Elsevier

Neuroscience

Volume 164, Issue 1, 24 November 2009, Pages 300-330
Neuroscience

Psychiatry-Developmental Disorder
Review
Imaging phenotypes of major depressive disorder: genetic correlates

https://doi.org/10.1016/j.neuroscience.2009.03.082Get rights and content

Abstract

Imaging techniques are a potentially powerful method of identifying phenotypes that are associated with, or are indicative of, a vulnerability to developing major depressive disorder (MDD). Here we identify seven promising MDD-associated traits identified by magnetic resonance imaging (MRI) or positron emission tomography (PET). We evaluate whether these traits are state-independent, heritable endophenotypes, or state-dependent phenotypes that may be useful markers of treatment efficacy. In MDD, increased activity of the amygdala in response to negative stimuli appears to be a mood-congruent phenomenon, and is likely moderated by the 5-HT transporter gene (SLC6A4) promoter polymorphism (5-HTTLPR). Hippocampal volume loss is characteristic of elderly or chronically-ill samples and may be impacted by the val66met brain-derived neurotrophic factor (BDNF) gene variant and the 5-HTTLPR SLC6A4 polymorphism. White matter pathology is salient in elderly MDD cohorts but is associated with cerebrovascular disease, and is unlikely to be a useful marker of a latent MDD diathesis. Increased blood flow or metabolism of the subgenual anterior cingulate cortex (sgACC), together with gray matter volume loss in this region, is a well-replicated finding in MDD. An attenuation of the usual pattern of fronto-limbic connectivity, particularly a decreased temporal correlation in amygdala–anterior cingulate cortex (ACC) activity, is another MDD-associated trait. Concerning neuroreceptor PET imaging, decreased 5-HT1A binding potential in the raphe, medial temporal lobe, and medial prefrontal cortex (mPFC) has been strongly associated with MDD, and may be impacted by a functional single nucleotide polymorphism in the promoter region of the 5-HT1A gene (HTR1A: −1019 C/G; rs6295). Potentially indicative of inter-study variation in MDD etiology or mood state, both increased and decreased binding potential of the 5-HT transporter has been reported. Challenges facing the field include the problem of phenotypic and etiological heterogeneity, technological limitations, the confounding effects of medication, and non-disease related inter-individual variation in brain morphology and function. Further advances are likely as epigenetic, copy-number variant, gene–gene interaction, and genome-wide association (GWA) approaches are brought to bear on imaging data.

Section snippets

The amygdala: an emotional processing bias

Patients with MDD have repeatedly demonstrated increased amygdala reactivity to negative stimuli as evinced by functional magnetic resonance imaging (fMRI) (Table 1). (Siegle et al., 2002) found that amygdalar responses to negative words were no longer visible after 10 s in healthy controls but persisted in depressed patients for a mean of 25 s. Similarly, depressed individuals reportedly remember negative words better than positive words (Watkins et al., 1992), a finding that correlates with

Phenotypic heterogeneity

A great deal of genetic and phenotypic variation is encompassed within current nosological categories, and it is thus likely that the exact pattern of MDD-associated neuropathology will vary across subgroups of affectively ill patients. The relatively embryonic state of the field has unfortunately meant that these issues have thus far been largely neglected.

For example, there is some evidence that patients who are recurrently ill and those subjects who have experienced one lifetime episode of

Gene–gene interactions

Assuming the veracity of the common disease–common variant (CDCV) hypothesis, analyzing the additive effects of common polymorphisms on imaging phenotypes, and by extension, genetic risk for MDD, is an important project. Evidence for gene–gene interactions is beginning to emerge in the literature. The SLC6A4 gene has been reported to interact with BDNF to impact amygdala and anterior cingulate cortex volume (Pezawas et al., 2008); TPH2 (Canli et al., 2008), and COMT (Smolka et al., 2007), to

Conclusion

We have discussed seven (MRI and PET) imaging phenotypes which appear to be strongly associated with MDD. Strictly speaking, an endophenotype is a heritable trait present in periods of illness and remission that should be found in biological relatives of affected individuals at a greater frequency than the general population (Gottesman and Gould, 2003). The extant literature is not mature enough to allow us to evaluate whether the neurophysiological markers discussed above qualify as

References (364)

  • C.L. Bethea et al.

    Serotonin-related gene expression in female monkeys with individual sensitivity to stress

    Neuroscience

    (2005)
  • H.P. Blumberg et al.

    Influence of vascular endothelial growth factor variation on human hippocampus morphology

    Biol Psychiatry

    (2008)
  • A.D. Boes et al.

    Rostral anterior cingulate cortex volume correlates with depressed mood in normal healthy children

    Biol Psychiatry

    (2008)
  • M. Boldrini et al.

    Serotonin-1A autoreceptor binding in the dorsal raphe nucleus of depressed suicides

    J Psychiatr Res

    (2008)
  • K.N. Botteron et al.

    Volumetric reduction in left subgenual prefrontal cortex in early onset depression

    Biol Psychiatry

    (2002)
  • J.A. Bueller et al.

    BDNF Val66Met allele is associated with reduced hippocampal volume in healthy subjects

    Biol Psychiatry

    (2006)
  • K.K. Caldwell et al.

    Fetal alcohol spectrum disorder-associated depression: evidence for reductions in the levels of brain-derived neurotrophic factor in a mouse model

    Pharmacol Biochem Behav

    (2008)
  • T. Canli et al.

    Additive effects of serotonin transporter and tryptophan hydroxylase-2 gene variation on neural correlates of affective processing

    Biol Psychol

    (2008)
  • D.M. Cannon et al.

    Elevated serotonin transporter binding in major depressive disorder assessed using positron emission tomography and [11C]DASB; comparison with bipolar disorder

    Biol Psychiatry

    (2007)
  • C.H. Chen et al.

    Brain imaging correlates of depressive symptom severity and predictors of symptom improvement after antidepressant treatment

    Biol Psychiatry

    (2007)
  • A. Convit et al.

    Hippocampal volume losses in minimally impaired elderly

    Lancet

    (1995)
  • E.W. Dickie et al.

    Amygdala responses to unattended fearful faces: interaction between sex and trait anxiety

    Psychiatry Res

    (2008)
  • K. Domschke et al.

    Influence of the catechol-O-methyltransferase val158met genotype on amygdala and prefrontal cortex emotional processing in panic disorder

    Psychiatry Res

    (2008)
  • W.C. Drevets et al.

    Functional anatomical correlates of antidepressant drug treatment assessed using PET measures of regional glucose metabolism

    Eur Neuropsychopharmacol

    (2002)
  • W.C. Drevets et al.

    Serotonin type-1A receptor imaging in depression

    Nucl Med Biol

    (2000)
  • W.C. Drevets et al.

    Serotonin-1A receptor imaging in recurrent depression: replication and literature review

    Nucl Med Biol

    (2007)
  • W.C. Drevets et al.

    PET imaging of serotonin 1A receptor binding in depression

    Biol Psychiatry

    (1999)
  • R.S. Duman et al.

    A neurotrophic model for stress-related mood disorders

    Biol Psychiatry

    (2006)
  • R.M. Dupont et al.

    Diagnostic specificity of focal white matter abnormalities in bipolar and unipolar mood disorder

    Biol Psychiatry

    (1995)
  • A. Etkin et al.

    Individual differences in trait anxiety predict the response of the basolateral amygdala to unconsciously processed fearful faces

    Neuron

    (2004)
  • C.L. Fales et al.

    Altered emotional interference processing in affective and cognitive-control brain circuitry in major depression

    Biol Psychiatry

    (2008)
  • S.H. Fatemi et al.

    Maternal infection leads to abnormal gene regulation and brain atrophy in mouse offspring: implications for genesis of neurodevelopmental disorders

    Schizophr Res

    (2008)
  • A. Fornito et al.

    The influence of sulcal variability on morphometry of the human anterior cingulate and paracingulate cortex

    Neuroimage

    (2006)
  • V.G. Frokjaer et al.

    High familial risk for mood disorder is associated with low dorsolateral prefrontal cortex serotonin transporter binding

    Neuroimage

    (2009)
  • C.H. Fu et al.

    Neural responses to sad facial expressions in major depression following cognitive behavioral therapy

    Biol Psychiatry

    (2008)
  • M. Fujita et al.

    Kinetic analysis in healthy humans of a novel positron emission tomography radioligand to image the peripheral benzodiazepine receptor, a potential biomarker for inflammation

    Neuroimage

    (2008)
  • S. Aalto et al.

    Neuroanatomical substrata of amusement and sadness: a PET activation study using film stimuli

    Neuroreport

    (2002)
  • G.S. Alexopoulos et al.

    Vascular depression' hypothesis

    Arch Gen Psychiatry

    (1997)
  • A. Anand et al.

    Antidepressant effect on connectivity of the mood-regulating circuit: an FMRI study

    Neuropsychopharmacology

    (2005)
  • E. Arce et al.

    Escitalopram effects on insula and amygdala BOLD activation during emotional processing

    Psychopharmacology (Berl)

    (2008)
  • M. Ashtari et al.

    Hippocampal/amygdala volumes in geriatric depression

    Psychol Med

    (1999)
  • C. Aston et al.

    Transcriptional profiling reveals evidence for signaling and oligodendroglial abnormalities in the temporal cortex from patients with major depressive disorder

    Mol Psychiatry

    (2005)
  • E.H. Aylward et al.

    MRI volumes of amygdala and hippocampus in non-mentally retarded autistic adolescents and adults

    Neurology

    (1999)
  • M. Ballmaier et al.

    Hippocampal morphology and distinguishing late-onset from early-onset elderly depression

    Am J Psychiatry

    (2008)
  • N. Barden

    Implication of the hypothalamic-pituitary-adrenal axis in the physiopathology of depression

    J Psychiatry Neurosci

    (2004)
  • K. Becker et al.

    Interaction of dopamine transporter genotype with prenatal smoke exposure on ADHD symptoms

    J Pediatr

    (2008)
  • C.G. Beevers et al.

    Serotonin transporter genetic variation and biased attention for emotional word stimuli among psychiatric inpatients

    J Abnorm Psychol

    (2007)
  • C. Benkelfat et al.

    Mood-lowering effect of tryptophan depletionEnhanced susceptibility in young men at genetic risk for major affective disorders

    Arch Gen Psychiatry

    (1994)
  • Z. Bhagwagar et al.

    Persistent reduction in brain serotonin1A receptor binding in recovered depressed men measured by positron emission tomography with [11C]WAY-100635

    Mol Psychiatry

    (2004)
  • Z. Bhagwagar et al.

    5-HTT binding in recovered depressed patients and healthy volunteers: a positron emission tomography study with [11C]DASB

    Am J Psychiatry

    (2007)
  • Cited by (202)

    • Resting state fMRI connectivity mapping across species: Challenges and opportunities

      2023, Advances in Resting-State Functional MRI: Methods, Interpretation, and Applications
    View all citing articles on Scopus
    View full text