The main goal of this study was to replicate and extend our prior unexpected finding of early frontal and temporal GM deficits in COS siblings that “normalized” by late adolescence. A nonoverlapping sample of nonpsychotic sibling scans and of matched controls again showed early cortical GM deficits that normalizeby age 17 years. When the two samples were combined, the consistency was striking, as shown in the supplementary movie (Video S1, available online). Both groups showed cortical thinning, with healthy controls having a higher rate (steeper slope) of gray matter loss during adolescence. Compared with controls, nonpsychotic siblings appeared to normalize GM at an annual rate of 3% to 5%, depending on region. This suggests that prefrontal and temporal cortical deficits in schizophrenia are age-specific familal/genetic trait markers.
Whether the cortical GM deficits in schizophrenia represent familial/genetic trait markers has remained an unsettled issue. Recent studies of the first-degree relative studies appear to point against such evidence and fail to show any focal cortical GM deficits in siblings/relatives/cotwins, thus arguing against the trait status of the deficits.14,33,34
In addition, studies of ultra-high risk subjects support the idea that cortical volume loss in schizophrenia is illness related,35,36
as brain deficits were not found in subjects who did not convert to psychosis. Furthermore, reductions in GM volume have been related to duration of untreated psychosis37
and duration of psychotic illness,38
bolstering support for GM loss being reflective of disease state.
Interestingly, the GM deficits appear to normalize around the same age at which GM deficits in probands become circumscribed to prefrontal and temporal regions. The normalization of GM deficits in nonpsychotic siblings could then be viewed as a parallel to the overall developmental process in probands, as they display early prefrontal and temporal GM deficits with earlier normalization. Adolescence appears to be a critical time of plasticity, as reflected by the relative restoration of prefrontal/temporal cortical thinning in siblings.
The mechanism by which cortical normalization occurs and its implications are unclear, although they clearly reflect plasticity of the brain both in schizophrenia as well as in nonpsychotic siblings and during adolescence. Prior in vitro and in vivo studies have shown significant alterations in prefrontal cortex synaptic plasticity induction with schizophrenia,39,40
and neurodevelopmental animal models suggest that the illness is associated with abnormal synaptic plasticity.39,41,42
By changing synaptic plasticity and reorganizing neuronal inputs/outputs,43
one could, in theory, alter the balance of information processing and avoid onset of psychotic illness, a process that is probably more efficient in healthy siblings.
The normalization could have functional advantage. Higher intelligence is associated with a delayed trajectory of frontal cortical development,44,45
and a positive correlation exists between cortical thickness and intelligence from late childhood onward.44
Recently, Hartberg et al. investigated the relationship between cortical thickness and cognitive performance in 67 patients with schizophrenia and 69 healthy controls, and found a similar relationships between prefrontal cortical thickness and verbal abilities and executive functioning.46
It is expected that the process of GM normalization in nonpsychotic siblings could theoretically modulate the preservation and enhancement of cognitive and language abilities.
Overall, there is a dearth in the literature on cognitive deficits in siblings of early-onset probands. Our comparison of neurocognitive measures (Trail Making Tests A and B and the Weschler Intelligence Scale–Revised Digit Span and Vocabulary) in 24 siblings and 67 parents of COS probands matched with 114 community controls revealed that COS siblings had significantly poorer performance and subtle deficits involving oculomotor/psychomotor speed than did community controls.47
However, the average age of the siblings examined was 19.3 years (standard deviation [SD] 7.0 years), which is past the age in which structural GM deficits would occur. Previous work has established that subtle cognitive deficits including abnormalities of attention, verbal memory, and executive functioning are seen in healthy relatives of patients with AOS.48,49
Our structural findings would support the notion that not only do cognitive deficits exist in nonpsychotic siblings but these deficits are potentially more severe at earlier ages. We are currently expanding our neuropsychological battery on the sibling sample as well as use multimodal imaging to gain insights into specific neurocircuitries.
In the same light, although the structural brain abnormalities normalize in nonpsychotic siblings, it is possible that they have long-term functional abnormalities. A recent systematic review of functional magnetic resonance imaging (fMRI) studies in nonpsychotic relatives of schizophrenic patients found consistent increases in activation in the right ventral prefrontal cortex and right parietal cortex.50
Similarly, a handful of studies examining white matter deficiencies in nonpsychotic siblings of schizophrenia patients found decreased fractional anisotropy in a variety of areas including left inferior frontal gyrus as well as in multiple regions of the cingulate WM bilaterally and in angular gyral WM bilaterally.51,52
Further longitudinal studies are needed to address whether more subtle disruptions of neural connectivity are indeed present in both childhood and adolescence in nonpsychotic siblings.
This study had a number of limitations. A total of 35 nonpsychotic siblings were less than 20 years of age and not past the age risk for schizophrenia and/or spectrum disorders, and in theory could develop these conditions as adults, although the use of stringent inclusionary criteria makes this unlikely. Second, a small percentage of siblings had three or more scans, making our study only partially longitudinal and potentially susceptible to cohort effects. In addition, older siblings were less likely to have follow-up scans compared with younger siblings. Ideally, it would be nice to see the same subjects from early ages through late adolescence, thus requiring more than 10 years of follow-up. Consequently, restrictions in study power and missing data could have affected the distribution and magnitude of cortical thickness differences between the two groups. For example, our study finding of linear rather than quadratic neuroanatomic GM changes over the specified age range might be due to limited power. Further attention and reanalysis using larger samples is clearly warranted to further characterize cortical development over time. Third, we were not able to match healthy controls to nonpsychotic siblings in a 2:1 fashion for the Hispanic/Other ethnic groups. As a result, these subgroups may have been overrepresented in our sibling sample. Finally, some siblings had a lifetime history of comorbid Axis I diagnoses, which theoretically could affect their cortical brain development. This was reflected in our analysis of the subgroup of nonpsychotic siblings with depressive disorders in which adjustments for multiple comparisons failed to localize deficits at the prefrontal and temporal cortices. Collectively, these results should be interpreted with caution, given the limitations of power and sample size.
In conclusion, we replicate findings from our previous studies showing nonpsychotic siblings of COS probands to have early GM structural deficits that ameliorate with time. Although the intimate mechanisms of this normalization are yet to be defined, continued exploration of this process could lead to identification of a potential intermediate phenotype and a future target for genetic studies and for treatment.