Social experience calibrates neural sensitivity to social feedback during adolescence: A functional connectivity approach

The adaptive calibration model suggests exposure to highly stressful or highly supportive early environments sensitizes the brain to later environmental input. We examined whether family and peer experiences predict neural sensitivity to social cues in 85 adolescent girls who completed a social feedback task during a functional brain scan and an interview assessing adversity. Whole-brain functional connectivity (FC) analyses revealed curvilinear associations between social experiences and FC between the ventral striatum and regions involved in emotion valuation, social cognition, and salience detection (e.g., insula, MPFC, dACC, dlPFC) during social reward processing, such that stronger FC was found at both very high and very low levels of adversity. Moreover, exposure to adversity predicted stronger FC between the amygdala and regions involved in salience detection, social cognition, and emotional memory (e.g., sgACC, precuneus, lingual gyrus, parahippocampal gyrus) during social threat processing. Analyses also revealed some evidence for blunted FC (VS-PCC for reward; amygdala-parahippocampal gyrus for threat) at very high and low levels of adversity. Overall, results suggest social experiences may play a critical role in shaping neural sensitivity to social feedback during adolescence. Future work will need to elucidate the implications of these patterns of neural function for the development of psychopathology.     

Atypical frontoamygdala functional connectivity in youth with autism

Functional connectivity (FC) between the amygdala and the ventromedial prefrontal cortex underlies socioemotional functioning, a core domain of impairment in autism spectrum disorder (ASD). Although frontoamygdala circuitry undergoes dynamic changes throughout development, little is known about age-related changes in frontoamygdala networks in ASD. Here we characterize frontoamygdala resting-state FC in a cross-sectional sample (ages 7–25) of 58 typically developing (TD) individuals and 53 individuals with ASD. Contrary to hypotheses, individuals with ASD did not show different age-related patterns of frontoamygdala FC compared with TD individuals. However, overall group differences in frontoamygdala FC were observed. Specifically, relative to TD individuals, individuals with ASD showed weaker frontoamygdala FC between the right basolateral (BL) amygdala and the rostral anterior cingulate cortex (rACC). These findings extend prior work to a broader developmental range in ASD, and indicate ASD-related differences in frontoamygdala FC that may underlie core socioemotional impairments in children and adolescents with ASD.     

Origin of noradrenergic afferents to the shell subregion of the nucleus accumbens: anterograde and retrograde tract-tracing studies in the rat

The nucleus accumbens (NAcc) can be subdivided into `core' and `shell' based on anatomical connections and histochemical markers. Previous studies have demonstrated dopamine-β-hydroxylase immunoreactive (DBH-ir) fibers in the NAcc shell, but the source of these noradrenergic (NE) afferents has not been determined. Therefore, we have investigated in detail the anatomy of NE afferents to this subregion. Dual immunohistochemistry for DBH and substance P demonstrated numerous DBH-ir fibers in the caudal NAcc shell. Neurons projecting to the NAcc were identified with Fluoro-Gold (FG) or cholera toxin B (CTb) retrograde tracing and tyrosine hydroxylase (TH) immunohistochemistry. Single- and double-labeled neurons were observed in the A2 and A1 NE cell groups following FG injections into the caudal NAcc shell. Numerous FG and CTb single-labeled neurons were found in the rostral locus coeruleus (LC), subcoeruleus and pericoerulear dendritic region, with an occasional double-labeled neuron in the LC. Few labeled neurons were seen in the brainstem after FG injections into the NAcc core, consistent with the lack of DBH-ir in this subterritory. To confirm these results, injections of Phaseolus vulgaris leucoagglutinin or biotinylated dextran amine were made into the LC or nucleus tractus solitarius (NTS). Virtually no labeled fibers were observed in the NAcc following injections into central LC. However, fibers were observed in the NAcc shell after injections in the NTS. These results indicate that the primary source(s) of NE afferents to the NAcc shell is the A2 region of the NTS, with lesser contributions from A1 and LC.     

Vulnerabilities of ventral mesencephalic neurons projecting to the nucleus accumbens following infusions of 6-hydroxydopamine into the medial forebrain bundle in the rat

The terminal arbors of dopaminergic projections in the nucleus accumbens (Acb) core degenerate more rapidly, completely and permanently in a variety of neurotoxic circumstances than do those in the medial shell. It is unknown if this always reflects purely losses of the distal parts of axons from the core (as proposed in methamphetamine intoxication), or whether, in some circumstances, the disproportionate loss of core axons may also stem from an intrinsic vulnerability to degeneration of core-projecting neuronal perikarya. Experiments described here addressed this issue in the following manner. Three days after Fluoro-Gold (FG), a retrogradely transported tracer, had been iontophoresed selectively into the core or medial shell of male Sprague-Dawley rats, each received an infusion of saline vehicle containing or lacking 6-hydroxydopamine (6-OHDA) in the ipsilateral medial forebrain bundle (MFB). Twenty-one days later the brains were processed to exhibit ventral mesencephalic neurons containing FG. Application of an unbiased sampling method revealed substantially greater losses of FG labeled neurons relative to controls in rats that had received 6-OHDA lesions and deposition of FG in the Acb core as compared to the medial shell. Of the few core-projecting neurons that remained in the ventral mesencephalon after these lesions, 54% did not co-localize tyrosine hydroxylase immunoreactivity (TH-ir) and, thus, were not expected to degenerate. The capacity to selectively remove core-projecting dopaminergic neurons may be useful in the determination of molecular correlates of vulnerability and resistance to neurotoxicity and to possibly test the role of the core in reinforcement paradigms.     

Neuropharmacology of the nucleus accumbens: Iontophoretic applications of morphine and nicotine have contrasting effects on single-unit responses evoked by ventral pallidal and fimbria stimulation

Extracellular recordings within the nucleus accumbens (NAS) of halothane anesthetized rats have revealed that iontophoretically applied morphine and nicotine have contrasting effects on neuronal responses evoked by fimbria or VP stimulation. Iontophoretically applied morphine inhibited NAS single-unit responses evoked by VP stimulation but did not affect unit responses evoked by fimbria stimulation. In contrast, iontophoretically applied nicotine had no effect on NAS single-unit responses evoked by VP stimulation but inhibited single-unit responses evoked by fimbria stimulation. Spontaneously active NAS units were inhibited by iontophoretically applied morphine but were unaffected by nicotine. In addition, experiments were conducted to determine whether NAS unit responses to electrical stimulation of the VP were likely to involve cell body as opposed to axonal activations. Selective cell body stimulation by glutamate microinfusions into the VP region excited spontaneously active VP single-units. Concurrently recorded NAS unit responses to electrical stimulation of the VP were also excited. These results are consistent with the idea that NAS evoked responses to VP electrical stimulation involve somal activation. Generally, these results suggest a specific neuropharmacological organization of the NAS. Analysis of the effects of morphine and nicotine on other NAS circuits will establish a systems level understanding of NAS responses to reinforcers. © 1995 Wiley-Liss, Inc.     

Evidence that the nucleus accumbens shell, ventral pallidum, and lateral hypothalamus are components of a lateralized feeding circuit

Pronounced feeding can be elicited by injections of the GABA_A agonist muscimol into the medial shell region of the nucleus accumbens (AcbSh). This region of AcbSh has been shown to project to both the lateral hypothalamus (LH) and the medial ventral pallidum (VPm). The current study examined the effects of unilateral LH or VPm lesions on the ingestive responses induced by injections of muscimol into the AcbSh on either the same or the opposite side of the brain. We found that lesions of either of these structures drastically attenuated feeding induced from the ipsilateral, as compared to the contralateral, AcbSh. The “ipsilateral/contralateral disruption design” employed here virtually rules out the possibility that the suppressive effects of the lesions were nonspecific and suggests that the VPm and LH play essential roles in mediating the ingestive effects of inactivation of the AcbSh.     

Functional connectivity and coactivation of the nucleus accumbens: a combined functional connectivity and structure-based meta-analysis

This article investigates the functional connectivity patterns of the nucleus accumbens (NAcc) in 18 healthy participants using a resting state functional connectivity (rsFC) protocol. Also, a meta-analytic connectivity modeling (MACM) was used to characterize patterns of functional coactivations involving NAcc: The results of a structure-based meta-analyses of 57 fMRI and PET studies were submitted to activation likelihood estimation analysis to estimate consistent activation patterns across the different imaging studies. The results of the combined rsFC and MACM analyses show that spontaneous activity in NAcc predicts activity in regions implicated in reward circuitries, including orbitomedial prefrontal cortex, globus pallidus, thalamus, midbrain, amygdala, and insula. This confirms the key role of NAcc in the mesocorticolimbic system, which integrates inputs from limbic and cortical regions. We also detected activity in brain regions having few or no direct anatomical connections with NAcc, such as sensorimotor cortex, cerebellum, medial and posterior parietal cortex, and medial/inferior temporal cortex, supporting the view that not all functional connections can be explained by anatomical connections but can also result from connections mediated by third areas. Our rsFC findings are in line with the results of the structure-based meta-analysis: MACM maps are superimposable with NAcc rsFC results, and the reward paradigm class is the one that most frequently generates activation in NAcc. Our results overlap considerably with recently proposed schemata of the main neuron systems in the limbic forebrain and in the anterior part of the limbic midbrain in rodents and nonhuman primates.     

The nucleus accumbens is involved in both the pursuit of social reward and the avoidance of social punishment

Human social motivation is characterized by the pursuit of social reward and the avoidance of social punishment. The ventral striatum/nucleus accumbens (VS/Nacc), in particular, has been implicated in the reward component of social motivation, i.e., the ‘wanting’ of social incentives like approval. However, it is unclear to what extent the VS/Nacc is involved in avoiding social punishment like disapproval, an intrinsically pleasant outcome. Thus, we conducted an event-related functional magnetic resonance imaging (fMRI) study using a social incentive delay task with dynamic video stimuli instead of static pictures as social incentives in order to examine participants’ motivation for social reward gain and social punishment avoidance. As predicted, the anticipation of avoidable social punishment (i.e., disapproval) recruited the VS/Nacc in a manner that was similar to VS/Nacc activation observed during the anticipation of social reward gain (i.e., approval). Stronger VS/Nacc activity was accompanied by faster reaction times of the participants to obtain those desired outcomes. This data support the assumption that dynamic social incentives elicit robust VS/Nacc activity, which likely reflects motivation to obtain social reward and to avoid social punishment. Clinical implications regarding the involvement of the VS/Nacc in social motivation dysfunction in autism and social phobia are discussed.     

Efferent projections of the nucleus accumbens in the rat with special reference to subdivision of the nucleus: biotinylated dextran amine study

The nucleus accumbens (Acb) of the rat has been divided immunohistochemically into shell and core, and further, it was subdivided into several portions in relation to functional significance. In this report, the efferent projection of each subdivision of the Acb was examined using biotinylated dextran amine as an anterograde tracer. In rostral Acb, the dorsomedial shell mainly projected to the dorsomedial ventral pallidum (VP), lateral hypothalamus (LH) and substantia nigra pars compacta (SNc), while the ventromedial shell projected to the ventromedial VP, lateral preoptic area, LH and ventral tegmental area (VTA). The dorsal core of rostral Acb projected to the caudate putamen, dorsolateral VP, globus pallidus (GP), LH, and substantia nigra pars reticulata (SNr). In the middle to caudal Acb, the dorsomedial shell mainly projected to the dorsomedial VP, LH and VTA, the ventromedial shell projected to the ventromedial VP, substantia innominata, VTA, SNc and retrorubral area, and the ventrolateral shell projected to the ventrolateral VP and SNc. Furthermore, the ventromedial shell projected to the parabrachial nucleus (PB). The dorsomedial core projected to the dorsal VP, LH, SNc and SNr, and the ventral and lateral core sent axons to the dorsolateral VP, GP and SNc. From the point of view of projection patterns, shell and core are distinct throughout the rostro-caudal extent of the Acb. The ventrolateral shell at the caudal Acb was clearly differentiated. A direct projection from the ventromedial shell of the Acb to PB was also recognised.     

Corticostriatal plasticity in the nucleus accumbens core

Small fluctuations in striatal glutamate and dopamine are required to establish goal-directed behaviors and motor learning, while large changes appear to underlie many neuropsychological disorders, including drug dependence and Parkinson's disease. A better understanding of how variations in neurotransmitter availability can modify striatal circuitry will lead to new therapeutic targets for these disorders. Here, we examined dopamine-induced plasticity in prefrontal cortical projections to the nucleus accumbens (NAc) core. We combined behavioral measures of male mice, presynaptic optical studies of glutamate release kinetics from prefrontal cortical projections, and postsynaptic electrophysiological recordings of spiny projection neurons within the NAc core. Our data show that repeated amphetamine promotes long-lasting but reversible changes along the corticoaccumbal pathway. In saline-treated mice, coincident cortical stimulation and dopamine release promoted presynaptic filtering by depressing exocytosis from glutamatergic boutons with a low-probability of release. The repeated use of amphetamine caused a frequency-dependent, progressive, and long-lasting depression in corticoaccumbal activity during withdrawal. This chronic presynaptic depression was relieved by a drug challenge which potentiated glutamate release from synapses with a low-probability of release. D1 receptors generated this synaptic potentiation, which corresponded with the degree of locomotor sensitization in individual mice. By reversing the synaptic depression, drug reinstatement may promote allostasis by returning corticoaccumbal activity to a more stable and normalized state. Therefore, dopamine-induced synaptic filtering of excitatory signals entering the NAc core in novice mice and paradoxical excitation of the corticoaccumbal pathway during drug reinstatement may encode motor learning, habit formation, and dependence.     

Resting state functional connectivity of the ventral auditory pathway in musicians with absolute pitch

Absolute pitch (AP) is the ability to recognize pitch chroma of tonal sound without external references, providing a unique model of the human auditory system (Zatorre: Nat Neurosci 6 ( 2003 ) 692–695). In a previous study (Kim and Knösche: Hum Brain Mapp ( 2016 ) 3486–3501), we identified enhanced intracortical myelination in the right planum polare (PP) in musicians with AP, which could be a potential site for perceptional processing of pitch chroma information. We speculated that this area, which initiates the ventral auditory pathway, might be crucially involved in the perceptual stage of the AP process in the context of the “dual pathway hypothesis” that suggests the role of the ventral pathway in processing nonspatial information related to the identity of an auditory object (Rauschecker: Eur J Neurosci 41 ( 2015 ) 579–585). To test our conjecture on the ventral pathway, we investigated resting state functional connectivity (RSFC) using functional magnetic resonance imaging (fMRI) from musicians with varying degrees of AP. Should our hypothesis be correct, RSFC via the ventral pathway is expected to be stronger in musicians with AP, whereas such group effect is not predicted in the RSFC via the dorsal pathway. In the current data, we found greater RSFC between the right PP and bilateral anteroventral auditory cortices in musicians with AP. In contrast, we did not find any group difference in the RSFC of the planum temporale (PT) between musicians with and without AP. We believe that these findings support our conjecture on the critical role of the ventral pathway in AP recognition. Hum Brain Mapp 38:3899–3916, 2017. © 2017 Wiley Periodicals, Inc.     

Resting state functional MRI reveals abnormal network connectivity in neurofibromatosis 1

Neurofibromatosis type I (NF1) is a genetic disorder caused by mutations in the neurofibromin 1 gene at locus 17q11.2. Individuals with NF1 have an increased incidence of learning disabilities, attention deficits, and autism spectrum disorders. As a single‐gene disorder, NF1 represents a valuable model for understanding gene–brain–behavior relationships. While mouse models have elucidated molecular and cellular mechanisms underlying learning deficits associated with this mutation, little is known about functional brain architecture in human subjects with NF1. To address this question, we used resting state functional connectivity magnetic resonance imaging (rs‐fcMRI) to elucidate the intrinsic network structure of 30 NF1 participants compared with 30 healthy demographically matched controls during an eyes‐open rs‐fcMRI scan. Novel statistical methods were employed to quantify differences in local connectivity (edge strength) and modularity structure, in combination with traditional global graph theory applications. Our findings suggest that individuals with NF1 have reduced anterior–posterior connectivity, weaker bilateral edges, and altered modularity clustering relative to healthy controls. Further, edge strength and modular clustering indices were correlated with IQ and internalizing symptoms. These findings suggest that Ras signaling disruption may lead to abnormal functional brain connectivity; further investigation into the functional consequences of these alterations in both humans and in animal models is warranted. Hum Brain Mapp 36:4566–4581, 2015. © 2015 Wiley Periodicals, Inc.     

Abnormal resting‐state functional connectivity of the nucleus accumbens in multi‐year abstinent heroin addicts

Functional neuroimaging studies suggest that abnormal brain functional connectivity may be the neural underpinning of addiction to illicit drugs and of relapse after successful cessation therapy. Aberrant brain networks have been demonstrated in addicted patients and in newly abstinent addicts. However, it is not known whether abnormal brain connectivity patterns persist after prolonged abstinence. In this cross‐sectional study, whole‐brain resting‐state functional magnetic resonance images (8 min) were collected from 30 heroin‐addicted individuals after a long period of abstinence (more than 3 years) and from 30 healthy controls. We first examined the group differences in the resting‐state functional connectivity of the nucleus accumbens (NAc), a brain region implicated in relapse‐related processes, including craving and reactivity to stress following acute and protracted withdrawal from heroin. We then examined the relation between the duration of abstinence and the altered NAc functional connectivity in the heroin group. We found that, compared with controls, heroin‐dependent participants exhibited significantly greater functional connectivity between the right ventromedial prefrontal cortex and the NAc and weaker functional connectivity between the NAc and the left putamen, left precuneus, and supplementary motor area. However, with longer abstinence time, the strength of NAc functional connectivity with the left putamen increased. These results indicate that dysfunction of the NAc functional network is still present in long‐term‐abstinent heroin‐dependent individuals. © 2015 Wiley Periodicals, Inc.     

Resting state functional connectivity of networks associated with reward and habit in anorexia nervosa

Neurobiological disturbances associated with reward and/or habit learning are theorized to maintain symptoms of anorexia nervosa (AN). Although research has investigated responses in brain regions associated with reward and habit to disorder‐specific cues (e.g., food) and presumed rewards (e.g., money), little is known about the functional organization of the circuits underlying these constructs independent of stimulus. This study aimed to provide initial data on the synchrony of networks associated with reward and habit in AN by comparing resting‐state functional connectivity (RSFC) patterns between AN and healthy control (HC) participants in these circuits and delineating how these patterns relate to symptoms. Using theoretically selected seeds in the nucleus accumbens (NAcc), ventral caudate, and dorsal caudate, reflecting a continuum from reward‐ to habit‐ oriented regions, RSFC patterns were compared between AN restricting subtype (n = 19) and HC (n = 19) participants (cluster threshold: p < .01). Exploratory correlations between RSFC z‐scores and Eating Disorder Examination (EDE) scores, BMI, and illness duration were conducted. The AN group demonstrated lower RSFC between the NAcc and superior frontal gyrus, between the ventral caudate and frontal and posterior regions, and between the dorsal caudate and frontal, temporal, and posterior regions. In the AN group, lower NAcc‐ superior frontal gyrus RSFC correlated with greater EDE Global scores (r = ?.58, CI: ?.83, ?.13). These resting‐state synchrony disruptions of the ventral and dorsal frontostriatal circuits, considered in context of the broader literature, support the utility of further investigating possible reward and habit disturbances supporting symptoms in AN.     

Resting state functional connectivity of the subthalamic nucleus in Parkinson's disease assessed using arterial spin‐labeled perfusion fMRI

Neurophysiological changes within the cortico‐basal ganglia‐thalamocortical circuits appear to be a characteristic of Parkinson's disease (PD) pathophysiology. The subthalamic nucleus (STN) is one of the basal ganglia components showing pathological neural activity patterns in PD. In this study, perfusion imaging data, acquired noninvasively using arterial spin‐labeled (ASL) perfusion MRI, were used to assess the resting state functional connectivity (FC) of the STN in 24 early‐to‐moderate PD patients and 34 age‐matched healthy controls, to determine whether altered FC in the very low frequency range of the perfusion time signal occurs as a result of the disease. Our results showed that the healthy STN was functionally connected with other nuclei of the basal ganglia and the thalamus, as well as with discrete cortical areas including the insular cortex and the hippocampus. In PD patients, connectivity of the STN was increased with two cortical areas involved in motor and cognitive processes. These findings suggest that hyperconnectivity of the STN could underlie some of the motor and cognitive deficits often present even at early stages of the disease. The FC measures provided good discrimination between controls and patients, suggesting that ASL‐derived FC metrics could be a putative PD biomarker. Hum Brain Mapp 36:1937–1950, 2015. © 2015 Wiley Periodicals, Inc .     

The development of functional connectivity within the dorsal striatum from early childhood to adulthood

Dorsal striatum, principally comprising of caudate and putamen, is well-known to support motor function but also various higher-order cognitive functions. This is enabled by developing short- and long-range connections to distributed cortical regions throughout the life span, but few studies have examined developmental changes from young children to adults in the same cohort. Here we investigated the development of dorsal-striatal network in a large (n = 476), single-site sample of healthy subjects 3–42 years of age in three groups (children, adolescence, adults). The results showed that the connectivity within the striatum and to sensorimotor regions was established at an early stage of life and remained strong in adolescence, supporting that sensory-seeking behaviours and habit formation are important learning mechanisms during the developmental periods. This connectivity diminished with age, as many behaviours become more efficient and automated. Adolescence demonstrated a remarkable transition phase where the connectivity to dorsolateral prefrontal cortex emerged but connectivity to the dorsomedial prefrontal and posterior brain, which belong to the ventral attentional and default mode networks, was only seen in adults. This prolonged maturation in between-network integration may explain the behavioural characteristics of adolescents in that they exhibit elaborated cognitive performance but also demonstrate high risk-taking behaviours.