Working Memory and Default Mode Network abnormalities in unaffected siblings of schizophrenia patients

Bohlken

Mandl

et al. 2016

Neuropsychopharmacol

Self Cite

Schizophrenia is associated with frontostriatal network impairments underlying clinical and cognitive symptoms. We previously found disruptions in anatomical pathways, including the tract connecting the left nucleus accumbens and left dorsolateral prefrontal cortex (DLPFC). Similar deficits are observed in unaffected siblings of schizophrenia patients, indicating that these deficits are linked to a genetic vulnerability for the disorder. Frontostriatal tract disruptions may arise during adolescence, preceding the clinical manifestation of the disorder. However, to date, no studies have been performed to investigate frontostriatal tract connections in adolescents who are at increased familial risk for schizophrenia. In this study, we investigate the impact of familial risk on frontostriatal tract connections using diffusion tensor imaging in 27 adolescent offspring of schizophrenia patients and 32 matched control adolescents, aged 10-18 years. Mean fractional anisotropy (FA) was calculated for the tracts connecting the striatum (caudate nucleus, putamen, nucleus accumbens) and frontal cortex regions (DLPFC, medial orbital frontal cortex, inferior frontal gyrus). As expected, based on siblings data, we found an impact of familial risk on frontostriatal development: schizophrenia offspring showed increased FA in the tracts connecting nucleus accumbens and DLPFC as compared with control adolescents. Moreover, while FA increased across age in control adolescents, it did not in schizophrenia offspring. We did not find differences in FA in other frontostriatal tracts. These results indicate altered development of white matter in subjects who are at familial risk for schizophrenia and may precede frontostriatal white matter alterations in adult schizophrenia patients and siblings.

Section: Introductionsupporting

confidence: 91%

Changes in White Matter Organization in Adolescent Offspring of Schizophrenia Patients

Bohlken

Mandl

et al. 2016

Neuropsychopharmacol

Self Cite

“…[18][19][20] However, reward experiments in siblings have never been performed, so it is unclear if behavioral deficits are to be expected. 2,33,82 Moreover, there have been various studies with other cognitive tasks showing brain activity abnormalities in siblings despite performance being equal to that of healthy participants. The task we used was relatively simple; more complex tasks may provoke behavioral deficits.…”

Section: Discussionmentioning

confidence: 99%

“…Impaired reward processing in siblings is anticipated given reports on fronto-striatal dysfunction during other cognitive functions such as inhibitory control, 2,9 emotion processing, 32 and working memory. 33,34 Here, we measured brain activity using fMRI during reward processing in 27 unaffected siblings of schizophrenia patients and 29 matched healthy controls. All subjects performed a modified monetary incentive delay task.…”

Section: Introductionmentioning

confidence: 99%

Fronto-striatal Dysfunction During Reward Processing in Unaffected Siblings of Schizophrenia Patients

Kahn

Vink

2014

Schizophrenia Bulletin

Schizophrenia is a psychiatric disorder that is associated with impaired functioning of the fronto-striatal network, in particular during reward processing. However, it is unclear whether this dysfunction is related to the illness itself or whether it reflects a genetic vulnerability to develop schizophrenia. Here, we examined reward processing in unaffected siblings of schizophrenia patients using functional magnetic resonance imaging. Brain activity was measured during reward anticipation and reward outcome in 27 unaffected siblings of schizophrenia patients and 29 healthy volunteers using a modified monetary incentive delay task. Task performance was manipulated online so that all subjects won the same amount of money. Despite equal performance, siblings showed reduced activation in the ventral striatum, insula, and supplementary motor area (SMA) during reward anticipation compared to controls. Decreased ventral striatal activation in siblings was correlated with sub-clinical negative symptoms. During the outcome of reward, siblings showed increased activation in the ventral striatum and orbitofrontal cortex compared to controls. Our finding of decreased activity in the ventral striatum during reward anticipation and increased activity in this region during receiving reward may indicate impaired cue processing in siblings. This is consistent with the notion of dopamine dysfunction typically associated with schizophrenia. Since unaffected siblings share on average 50% of their genes with their ill relatives, these deficits may be related to the genetic vulnerability for schizophrenia.

“…These siblings do not have the illness, but share on average 50% of their genes with their ill relative including schizophrenia-risk genes, 11,12 and have a 10-fold increased risk to develop schizophrenia. 13 Although unaffected siblings of schizophrenia patients do not have symptoms, they do show striatal activation deficits during reward anticipation, 14 working memory, 15 antisaccade eye movements, 5 and proactive response inhibition. 6,7 Here, we test for an association between the DRD2 rs2514218 polymorphism and striatal function using functional Magnetic resonance imaging (fMRI) in 45 unaffected siblings of schizophrenia patients.…”

Section: Introductionmentioning

confidence: 99%

DRD2 Schizophrenia-Risk Allele Is Associated With Impaired Striatal Functioning in Unaffected Siblings of Schizophrenia Patients

Vink

Luykx

et al. 2015

SCHBUL

Self Cite

A recent Genome-Wide Association Study showed that the rs2514218 single nucleotide polymorphism (SNP) in close proximity to dopamine receptor D2 is strongly associated with schizophrenia. Further, an in silico experiment showed that rs2514218 has a cis expression quantitative trait locus effect in the basal ganglia. To date, however, the functional consequence of this SNP is unknown. Here, we used functional Magnetic resonance imaging to investigate the impact of this risk allele on striatal activation during proactive and reactive response inhibition in 45 unaffected siblings of schizophrenia patients. We included siblings to circumvent the illness specific confounds affecting striatal functioning independent from gene effects. Behavioral analyses revealed no differences between the carriers (n = 21) and noncarriers (n = 24). Risk allele carriers showed a diminished striatal response to increasing proactive inhibitory control demands, whereas overall level of striatal activation in carriers was elevated compared to noncarriers. Finally, risk allele carriers showed a blunted striatal response during successful reactive inhibition compared to the noncarriers. These data are consistent with earlier reports showing similar deficits in schizophrenia patients, and point to a failure to flexibly engage the striatum in response to contextual cues. This is the first study to demonstrate an association between impaired striatal functioning and the rs2514218 polymorphism. We take our findings to indicate that striatal functioning is impaired in carriers of the DRD2 risk allele, likely due to dopamine dysregulation at the DRD2 location.