the Embedded Figures Task has been demonstrated in autism, but has not been investigated in siblings or related to measures of clinical severity. We identified atypical activation during the Embedded Figures Task in participants with autism and unaffected siblings compared with control subjects in a number of temporal and frontal brain regions. Autism and sibling groups, however, did not differ in terms of activation during this task. This suggests that the pattern of atypical activation identified may represent a functional endophenotype of autism, related to familial risk for the condition shared between individuals with autism and their siblings. We also found that reduced activation in autism relative to control subjects in regions including associative visual and face processing areas was strongly correlated with the clinical severity of impairments in reciprocal social interaction. Behavioural performance was intact in autism and sibling groups. Results are discussed in terms of atypical information processing styles or of increased activation in temporal and frontal regions in autism and the broader phenotype. By separating the aspects of atypical activation as markers of familial risk for the condition from those that are autism-specific, our findings offer new insight into the factors that might cause the expression of autism in families, affecting some children but not others.

Cingulate biochemistry in heroin users on substitution pharmacotherapy.

OBJECTIVE: High doses of opiate substitution pharmacotherapy are associated with greater treatment retention and lower illicit drug consumption, although the neurobiological bases of these benefits are poorly understood. Dysfunction of the anterior cingulate cortex (ACC) is associated with greater addiction severity and mood dysregulation in opiate users, such that the beneficial effects of substitution pharmacotherapy may relate to normalisation of ACC function. This study aimed to investigate the differential impact of methadone compared with buprenorphine on dorsal ACC biochemistry. A secondary aim was to explore the differential effects of methadone and buprenorphine on dorsal ACC biochemistry in relation to depressive symptoms. METHODS: Twenty-four heroin-dependent individuals stabilised on methadone (n=10) or buprenorphine (n=14) and 24 healthy controls were scanned using proton Magnetic Resonance Spectroscopy and compared for metabolite concentrations of N-acetylaspartate, glutamate/glutamine, and myo-inositol. RESULTS: (1) Methadone was associated with normalisation of dorsal ACC biochemistry (increased N-acetylaspartate and glutamate/glutamine levels, and decreased myo-inositol levels) in a dose-dependent manner; (2) buprenorphine-treated individuals had higher myo-inositol and glutamate/glutamine levels than methadone-treated patients in the right dorsal ACC; and (3) myo-inositol levels were positively correlated with depressive symptoms in participants stabilised on buprenorphine. CONCLUSIONS: These findings point to a beneficial role of high-dose methadone on dorsal ACC biochemistry, and suggest a link between elevated myo-inositol levels and depressive symptoms in the context of buprenorphine treatment.

Metabolite profiles in the anterior cingulate cortex of depressed patients differentiate those taking N-acetyl-cysteine versus placebo.

BACKGROUND: Increased oxidative stress is thought to contribute to the pathophysiology of major depressive disorder (MDD), which is in part due to diminished levels of glutathione, the primary anti-oxidant of the brain. Oral administration of N-acetyl-cysteine (NAC) replenishes glutathione and has therefore been shown to reduce depressive symptoms. Proton magnetic spectroscopy ((1)H-MRS) that allows quantification of brain metabolites pertinent to both MDD and oxidative biology may provide some novel insights into the neurobiological effects of NAC, and in particular metabolite concentrations within the anterior cingulate cortex (ACC) are likely to be important given the key role of this region in the regulation of affect. OBJECTIVE: The aim of this study was to determine whether the metabolite profile of the ACC in MDD patients predicts treatment with adjunctive NAC versus placebo. METHODS: This study was nested within a multicentre, randomized, double-blind, placebo-controlled study of MDD participants treated with adjunctive NAC. Participants (n = 76) from one site completed the spectroscopy component at the end of treatment (12 weeks). Spectra from a single-voxel in the ACC were acquired and absolute concentrations of glutamate (Glu), glutamate-glutamine (Glx), N-acetyl-aspartate (NAA) and myo-inositol (mI) were obtained. Binary logistic regression analysis was performed to determine whether metabolite profiles could predict NAC versus placebo group membership. RESULTS: When predicting group outcome (NAC or placebo), Glx, NAA and mI were a significant model, and had 75% accuracy, while controlling for depression severity and sex. However, the Glu, NAA and mI profile was only predictive at a trend level, with 68.3% accuracy. For both models, the log of the odds of a participant being in the NAC group was positively related to NAA, Glx and Glu levels and negatively related to mI levels. CONCLUSION: The finding of higher Glx and NAA levels being predictive of the NAC group provides preliminary support for the putative anti-oxidative role of NAC in MDD.