Family Matters: imaging the vulnerability for schizophrenia

Abstract

Schizophrenia is a highly heritable psychiatric disorder that is characterized by impairments in the fronto-striatal network underlying cognitive deficits. Subjects who are at increased familial risk such as siblings and offspring of schizophrenia patients, also show cognitive impairments intermediate between patients and controls although these relatives are not (yet) ill. This may very well indicate fronto-striatal network dysfunction in these relatives in the absence of the illness. Therefore, the aim of this thesis is to present data on fronto-striatal network function in first-degree relatives. First, fronto-striatal network function in unaffected siblings of schizophrenia patients was investigated. Siblings share on average 50% of their genes with their ill relative, allowing the investigating of genetic vulnerability for schizophrenia in adult state. To measure fronto-striatal function in siblings, a working memory task and a reward task were used during functional MRI scanning. Activation in siblings was compared to that of matched healthy controls. Importantly, task-performance was matched across group in order to eliminate cognitive impairements in siblings from confounding the imaging results. Siblings show fronto-striatal impairements during both tasks. The results during working memory suggest that siblings fail to deactivate the default mode network. Fronto-striatal network abnormalities during reward processing may indicate impaired cue processing. Both results may reflect abnormalities in dopamine transmission in siblings. In addition to measuring task related activation, fronto-striatal white-matters tracts were investigated using DTI in schizophrenia patients and siblings as compared to healthy controls. Patients as well as unaffected siblings showed reduced fractional anisotropy in the tract connecting the left nucleus accumbens and left dorsolateral prefrontal cortex (DLPFC) and this may indicate decreased white matter integrity. Given the notion that abovementioned findings suggest dopamine dysfunction in schizophrenia (siblings), the impact of the strongest dopamine receptor D2 (DRD2) schizophrenia-associated polymorphism to date (rs2514218) on striatal activation in siblings was explored, using a stop-signal anticipation task. The findings presented indicate striatal dysfunction during contextual cue-processing to be the functional consequence of carrying the schizophrenia risk allele. Finally, fronto-striatal network dysfunction in adolescent offspring of schizophrenia patients were tested, thereby unravelling the impact of genetic vulnerability on fronto-striatal network development. Activation during working memory in the ventral striatum declined across age in schizophrenia offspring. In addition to functional measurements, fronto-striatal white-matter tracts were investigated in schizophrenia offspring and control adolescents. In schizophrenia offspring, mean fractional anisotropy did not increase across age in the tract that is affected in siblings and patients, i.e. the tract connecting the left nucleus accumbens and left DLPFC. This result may suggest stagnated white matter fiber maturation possibly as a result of genetic vulnerability for schizophrenia. Both functional and structural results in offspring of schizophrenia patients are consistent with the notion that genetic factors, in combination with environmental factors, may be at the base of fronto-striatal deficits.