Altered patterns of brain activity during transient sadness in children at familial risk for major depression.

INTRODUCTION: We used functional magnetic resonance imaging (fMRI) to investigate the neural correlates of sadness, the prevailing mood in major depression (MD), in a prospective, well-documented community sample followed since birth. METHODS: The children, comprising 136 children (65 boys and 71 girls) of mothers with varying levels of depressive symptomatology, were scanned - using a 1.5-Tesla system - while they watched 5 blocks of both sad and neutral film excerpts. Following scanning, they rated the emotions they experienced, and if they identified sadness, they were also asked to rate its intensity. RESULTS: In children whose mothers exhibited higher depressive symptomatology, compared to children whose mothers displayed lower depressive symptomatology, altered neural responses to sad film excerpts were noted in brain regions known to be involved in sadness and MD, notably the insula, anterior cingulate cortex and caudate nucleus, even though the children did not differ in current mood. LIMITATIONS: Whether this represents genetic vulnerability or a consequence of exposure to maternal depressive symptoms at a young age is unknown. DISCUSSION: The results are consistent with the results of studies in healthy adults and MD patients. The present study suggests that an altered pattern of regional brain responses to sad stimuli, is already present in childhood and might represent vulnerability for MD later in life.

Early influence of the rs4675690 on the neural substrates of sadness.

BACKGROUND: CREB1 has previously been implicated in mood disorders, suicide, and antidepressant response. There is some evidence that the T allele in rs4675690, a single-nucleotide polymorphism near the CREB1 gene, is involved in the modulation of neural responses to negative stimuli. It is not known whether differential brain activity during negative mood state appears early in life in T allele carriers. METHODS: Functional magnetic resonance imaging (fMRI) was used to measure brain activity, during a transient state of sadness, in children homozygous for the T allele or the C allele. This primary emotion was selected given that it is the prevailing mood in major depressive disorder (MDD). Blood-oxygen-level dependent (BOLD) signal changes were measured while subjects viewed blocks of neutral film excerpts and blocks of sad film excerpts. RESULTS: There was significantly greater BOLD activation in the TT group, compared to the CC group, in the right dorsal anterior cingulate cortex (Brodmann area [BA 24]), right putamen, right caudate nucleus and left anterior temporal pole (BA 21), when the brain activity associated with the viewing of the emotionally neutral film excerpts was subtracted from that associated with the viewing of the sad film excerpts. LIMITATIONS: A replication study using larger samples may be required for more definitive conclusions. CONCLUSIONS: The different pattern of regional brain activation found here during transient sadness - in children carrying the T allele, compared to those carrying the C allele - might increase later in life susceptibility to emotional dysregulation and depressive symptoms.

Early impact of 5-HTTLPR polymorphism on the neural correlates of sadness.

Healthy adults carrying the short (S) allele of the human serotonin transporter gene linked polymorphism (5-HTTLPR) show increased amygdala activation during visual processing of emotionally negative stimuli compared to healthy adults homozygous for the long (L) allele. To determine whether abnormal brain responses during negative emotion appear early in life in S allele carriers, functional magnetic resonance imaging (fMRI) was used to measure brain activity during a transient state of sadness in children carrying the S allele (S group) or homozygous for the L allele (L group). Blood-oxygen-level dependent (BOLD) signal changes were measured while subjects viewed blocks of neutral film excerpts and sad film excerpts. During the sad condition (relative to the neutral condition), there was significantly greater activation in the S group compared to the L group in brain regions known to be involved in normal sadness and major depression. Given that the 5-HTTLPR polymorphism has been associated with mood disorders, it is plausible that the abnormal pattern of regional brain activity detected here, in children carrying the S allele, increases susceptibility to emotional dysregulation and depressive symptoms.