Abnormal interactions of verbal- and spatial-memory networks in young people at familial high-risk for schizophrenia
Introduction
Schizophrenia is a chronic and heritable mental disorder that is characterized by positive and negative symptoms and neurocognitive impairments (Bang et al., 2015). First-degree relatives (offspring and siblings) of patients with schizophrenia have an almost 10-fold increased risk of developing schizophrenia compared with the general population (Gottesman, 1994). Those first-degree relatives of the schizophrenia patients, who are still within the age range of risk for developing schizophrenia (ages from 13 to 30 defined in Li et al. (2007b))), are considered at heightened risk (FHR). From the literature, FHR subjects for developing schizophrenia have received increased attention in clinical and neuroimaging studies aimed at determining the underlying neurobiological vulnerability that leads to, and predict the onset of schizophrenia.
Clinical studies have suggested that in the FHR individuals, neurocognitive deficits, especially in the verbal- and spatial-working memory domains, exist prior the presentation of positive and negative symptoms, and can be used as strong predictors of schizophrenia (Pukrop and Klosterkotter, 2010, Dickson et al., 2014, Scala et al., 2014, Bang et al., 2015, Hou et al., 2016). Among these studies, Bang et al. found that behavioral performance scores of the tests for verbal- and spatial-working memory in the FHR subjects were intermediate between low risk controls and patients with first-episode schizophrenia (FES) (Bang et al., 2015). A Meta-analysis of 25 studies [published between January 1987 and February 2013, including clinical longitudinal data from 905 FES, 560 HR (including both clinical HR and FHR), and 405 healthy controls (HC)] suggested that verbal-memory deficits were already established in the HR subjects before the prodromal phase of psychosis, while no further decline occurred during follow-up assessments (Bora and Murray, 2014). In a new study, Dickson et al. also found verbal- and spatial memory deficits in the FHR subjects when compared to HC; whereas by adjusting statistical analyses for IQ, no significant between-group differences in any neurocognitive domains were remained (Dickson et al., 2014). The inconsistency among these existing neurobehavioral studies may be caused by the heterogeneity of the study samples, different tasks and assessment criteria being used, as well as other factors.
Although the etiology of schizophrenia is still unknown, neuroimaging studies have established that disturbed activities and connectivities in the functional brain networks for sensory and cognitive processing underlie neurocognitive deficits in patients with schizophrenia and the FHR population (Li et al., 2009, Li et al., 2010, Li et al., 2012). Several spatial-working memory tasked-based fMRI studies have reported that compared to HC, the FHR subjects had decreased activation in the dorsolateral prefrontal cortex (DLPFC) and the inferior parietal cortex (IPC) (Callicott et al., 2000, Keshavan et al., 2002). One early fMRI study reported that during a verbal-working memory task, the FHR subjects showed greater task-elicited activation in prefrontal cortex (PFC) and anterior cingulate cortex (ACC) (Thermenos et al., 2004). A recent resting-state electroencephalogram (EEG) study demonstrated that compared to HC, FES had increased theta-band resting-state connectivity across midline, sensorimotor, orbitofrontal regions and the left temporoparietal junction, whereas the FHR subjects displayed intermediate theta-band connectivity patterns that did not differ from either FES or HC. Mean theta-band connectivity within the above network partially mediated verbal-working memory deficits in FES and FHR (Andreou et al., 2015).
Of note, as two of the core features of cognitive impairment in schizophrenia, verbal- and spatial-working memory deficits are often observed together, instead of distinctively in the diagnosed patients and even early in the HR status (Scala et al., 2013). However, most of the existing neuroimaging studies investigated the neural mechanisms associated with only verbal- or only spatial working memory processing. Inconsistent results of these studies (partly briefly review in last paragraph) can from sample differences and lack of understanding on interactions of the brain regions for processing verbal- and spatial-working memory. The current study proposed to investigate the pattern of interactions between the verbal- and spatial-working memory processing networks in the FHR population, and its differences from that in a well-match sample of low risk controls.
Section snippets
Participants
A total of 75 young adults were involved in this study. The 43 non-psychotic FHR subjects had at least one other first-degree relative with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder, and at least one 1st, 2nd or 3rd degree relative with a history of psychosis, suicide, psychiatric hospitalization or Axis I disorder. The 32 controls had no family history of a psychosis in 1st, 2nd or 3rd degree relatives. The two diagnostic groups were matched in age, gender, ethnicity and
Results
Analyses of the demographic and cognitive data showed no significant between-group differences. All subjects finished the task during fMRI acquisition with 80% or higher accuracies. Table 1 depicts the details of the demographic, cognitive and behavioral data analyses.
The fMRI data analysis showed that during the verbal-memory condition, the control group had significantly more activated brain regions in left inferior frontal gyrus (p = 0.01, Z = 3.34, local maximum MNI coordinates = [− 40, 26, 10],
Discussion
During performance of a visual verbal- and spatial-working memory task, the group of FHR for developing schizophrenia exhibited significantly decreased functional activities in left inferior frontal and left precentral gyrus during verbal-working memory processing, compared to the low-risk control group. The language information processing related laterality index in the inferior frontal lobe (BA 44/45) showed deceased left-higher-than-right pattern in the HR group. Analyses of the interactions
Conflict of interests
All authors reported no actual and potential conflict of interests.
Contributors
Xiaobo Li designed the neuroimaging data analysis pipeline, analyzed the neuroimaging data, managed the literature searches, and wrote the draft of the manuscript.
Heidi Thermenos designed and oversaw the MRI data collection.
Ziyan Wu and Kai Wu contributed to the neuroimaging data and statistical analyses.
Yoko Nomura contributed to data interpretations.
Lynn Delisi provided the design and overall leadership for coordination of this project.
Drs. Seidman and Keshavan worked with Dr. DeLisi to
Acknowledgement
None.
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