Reward system dysfunction in autism spectrum disorders
01 Jun 2013-Social Cognitive and Affective Neuroscience (Oxford University Press)-Vol. 8, Iss: 5, pp 565-572
TL;DR: There is evidence for a general reward dysfunction in ASD, and more ecologically valid social reward paradigms are needed to fully understand, whether there is any domain specificity to the reward deficit that appears evident in ASD.
Abstract: Although it has been suggested that social deficits of autism spectrum disorders (ASDs) are related to reward circuitry dysfunction, very little is known about the neural reward mechanisms in ASD. In the current functional magnetic resonance imaging study, we investigated brain activations in response to both social and monetary reward in a group of children with ASD, relative to matched controls. Participants with ASD showed the expected hypoactivation in the mesocorticolimbic circuitry in response to both reward types. In particular, diminished activation in the nucleus accumbens was observed when money, but not when social reward, was at stake, whereas the amygdala and anterior cingulate cortex were hypoactivated within the ASD group in response to both rewards. These data indicate that the reward circuitry is compromised in ASD in social as well as in non-social, i.e. monetary conditions, which likely contributes to atypical motivated behaviour. Taken together, with incentives used in this study sample, there is evidence for a general reward dysfunction in ASD. However, more ecologically valid social reward paradigms are needed to fully understand, whether there is any domain specificity to the reward deficit that appears evident in ASD, which would be most consistent with the ASD social phenotype.
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TL;DR: Meta-analytic data is presented revealing distinct subregions within the vmPFC that correspond to each of these three functions, as well as the associations between these subregion and specific psychiatric disorders (depression, posttraumatic stress disorder, addiction, social anxiety disorder, bipolar disorder, schizophrenia, and attention-deficit/hyperactivity disorder).
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TL;DR: Interdisciplinary evidence highlights the motivated nature of empathy, and a motivated model holds wide-ranging implications for basic theory, models of psychiatric illness, and intervention efforts to maximize empathy.
Abstract: Empathy features a tension between automaticity and context dependency. On the one hand, people often take on each other's internal states reflexively and outside of awareness. On the other hand, empathy shifts with characteristics of empathizers and situations. These 2 characteristics of empathy can be reconciled by acknowledging the key role of motivation in driving people to avoid or approach engagement with others' emotions. In particular, at least 3 phenomena-suffering, material costs, and interference with competition-motivate people to avoid empathy, and at least 3 phenomena-positive affect, affiliation, and social desirability-motivate them to approach empathy. Would-be empathizers carry out these motives through regulatory strategies including situation selection, attentional modulation, and appraisal, which alter the course of empathic episodes. Interdisciplinary evidence highlights the motivated nature of empathy, and a motivated model holds wide-ranging implications for basic theory, models of psychiatric illness, and intervention efforts to maximize empathy.
496 citations
TL;DR: Restricted and repetitive behaviors in ASD are associated with neurocognitive deficits in flexible choice behavior, and alterations in frontostriatal circuitry may contribute to behavioral rigidity in ASD and represent a target for therapeutic intervention.
Abstract: Reduced Behavioral Flexibility in Autism Spectrum Disorders Autism spectrum disorders (ASD) are characterized by pervasive disturbances in social interactions and communication, and by circumscribed interests and restricted and repetitive behaviors (Diagnostic and Statistical Manual of Mental Disorders; 4th ed., text rev; DSM-IV-TR; American Psychiatric Association, 2000). Understanding of the latter symptom domain remains limited, despite it contributing significantly to clinical distress and behavioral problems (Bishop, Richler, Cain, & Lord, 2007; South, Ozonoff, & McMahon, 2005). Clarifying the cognitive bases of behavioral rigidity in ASD has the potential to provide clues as to its pathophysiology, improve its clinical assessment, and guide development of new treatments that can alleviate this core feature of ASD.
One possibility is that a specific impairment in the ability to transition away from preferred behaviors to new, more adaptive ones contributes to the occurrence of restrictive and repetitive behaviors. Some prior studies suggest that these behaviors are related to broad deficits in executive function and cognitive control in ASD (Lopez, Lincoln, Ozonoff, & Lai, 2005; Mosconi et al., 2009). However, results are inconsistent, and the specific cognitive impairments that may contribute to clinical manifestations of rigid behavior remain to be clarified. Studies have documented deficits in cognitive flexibility in ASD using the Wisconsin Card Sort Test and the CANTAB ID/ED set shifting task, showing that individuals with autism are impaired when learning to shift set to a new perceptual sorting category (Corbett, Constantine, Hendren, Rocke, & Ozonoff, 2009; Goldstein, Johnson, & Minshew, 2001; Hughes, Russell, & Robbins, 1994). It is of note that these tests place demands not only on behavioral flexibility but also on multiple higher-order cognitive processes that are known to be impaired in ASD, such as perceptual reasoning skills. Thus, it remains uncertain as to what degree previous findings reflect deficits in flexible behavioral control versus impaired cognition in other domains. Further, prior studies have not parsed apart different aspects of behavioral flexibility that are known to be supported by different cognitive and brain systems. For example, a behavioral flexibility deficit could result from the inability to initially inhibit a previously preferred choice pattern, or a deficit in maintaining a new choice pattern over time, which would point to impairments in frontal cortical and striatal functioning respectively (Dias, Robbins, & Roberts, 1996; Ragozzino, 2007; Robbins, 2007).
Reversal learning tasks provide a direct approach to examining flexible choice behavior. This methodology is widely used across species, and thus is useful for testing mechanistic biological models, and for translational studies that can facilitate drug development (Brown, Amodeo, Sweeney, & Ragozzino, 2012; Ghahremani, Monterosso, Jentsch, Bilder, & Poldrack, 2010; Glascher, Hampton, & O’Doherty, 2009; Ragozzino, Mohler, Prior, Palencia, & Rozman, 2009). In contrast to extradimensional shifting which is more dependent on prefrontal cortical functions, reversal learning is primarily dependent upon striatal circuitry (Robbins, 2007). Reversal learning tasks assess simple intradimensional shifts in behavior, e.g. shifting from choosing one spatial location to another, rather than shifting across dimensions, such as from the color to the shape of stimuli. This is accomplished by requiring subjects to acquire a behavioral response strategy using performance feedback, and then to reverse that response to an alternative option when the previously correct choice is no longer reinforced. Importantly, reversal learning tasks are designed to distinguish between deficits in disengaging from preferred behaviors versus maintaining new choice patterns.
Few studies have examined reversal learning in ASD. Most have used small samples of young children who showed alterations in the ability to learn an initial response pattern in addition to reversal deficits (Coldren & Halloran, 2003; Lionello-Denolf, McIlvane, Canovas, de Souza, & Barros, 2008). If initial acquisition of a response is impaired, that can confound the interpretation of problems in switching to a new response, because this could result from a generalized learning deficit rather than a specific impairment in response shifting. Reports from larger and primarily adolescent samples using intradimensional subtests of the CANTAB ID/ED task do not show deficits in reversal learning in ASD (Edgin & Pennington, 2005; Goldberg et al., 2005; Ozonoff et al., 2004; Ozonoff, South, & Miller, 2000). However, a number of important issues remain to be resolved. First, reversal learning studies to date have not clarified whether there are deficits in the specific processes of selecting or maintaining new responses; whether one or the other is selectively affected could indicate alterations in distinct cognitive and brain systems. Second, studies have not systematically examined whether reversal learning performance is related to clinical manifestations of behavioral rigidity. Third, because delayed maturation of behavioral flexibility in ASD may result in deficits that are more pronounced at younger ages, studies with older adolescents and young adults may have missed deficits evident in younger individuals.
Finally, critical to a comprehensive understanding of behavioral flexibility in ASD is an understanding of how dynamically changing consequences for choice behaviors support or disturb flexible behavioral control. Probabilistic reversal learning paradigms, in which accurate feedback or reinforcement for response choices is provided on only a proportion of trials, allow for an examination of the effect of inconsistent reinforcement on behavioral flexibility. The intermittent non-reinforcement used in probabilistic tasks increases the difficulty associated with establishing, maintaining, and reversing a behavioral set. For this reason, such tasks may be more sensitive to behavioral flexibility deficits, as misleading feedback might slow learning of new responses after reversal, or increase the likelihood of reverting back to a previously reinforced and preferred response choice. A psychometric advantage is that probabilistic paradigms may be less susceptible to ceiling effects in test performance that could contribute to the failure to identify deficits in prior studies in ASD, in which all correct responses were accurately reinforced. The unpredictable and inconsistent nature of reinforcement for choice behaviors used in probabilistic tasks also corresponds more closely to the behavioral flexibility demands of typical day-to-day life.
In the present study, individuals with ASD and matched controls performed a probabilistic reversal learning task. Performance at acquisition and at reversal was examined. The primary measures of interest were the number of trials required to learn a behavioral response and to shift to a new response when reinforcement contingencies changed, the number of errors made after reversal when sustaining a new response over a previously preferred choice, and the number of errors made following intermittent non-reinforcement. We evaluated test performance in relation to independently ascertained clinical measures of restricted and repetitive behaviors, and other clinical features of ASD. Given reports of altered cognitive development across the lifespan in ASD (Luna, Doll, Hegedus, Minshew, & Sweeney, 2007; Solomon, Ozonoff, Cummings, & Carter, 2008), in secondary analyses we examined performance across a broad age range to identify preliminary indications of an altered trajectory in the development of behavioral flexibility.
203 citations
Cites background from "Reward system dysfunction in autism..."
...This is interesting in light of recent functional neuroimaging studies showing an altered response to reward in ventral striatum in ASD (Dichter, Richey, Rittenberg, Sabatino, & Bodfish, 2012; Kohls et al., 2012; Scott-Van Zeeland, Dapretto, Ghahremani, Poldrack, & Bookheimer, 2010)....
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TL;DR: This review investigates multiple genetic mouse models of ASD to explore whether abnormalities in striatal circuits constitute a common pathophysiological mechanism in the development of autism-related behaviors, and investigates striatal mechanisms of behavioral regulation.
Abstract: Autism spectrum disorders (ASD) are characterized by two seemingly unrelated symptom domains-deficits in social interactions and restrictive, repetitive patterns of behavioral output. Whether the diverse nature of ASD symptomatology represents distributed dysfunction of brain networks or abnormalities within specific neural circuits is unclear. Striatal dysfunction is postulated to underlie the repetitive motor behaviors seen in ASD, and neurological and brain-imaging studies have supported this assumption. However, as our appreciation of striatal function expands to include regulation of behavioral flexibility, motivational state, goal-directed learning, and attention, we consider whether alterations in striatal physiology are a central node mediating a range of autism-associated behaviors, including social and cognitive deficits that are hallmarks of the disease. This review investigates multiple genetic mouse models of ASD to explore whether abnormalities in striatal circuits constitute a common pathophysiological mechanism in the development of autism-related behaviors. Despite the heterogeneity of genetic insult investigated, numerous genetic ASD models display alterations in the structure and function of striatal circuits, as well as abnormal behaviors including repetitive grooming, stereotypic motor routines, deficits in social interaction and decision-making. Comparative analysis in rodents provides a unique opportunity to leverage growing genetic association data to reveal canonical neural circuits whose dysfunction directly contributes to discrete aspects of ASD symptomatology. The description of such circuits could provide both organizing principles for understanding the complex genetic etiology of ASD as well as novel treatment routes. Furthermore, this focus on striatal mechanisms of behavioral regulation may also prove useful for exploring the pathogenesis of other neuropsychiatric diseases, which display overlapping behavioral deficits with ASD.
191 citations
TL;DR: Translational proton magnetic resonance spectroscopy is used to compare glutamate and GABA levels in adult humans with ASD and in a panel of six diverse rodent ASD models, encompassing genetic and environmental etiologies, to suggest abnormalities in the corticostriatal circuitry may be a key pathological mechanism in ASD.
Abstract: Autism spectrum disorder (ASD) is a pervasive neurodevelopmental syndrome with a high human and economic burden. The pathophysiology of ASD is largely unclear, thus hampering development of pharmacological treatments for the core symptoms of the disorder. Abnormalities in glutamate and GABA signaling have been hypothesized to underlie ASD symptoms, and may form a therapeutic target, but it is not known whether these abnormalities are recapitulated in humans with ASD, as well as in rodent models of the disorder. We used translational proton magnetic resonance spectroscopy ([1H]MRS) to compare glutamate and GABA levels in adult humans with ASD and in a panel of six diverse rodent ASD models, encompassing genetic and environmental etiologies. [1H]MRS was performed in the striatum and the medial prefrontal cortex, of the humans, mice, and rats in order to allow for direct cross-species comparisons in specific cortical and subcortical brain regions implicated in ASD. In humans with ASD, glutamate concentration was reduced in the striatum and this was correlated with the severity of social symptoms. GABA levels were not altered in either brain region. The reduction in striatal glutamate was recapitulated in mice prenatally exposed to valproate, and in mice and rats carrying Nlgn3 mutations, but not in rodent ASD models with other etiologies. Our findings suggest that glutamate/GABA abnormalities in the corticostriatal circuitry may be a key pathological mechanism in ASD; and may be linked to alterations in the neuroligin–neurexin signaling complex.
176 citations
References
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01 Jun 1991
12,618 citations
"Reward system dysfunction in autism..." refers methods in this paper
...In addition, parents evaluated the behaviour of their children with regard to psychopathology using the Child Behaviour Checklist (CBCL 4–18; Achenbach, 1991)....
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TL;DR: Results suggest the K-SADS-PL generates reliable and valid child psychiatric diagnoses.
Abstract: Objective To describe the psychometric properties of the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version (K-SADS-PL) interview, which surveys additional disorders not assessed in prior K-SADS, contains improved probes and anchor points, includes diagnosis-specific impairment ratings, generates DSM-III-R and DSM-IV diagnoses, and divides symptoms surveyed into a screening interview and five diagnostic supplements. Method Subjects were 55 psychiatric outpatients and 11 normal controls (aged 7 through 17 years). Both parents and children were used as informants. Concurrent validity of the screen criteria and the K-SADS-PL diagnoses was assessed against standard self-report scales. Interrater ( n = 15) and test-retest ( n = 20) reliability data were also collected (mean retest interval: 18 days; range: 2 to 38 days). Results Rating scale data support the concurrent validity of screens and K-SADS-PL diagnoses. Interrater agreement in scoring screens and diagnoses was high (range: 93% to 100%). Test-retest reliability κ coefficients were in the excellent range for present and/or lifetime diagnoses of major depression, any bipolar, generalized anxiety, conduct, and oppositional defiant disorder (.77 to 1.00) and in the good range for present diagnoses of posttraumatic stress disorder and attention-deficit hyperactivity disorder (.63 to .67). Conclusion Results suggest the K-SADS-PL generates reliable and valid child psychiatric diagnoses. J. Am. Acad. Child Adolesc. Psychiatry , 1997, 36(7): 980–988.
8,742 citations
"Reward system dysfunction in autism..." refers methods in this paper
...The TDC were recruited from local schools and underwent an extensive psychiatric examination using a standardized, semi-structured interview to assess current and past episodes of psychopathology according to DSM-IV criteria (K-SADS-PL; Kaufman et al., 1997)....
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...The TDC were recruited from local schools and underwent an extensive psychiatric examination using a standardized, semi-structured interview to assess current and past episodes of psychopathology according to DSM-IV criteria (K-SADS-PL; Kaufman et al., 1997)....
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TL;DR: The revised interview has been reorganized, shortened, modified to be appropriate for children with mental ages from about 18 months into adulthood and linked to ICD-10 and DSM-IV criteria.
Abstract: Describes the Autism Diagnostic Interview-Revised (ADI-R), a revision of the Autism Diagnostic Interview, a semistructured, investigator-based interview for caregivers of children and adults for whom autism or pervasive developmental disorders is a possible diagnosis. The revised interview has been reorganized, shortened, modified to be appropriate for children with mental ages from about 18 months into adulthood and linked to ICD-10 and DSM-IV criteria. Psychometric data are presented for a sample of preschool children.
8,264 citations
"Reward system dysfunction in autism..." refers methods in this paper
..., 2000) and the Autism Diagnostic Interview-Revised (ADI-R; Lord et al., 1994) conducted by a trained examiner (M....
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...Diagnoses were confirmed using the Autism Diagnostic Observation Schedule (ADOS-G; Lord et al., 2000) and the Autism Diagnostic Interview-Revised (ADI-R; Lord et al., 1994) conducted by a trained examiner (M.S.-R., I.K.-B.)....
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TL;DR: Algorithm sensitivities and specificities for autism and PD DNOS relative to nonspectrum disorders were excellent, with moderate differentiation of autism from PDDNOS.
Abstract: The Autism Diagnostic Observation Schedule-Generic (ADOS-G) is a semistructured, standardized assessment of social interaction, communication, play, and imaginative use of materials for individuals suspected of having autism spectrum disorders. The observational schedule consists of four 30-minute modules, each designed to be administered to different individuals according to their level of expressive language. Psychometric data are presented for 223 children and adults with Autistic Disorder (autism), Pervasive Developmental Disorder Not Otherwise Specified (PDDNOS) or nonspectrum diagnoses. Within each module, diagnostic groups were equivalent on expressive language level. Results indicate substantial interrater and test-retest reliability for individual items, excellent interrater reliability within domains and excellent internal consistency. Comparisons of means indicated consistent differentiation of autism and PDDNOS from nonspectrum individuals, with some, but less consistent, differentiation of autism from PDDNOS. A priori operationalization of DSM-IV/ICD-10 criteria, factor analyses, and ROC curves were used to generate diagnostic algorithms with thresholds set for autism and broader autism spectrum/PDD. Algorithm sensitivities and specificities for autism and PDDNOS relative to nonspectrum disorders were excellent, with moderate differentiation of autism from PDDNOS.
7,012 citations
"Reward system dysfunction in autism..." refers methods in this paper
...Diagnoses were confirmed using the Autism Diagnostic Observation Schedule (ADOS-G; Lord et al., 2000) and the Autism Diagnostic Interview-Revised (ADI-R; Lord et al....
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...Diagnoses were confirmed using the Autism Diagnostic Observation Schedule (ADOS-G; Lord et al., 2000) and the Autism Diagnostic Interview-Revised (ADI-R; Lord et al., 1994) conducted by a trained examiner (M.S.-R., I.K.-B.)....
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