Executive function and genetic predisposition to schizophrenia—the Maudsley family study

Birkett, Paul; Sigmundsson, Thordur; Sharma, Tonmoy; Toulopoulou, Timothea; Griffiths, Timothy D.; Reveley, Adrianne; Murray, Robin M.

doi:10.1002/ajmg.b.30594

Cited by 48 publications

(40 citation statements)

References 42 publications

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“…This notion is further supported by the detected association between network flexibility and WCST perseveration score in the patients. The WCST taps into a cognitive domain (cognitive set shifting or flexibility) that may plausibly relate to the quantified dynamic network flexibility measure and has previously been related to the genetic predisposition to schizophrenia (32).…”

Section: Discussionmentioning

confidence: 99%

Dynamic brain network reconfiguration as a potential schizophrenia genetic risk mechanism modulated by NMDA receptor function

Braun

Schäfer

Bassett

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

186

187

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Schizophrenia is increasingly recognized as a disorder of distributed neural dynamics, but the molecular and genetic contributions are poorly understood. Recent work highlights a role for altered N-methyl-D-aspartate (NMDA) receptor signaling and related impairments in the excitation-inhibitory balance and synchrony of large-scale neural networks. Here, we combined a pharmacological intervention with novel techniques from dynamic network neuroscience applied to functional magnetic resonance imaging (fMRI) to identify alterations in the dynamic reconfiguration of brain networks related to schizophrenia genetic risk and NMDA receptor hypofunction. We quantified "network flexibility," a measure of the dynamic reconfiguration of the community structure of time-variant brain networks during working memory performance. Comparing 28 patients with schizophrenia, 37 unaffected first-degree relatives, and 139 healthy controls, we detected significant differences in network flexibility [F(2,196) = 6.541, P = 0.002] in a pattern consistent with the assumed genetic risk load of the groups (highest for patients, intermediate for relatives, and lowest for controls). In an observer-blinded, placebo-controlled, randomized, cross-over pharmacological challenge study in 37 healthy controls, we further detected a significant increase in network flexibility as a result of NMDA receptor antagonism with 120 mg dextromethorphan [F(1,34) = 5.291, P = 0.028]. Our results identify a potential dynamic network intermediate phenotype related to the genetic liability for schizophrenia that manifests as altered reconfiguration of brain networks during working memory. The phenotype appears to be influenced by NMDA receptor antagonism, consistent with a critical role for glutamate in the temporal coordination of neural networks and the pathophysiology of schizophrenia. S chizophrenia is a highly heritable mental disorder for which aberrant interactions between brain regions or "dysconnectivity" have been proposed as a core neural mechanism (1). Functional magnetic resonance imaging (fMRI) studies demonstrate alterations in specific neural subcircuits in schizophrenia (2, 3) that are under genetic control (4), although recent data from network neuroscience point to more widespread disturbances in the dynamics of large-scale brain networks (5, 6). Uhlhaas (5), Uhlhaas and Singer (6), and Phillips and Silverstein (7) have proposed a plausible pathophysiological mechanism for these phenomena: They argue that alterations in the cellular excitation-inhibitory balance may lead to disturbances in the neural synchrony of large-scale cell ensembles and give rise to the dysconnectivity phenomena at the level of neural ensembles.The neural excitation-inhibitory balance is highly dependent on glutamatergic N-methyl-D-aspartate (NMDA) receptor function (8), and alterations in NMDA receptor signaling have been associated with schizophrenia risk (9), disorder-related cognitive abnormalities (10, 11), and deficits in the temporal coordination of large-scale bra...

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Section: Discussionmentioning

confidence: 99%

Dynamic brain network reconfiguration as a potential schizophrenia genetic risk mechanism modulated by NMDA receptor function

Braun

Schäfer

Bassett

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

186

187

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“…Memory function was found to be impaired in bipolar patients and their relatives [20,83,128] and in schizophrenic patients as well [71,91,131]. Moreover, working memory and executive functions have been claimed to be promising endophenotypes through which early signs of psychotic disease can be detected [12,16]. Finally, the conditioning events related to the activation of the amygdala have been associated with psychiatric disorders in a consistent number of reports (reviewed in Quirk and Gehlert [127]).…”

Section: Implications For Psychiatric Disordersmentioning

confidence: 95%

HTR1B as a risk profile maker in psychiatric disorders: a review through motivation and memory

Drago

Alboni

Brunello

et al. 2009

Eur J Clin Pharmacol

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Purpose Serotonin receptor 1B (HTR1B) is involved in the regulation of the serotonin system, playing different roles in specific areas of the brain. We review the characteristics of the gene coding for HTR1B, its product and the functional role of HTR1B in the neural networks involved in motivation and memory; the central role played by HTR1B in these functions is thoroughly depicted and show HTR1B to be a candidate modulator of the mnemonic and motivationally related symptoms in psychiatric illnesses. Methods In order to challenge this assessment, we analyze how and how much the genetic variations located in the gene that codes for HTR1B impacts on the psychiatric phenotypes by reviewing the literature on this topic. Results We gathered partial evidence arising from genetic association studies, which suggests that HTR1B plays a relevant role in substance-related and obsessive compulsive disorders. On the other hand, no solid evidence for other psychiatric disorders was found. This finding is quite striking because of the heavy impairment of motivation and of mnemonic-related functions (for example, recall bias) that characterize major psychiatric disorders. Conclusions The possible reasons for the contrast between the prime relevance of HTR1B in regulating memory and motivation and the limited evidence brought by genetic association studies in humans are discussed, and some suggestions for possible future directions are provided.

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“…25 It needs to be noted that the sample sizes of these 2 studies were small (about 30-50 subjects in each type of families); particularly, the number of controls that were used for the standardization of z score was relatively small (40 and 100, respectively, vs 440 in this study). Furthermore, the administration of the WCST in Birkett et al 25 was different from conventional way in that the examiners told the subject when the matching principle changed. Whether this change of test administration of the WCST helps increase the discrimination of simplex relatives from normal comparisons needs further investigation.…”

Section: Discussionmentioning

confidence: 84%

“…24 In the 2 studies that examined nonpsychotic relatives of familial vs nonfamilial schizophrenia on WCST performance, one failed to show any deficits in both groups of relatives, 21 whereas the other one reported deficits on 2 scores for familial relatives as well as 1 score for nonfamilial relatives. 25 However, the numbers of families in these 2 studies were small.…”

Section: Introductionmentioning

confidence: 94%

Performance on the Wisconsin Card Sorting Test in Families of Schizophrenia Patients With Different Familial Loadings

Lin

Liu

Hwang

et al. 2011

Schizophrenia Bulletin

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Despite the consistent presence of performance deficits on the Wisconsin Card Sorting Test (WCST) in schizophrenia patients, whether poorer performance is also present in their nonpsychotic relatives is not certain. This study aimed to estimate both the recurrence risk ratio (λs) and the heritability of WCST scores in simplex and multiplex families, respectively, and to examine the influence of familial loading on these estimates. Participants were patients with schizophrenia and their nonpsychotic first-degree relatives from 168 simplex families and 653 multiplex families as well as 440 normal comparisons. On the basis of adjusted z scores, both the λs at a series of cutoff points and heritability estimates based on variance component modeling in the nonpsychotic relatives of schizophrenia patients were estimated. The WCST deficits in schizophrenia patients were more prominent in multiplex families than in simplex ones. Among relatives, WCST deficits were limited to parents of multiplex families for most WCST scores and siblings from multiplex families for total errors, perseverative responses, and perseverative errors. Pertaining to λs, the estimates for multiplex families (highest estimates ranging from 7.9 to 11.0) were greater than those for simplex ones (<2.5). Nevertheless, the heritability estimates were very similar between simplex (ranging from 0% to 17%) and multiplex (ranging from 0% to 21%) families, with the latter having slightly greater values than the former. There is only a small-to-modest familial aggregation on part of WCST scores in families of schizophrenia patients, and this may limit its use as endophenotypic markers to schizophrenia susceptibility.

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Executive function and genetic predisposition to schizophrenia—the Maudsley family study

Cited by 48 publications

References 42 publications

Dynamic brain network reconfiguration as a potential schizophrenia genetic risk mechanism modulated by NMDA receptor function

Dynamic brain network reconfiguration as a potential schizophrenia genetic risk mechanism modulated by NMDA receptor function

HTR1B as a risk profile maker in psychiatric disorders: a review through motivation and memory

Performance on the Wisconsin Card Sorting Test in Families of Schizophrenia Patients With Different Familial Loadings

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