Abnormal Brain Connectivity in Children After Early Severe Socioemotional Deprivation: A Diffusion Tensor Imaging Study

Eluvathingal, Thomas J.; Chugani, Harry T.; Behen, Michael E.; Juhász, Csaba; Muzik, Otto; Maqbool, Mohsin; Chugani, Diane C.; Makki, Malek

doi:10.1542/peds.2005-1727

Cited by 395 publications

(322 citation statements)

References 29 publications

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“…The aforementioned observations of a specific role of the UF in those cognitive and emotional domains altered in autism, its function as main limbic connection between frontal and temporal territories, and its modulation by environmental stimuli such as social deprivation (Eluvathingal et al 2006) seem to be consistent with our observations. UF mean FA could thus potentially represent a sensitive MRI marker of treatment-related white matter architectural modifications; future studies are needed to verify this hypothesis.…”

Section: Discussionsupporting

confidence: 92%

“…Moreover, severe socio-emotional deprivation has been shown to impact UF maturation and to be correlated with reduced uncinate fasciculus mean FA values (Eluvathingal et al 2006). Lastly, UF maturation has been linked with the acquisition of verbal language in DTI studies (Mabbott et al 2009) and it is thought to play a significant role in emotion expression (Schmahmann et al 2008).…”

Section: Discussionmentioning

confidence: 99%

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Long-term Cognitive and Behavioral Therapies, Combined with Augmentative Communication, are Related to Uncinate Fasciculus Integrity in Autism

Pardini

Elia

Garaci

et al. 2011

J Autism Dev Disord

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Recent evidence points to white-matter abnormalities as a key factor in autism physiopathology. Using Diffusion Tensor Imaging, we studied white-matter structural properties in a convenience sample of twenty-two subjects with low-functioning autism exposed to long-term augmentative and alternative communication, combined with sessions of cognitive and behavioral therapy. Uncinate fasciculus structural properties correlated significantly with therapy length and early onset, as well as to clinical outcome, independently from IQ, age or symptoms severity at therapy onset. Moreover, adherence to therapy was linked with better clinical outcome and uncinate fasciculus structural integrity. The results point to the capability of a long-term rehabilitation of subjects with low-functioning autism to produce white-matter structural modifications, which could thus play a role in the rehabilitative outcome.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Long-term Cognitive and Behavioral Therapies, Combined with Augmentative Communication, are Related to Uncinate Fasciculus Integrity in Autism

Pardini

Elia

Garaci

et al. 2011

J Autism Dev Disord

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“…Chronic stress increases dendritic arborization of the amygdala and decreases arborization of the PFC in male rats, but there are few such studies in female rats (49,51). In humans, structural connectivity between the vmPFC and amygdala/hippocampus is reduced in children who have suffered early neglect/maltreatment (52,53), but whether there are sex differences in the effects of stress on these white matter tracts remains unclear. Ultimately, more studies exploring developmental sex differences in the sensitivity of these brain regions and their connecting fibers to stress will be needed in humans as well as in animal models.…”

Section: Discussionmentioning

confidence: 99%

Childhood maltreatment is associated with altered fear circuitry and increased internalizing symptoms by late adolescence

Herringa

Birn

Ruttle

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

354

314

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Maltreatment during childhood is a major risk factor for anxiety and depression, which are major public health problems. However, the underlying brain mechanism linking maltreatment and internalizing disorders remains poorly understood. Maltreatment may alter the activation of fear circuitry, but little is known about its impact on the connectivity of this circuitry in adolescence and whether such brain changes actually lead to internalizing symptoms. We examined the associations between experiences of maltreatment during childhood, resting-state functional brain connectivity (rs-FC) of the amygdala and hippocampus, and internalizing symptoms in 64 adolescents participating in a longitudinal community study. Childhood experiences of maltreatment were associated with lower hippocampus-subgenual cingulate rs-FC in both adolescent females and males and lower amygdalasubgenual cingulate rs-FC in females only. Furthermore, rs-FC mediated the association of maltreatment during childhood with adolescent internalizing symptoms. Thus, maltreatment in childhood, even at the lower severity levels found in a community sample, may alter the regulatory capacity of the brain's fear circuit, leading to increased internalizing symptoms by late adolescence. These findings highlight the importance of fronto-hippocampal connectivity for both sexes in internalizing symptoms following maltreatment in childhood. Furthermore, the impact of maltreatment during childhood on both fronto-amygdala and -hippocampal connectivity in females may help explain their higher risk for internalizing disorders such as anxiety and depression.child maltreatment | sex differences | ventromedial prefrontal cortex I n both clinical and community samples, maltreatment during childhood represents one of the strongest risk factors for developing depression and anxiety (1-3). Childhood maltreatment and other adversities account for up to a third of the risk for mood and anxiety disorders (4). Further, depression and anxiety disorders are major public health problems, affecting 15 and 32% of youth, respectively, by the age of 18 y (5). The burden of these disorders is significant, representing the second and fifth leading causes, respectively, of years lived with disability in the United States (6). Some evidence suggests that maltreatment may impart greater risk for the development of internalizing symptoms in females than in males (e.g., refs. 7-9). This differential risk could account, in part, for the higher incidence of internalizing problems in females than in males (10, 11). However, the neurobiological pathways from maltreatment during childhood to the expression of internalizing problems, including potential differences for females and males, remain poorly understood. Such information is crucial for improving the treatment of depression and anxiety disorders and for mitigating the effects of maltreatment during childhood.Both maltreatment during childhood (12) and internalizing disorders (13, 14) have been associated with altered activity in specific b...

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“…Adverse events during early life are risk factors for the psychopathology and myelin development. 73,74 This also suggests that there are several critical periods during which environmental risk factors could impact the normal development of myelin. Indeed, transient changes in GSH levels induced by environmental insults during pre-, peri-and postnatal periods may have an impact on oligodendrocyte maturation, consequently affecting later structural connectivity.…”

Section: Discussionmentioning

confidence: 99%

Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients

et al. 2014

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Schizophrenia pathophysiology implies both abnormal redox control and dysconnectivity of the prefrontal cortex, partly related to oligodendrocyte and myelin impairments. As oligodendrocytes are highly vulnerable to altered redox state, we investigated the interplay between glutathione and myelin. In control subjects, multimodal brain imaging revealed a positive association between medial prefrontal glutathione levels and both white matter integrity and resting-state functional connectivity along the cingulum bundle. In early psychosis patients, only white matter integrity was correlated with glutathione levels. On the other side, in the prefrontal cortex of peripubertal mice with genetically impaired glutathione synthesis, mature oligodendrocyte numbers, as well as myelin markers, were decreased. At the molecular levels, under glutathione-deficit conditions induced by short hairpin RNA targeting the key glutathione synthesis enzyme, oligodendrocyte progenitors showed a decreased proliferation mediated by an upregulation of Fyn kinase activity, reversed by either the antioxidant N-acetylcysteine or Fyn kinase inhibitors. In addition, oligodendrocyte maturation was impaired. Interestingly, the regulation of Fyn mRNA and protein expression was also impaired in fibroblasts of patients deficient in glutathione synthesis. Thus, glutathione and redox regulation have a critical role in myelination processes and white matter maturation in the prefrontal cortex of rodent and human, a mechanism potentially disrupted in schizophrenia.

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Abnormal Brain Connectivity in Children After Early Severe Socioemotional Deprivation: A Diffusion Tensor Imaging Study

Abstract: Our study demonstrates in children who experienced socioemotional deprivation a structural change in the left uncinate fasciculus that partly may underlie the cognitive, socioemotional, and behavioral difficulties that commonly are observed in these children.

Cited by 395 publications

References 29 publications

Long-term Cognitive and Behavioral Therapies, Combined with Augmentative Communication, are Related to Uncinate Fasciculus Integrity in Autism

Long-term Cognitive and Behavioral Therapies, Combined with Augmentative Communication, are Related to Uncinate Fasciculus Integrity in Autism

Childhood maltreatment is associated with altered fear circuitry and increased internalizing symptoms by late adolescence

Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients

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