The study’s findings demonstrate that thought disorder in the CPS group was related to reduced OFG and IFG gray matter volumes, increased HG gray matter volumes, smaller white matter DLPFC volumes, and increased temporal lobe white matter volumes, above and beyond the effects of seizure variables. These findings suggest that thought disorder might reflect the neuropathology underlying CPS. However, the association of age at onset, history of prolonged seizures, and left focal EEG findings with both thought disorder [1
] and OFG, IFG, and temporal lobe volumes [7
] also implies a seizure-related developmental vulnerability of both these higher-level linguistic skills and the associated brain regions in children with CPS. Supporting this conclusion, Ben Ari and Holmes [32
] hypothesize that in the young animal, recurrent seizures might affect the ongoing construction of cortical networks or lead to displaced cells and migration disorders.
In contrast, thought disorder in young normal children during middle childhood and prepuberty [4
] and its association with increased OFG and STG gray matter volumes but reduced HG white matter volumes might reflect a delay in the normal age-related decrease [9
] in gray matter density and volumes and increase in white matter volumes in brain regions associated with language. The process of gray matter loss begins first in dorsal parietal cortices, particularly the primary sensorimotor areas near the inter-hemispheric margin, and then spreads rostrally over the frontal cortex and caudally and laterally over the parietal, occipital, and, finally, temporal cortex, particularly the posterior superior temporal gyrus [8
]. This process is thought to reflect synaptic pruning together with trophic glial and vascular changes and/or cell shrinkage [8
In parallel, children’s higher-level linguistic and discourse skills begin in the toddler period, undergo accelerated maturation during middle childhood, and continue to mature through the teenage years [see review in 33
]. Thus, younger normal children have thought disorder compared with older normal children. They are illogical, make topic changes without preparing the listener for the topic change, use a narrow range of linguistic devices to connect ideas across sentences and to make reference to people, objects, or events, and also underuse linguistic devices to monitor and clarify communication breakdowns that occur while they speak.
The developmental implications of our findings are also supported by evidence that HG with its central role in processing speech, language, and rapid acoustic changes [34
] has the highest concentration of white matter compared with other temporal lobe subregions [35
]. Thus, reduced HG white matter volumes in the control subjects with impaired use of revision but increased HG gray matter volumes in the CPS subjects with impaired cohesion, repair, and revision might represent abnormalities in the parallel processes of increased myelination and decreased gray matter volumes that occur with age [8
Interestingly, different brain regions were associated with the individual thought disorder components in the subjects with CPS compared with the control subjects. However, in both the CPS and control groups, the frontotemporal network involved in how children organize, monitor, and repair the coherence of their speech includes brain regions participating in language [36
], the integration of linguistic function with semantic knowledge [39
], and executive functions [40
]. The consistent relationship of thought disorder with the OFG supports recent findings in schizophrenic adults whose thought disorder was associated with smaller left middle orbital frontal gyrus volumes [14
]. It is also possible that the OFG findings reflect inclusion of Brodmann area (BA) 47, which contributes to semantic processing and control of semantic information [36
], in the lateral boundaries of OFG. We defined the OFG as the cortex inferior to the frontal marginal sulcus, inferior and anterior to the lateral orbital sulcus, and lateral to the olfactory sulcus. The circular insular sulcus served as the most posterior boundary of the OFG [22
Of relevance to epilepsy, the lateral OFG is also vulnerable to the propagation of mesial temporal seizures from the epileptogenic region to distant areas mediated by fiber tracts connecting the mesial temporal structures with ipsilateral lateral temporal, via the subicular cortex, the enthorhinal cortex, and perirhinal/parahippocampal cortices [17
]. Thus, as suggested by our secondary analysis findings in the subjects with left CPS, the association of reduced OFG volumes with thought disorder might also represent effects of seizure propagation. The relationship of increased gray matter OFG volumes to thought disorder in the subjects with right CPS, similar to that in the control children with thought disorder, implies that the thought disorder of children with left and right CPS might involve different processes.
Formal thought disorder, which involves abnormal use of language to formulate, organize, and process thoughts, was related to DLPFC volumes. Yet, underuse of cohesion and repair, more basic linguistic functions, was associated with IFG, STG, HG, and temporal lobe volumes. These findings can be understood in light of the role of the DLPFC in executive functions [see review in 40
] and thought disorder [41
], whereas the STG and HG are implicated in semantics, syntax, phonology, and sentence processing [see review in 38
]. As children with CPS have deficits in both executive [42
] and basic linguistic [43
] functions, we are currently studying how impaired executive function and language might mediate the impact of pediatric CPS on both thought disorder and frontotemporal volumes.
Study limitations include multiple, albeit hypothesis-driven statistical comparisons, retrospective rather than current EEG data, the relatively small sample size, particularly of children with right CPS, and the cross-sectional design of the study. Nevertheless, the findings suggest that thought disorder might represent a developmental disability involving decreased frontotemporal volumes of brain regions involved in language in pediatric CPS. They also add to the growing evidence of smaller IFG and OFG gray matter volumes in children with temporal lobe epilepsy with impaired executive function [44
], reduced left posterior hemisphere gray matter volumes with poor academic performance in new-onset pediatric epilepsy [45
], lower language and IQ scores in children with new-onset epilepsy with MRI evidence of structural abnormalities [46
], and widespread decreased gray matter density that includes the left and right superior temporal gyrus in intractable pediatric temporal lobe epilepsy [47