Introduction
Orofacial clefts are the most common major birth defect in America, affecting over 6,800 births annually (Canfield et al.
2006). These oral clefts are developmental craniofacial abnormalities that result, at least in part, from a failure of neural crest cells to migrate properly. As a group, 70% of clefting disorders are comprised of those that are isolated to facial clefts only (non-syndromic), and 30% are those in which the facial cleft is part of a well-defined syndrome of additional anomalies (Jones
1988). Isolated oral clefts are further divided anatomically into clefts of the lip and/or palate (CLP) and clefts of the palate only (CPO).
In addition to the facial cleft, persons affected with isolated clefts of the lip and/or palate (ICLP) suffer from a constellation of other problems including persistent problems with speech (even after cleft repair), as well as cognitive and behavioral abnormalities. The cognitive deficits associated with ICLP are well documented and characterized with a lowering of overall intelligence quotient (IQ) (though not to mental retardation level) and specific deficits in language function (Richman and Eliason
2009; Richman and Eliason
2001). These deficits are severe enough that reading disabilities have been reported to be as common as 35% of children with ICLP (Richman et al.
1988; Broder et al.
1998).
In regard to behavior, an estimated 30% to 50% of children with ICLP experience at least some periods of behavioral abnormality (Richman and Millard
1997). Subjects with ICLP have been consistently shown to have increased internalizing behavior problems (social inhibition or shyness, depressed mood) (Endriga et al.
2003); however, very few studies have evaluated externalizing behaviors such as aggression, opposition, hyperactivity, impulsivity or inattention. A recent large study by Hunt et al. found that parent ratings of children with ICLP showed a significant increase in both internalizing and externalizing behaviors compared to children without ICLP (Hunt et al.
2007); however, the externalizing behaviors were not subdivided to isolate or characterize specific types.
The behavioral traits of hyperactivity/motor impulsivity, impulsivity/non-planning, and inattentiveness form a core dimension of personality that is heritable, emerges early in the course of development, and persists across developmental stages (McKay and Halperin
2001; Kochanska and Knaack
2003). Moreover, these behaviors can be elevated to pathological levels and are the hallmarks of the neuropsychiatric diagnosis of attention-deficit hyperactivity disorder (ADHD); however, they also occur at elevated levels (though often below diagnostic criteria for ADHD) in a multitude of developmental disorders.
In a previous study from our lab, we investigated the neural underpinnings of externalizing behaviors and found that in a sample of healthy normal boys (no psychiatric diagnosis including ADHD), the region of the brain that was directly related to behaviors of impulse control was the right ventromedial prefrontal cortex (vmPFC). Those boys with the highest ratings of hyperactivity and impulsivity had the lowest volumes of the right vmPFC (Boes et al.
2009). These findings are conceptualized as supporting the notion that the right vmPFC acts as a neuroanatomical correlate of impulse control in normal healthy boys, extending upon structure-function studies of pathologic samples with ADHD that have also highlighted the right vmPFC (Shaw et al.
2007a).
In an additional study from our lab, we have found that the structure of the brain in children with ICLP is substantially abnormal (Nopoulos et al.
2007). There are overall decrements in the size of the intracranial volume (ICV), and a proportional decrement in the frontal lobe, basal ganglia, and cerebellum after controlling for overall ICV. Moreover, there was a sex-specific finding in that for boys with ICLP, the cerebral cortex was proportionately enlarged compared to healthy boys—a tissue distribution abnormality.
Given the previous literature on elevated externalizing behavior in ICLP, our study of hyperactivity and impulsivity and its neuroanatomical correlate in healthy boys, and finally our study of brain structure in children with ICLP, the current study was designed to address the following questions: (1) Do boys with ICLP have elevations in hyperactivity/impulsivity/inattention (HII)? (2) Do boys with ICLP have structural abnormalities in the right vmPFC compared to healthy control boys? Finally, (3) what is the relationship between right vmPFC and HII in both healthy and ICLP boys?
Discussion
The current study finds that boys with ICLP have elevated levels of HII behaviors. Although externalizing behaviors have been documented as being elevated in ICLP children, no study to date has systematically evaluated HII behaviors in this population. One important exception is the study by Richman et al. that examined a sample of children with ICLP and diagnosed ADHD by an outside clinician (Richman et al.
2004). After careful examination to determine the accuracy of the ADHD diagnosis, they reported that many ICLP children that were diagnosed ADHD were actually misclassified and were manifesting learning disabilities instead.
The proportion of boys in our ICLP sample that carried a clinical diagnosis of ADHD (based on separate a assessment of local clinician) was five of 50 or 10%, somewhat higher than the ∼3–7% of all children in the general population (Richman et al.
2004); however, by ratings of parent and teacher’s assessment of HII behaviors, nine of 50 or 18% of the ICLP boys had clinically significant elevations of these behaviors. Even without consideration of what is deemed
clinically significant or pathologically elevated, as a whole, boys with ICLP exhibit these behaviors more frequently or to a greater degree than their peer counterparts.
The region of the brain thought to be a neuroanatomic correlate of these behaviors, the ventromedial prefrontal cortex (vmPFC) was structurally abnormal in the boys with ICLP. Compared to healthy boys, the vmPFC was proportionately enlarged. This is despite the finding in our previous work that the frontal lobe of children with ICLP is proportionately smaller. Therefore, it is important to emphasize that despite the overall smaller volume of the frontal lobe in ICLP (both white and gray matter), the right vmPFC, a subregion within the frontal cortex, is enlarged. It is thought that an important function of this cortical region is to identify the emotional salience of stimuli and use that information to assign values to possible behavioral outcomes (Bechara
2005; Bechara and Van Der Linden
2005). In the context of a neurocognitive theory of impulse control, the amygdala (the impulsive system) tags stimuli as having immediate pain or pleasure. This is then countered by the reflective system (the vmPFC) which weighs the long-term consequences of any given action. Thus, impulsive behavior may be due to imbalance of the system with the amygdala having overactive or stronger than normal input compared to the vmPFC. Future studies are required to evaluate these relationships in subjects with ICLP.
Although the left vmPFC was slightly enlarged as well, this did not reach statistical significance. This is consistent with some functional lesion studies that show in males where right unilateral damage to the vmPFC results in substantially more severe behavioral impairment in males compared to damage in the left vmPFC (Tranel et al.
2005). This suggests that for males, it is the right hemisphere that is more important in relationship to behaviors and behavioral impairments.
The fact that the ICLP boys show excess HII and structural abnormalities in the right vmPFC seems in line with what is seen in the healthy controls. While the fact that the cortex is enlarged rather than smaller than normal may at first seem counterintuitive, the phenomenon of excess cortical tissue in males with ICLP has been previously well documented in our previous work. This phenomenon is also seen in other neurodevelopmental disorders, including autism (Piven et al.
1996). Moreover, the positive correlation between HII scores and vmPFC morphology in ICLP boys (the greater the volume, the more abnormal the behavior) support the notion that this is indeed
pathological enlargement and not conceptualized as a compensatory mechanism of some type.
The spectrum of morphology of the vmPFC from abnormally small/thin to abnormally thick/large can be correlated with the same spectrum of severity of behavior. In ADHD, the vmPFC has been shown to be abnormally thin (Shaw et al.
2007b); however on the opposite side of the morphology spectrum, where the vmPFC is abnormally large (as in the current study), there are again higher levels of impulsivity. This relationship can be conceptualized as a U-shaped curve in which abnormally small or abnormally large volumes of vmPFC are correlated to pathologic elevations of HII, whereas intermediate volumes are associated with low levels of these types of behaviors. ICLP boys would thus be considered to not have the same pathoetiology of the typical ADHD, but instead a
phenocopy in which the behaviors are descriptively the same as that of ADHD, and the region of the brain sub-serving impulse control is affected, but clearly by an altogether different pathologic process. This same phenomenon is seen in the context of total brain volume in which both microcephaly and macrocephaly are associated with mental retardation—again, a U-shaped curve in the relationship between IQ and total brain size.
The current finding of pathological enlargement of cortex in ICLP boys is similar in some ways to a recent study of children with idiopathic epilepsy who, like the ICLP kids, also showed elevated rates of hyperactivity and inattention. Similar to the current study, they also found cortical thickening in association with these behaviors (Hermann et al.
2007); however the location was different—the dorsolateral prefrontal cortex (rather than the ventral prefrontal cortex) was enlarged in the children with epilepsy. Although ICLP and epilepsy both have elevated rates of hyperactivity and inattention, there is little else that is clinically similar between the two; however, they are both neurodevelopmental disorders. The children with idiopathic epilepsy example highlights the notion that developmental aberration
in general can lead to structural abnormalities in the brain (for example, cortical thickening) and can be manifested in symptoms of hyperactivity and inattention, presenting as a
phenocopy of ADHD.
The microstructure of the ICLP cortex is unknown, therefore the exact nature of the cortical enlargement is also unknown. Whether it be enlarged neurons, excess glia or neuropil, or excess dendrites, the end result suggests that whatever the mechanism, the functionality of this region is clearly compromised. Moreover, the connectivity of an abnormally structured region could also be impaired, a finding that future studies evaluating white matter integrity should focus on.
In sum, the current study identifies ICLP boys to have substantially elevated HII scores compared to a healthy comparison group. Moreoever, the quantitative measures of HII were directly related to the volume of the vmPFC, an area of the brain with an important role in these behaviors. Further studies will be needed to replicate and extend the findings in order to assess factors such as effects of clefting phenotype and whether these findings would also extend to females with ICLP.