Modulation of default-mode network activity by acute tryptophan depletion is associated with mood change: A resting state functional magnetic resonance imaging study
Research highlights
▶ Serotonin depletion decreased the activity in orbitofrontal cortex and precuneus. ▶ Serotonin depletion increased the activity in the sensory-motor areas. ▶ Decreased orbitofrontal activity was correlated with the increased depressive mood. ▶ Increased superior parietal activity was correlated with the increased anger. ▶ Increased paracentral cortex activity was correlated with the decreased vigor.
Introduction
The acute tryptophan depletion (ATD) technique is widely used to study the function of serotonergic transmission on behavior, mood, and neural activity (Fusar-Poli et al., 2006, Mendelsohn et al., 2009, Ruhe et al., 2007). With the ATD procedure, the plasma levels of tryptophan, the precursor of serotonin (5-HT), are decreased by drinking an amino acid mixture that lacks tryptophan. Although ATD does not always increase depressive mood in healthy subjects, it has been shown to increase depressive mood in healthy subjects with a family history of major depressive disorder (MDD) (Ruhe et al., 2007). Also, vulnerability to ATD is a well known endophenotype of MDD (Hasler et al., 2004, Leyton et al., 2000, Smith et al., 1997, Smith et al., 1999).
Prior studies have investigated the effects of ATD on resting state regional cerebral blood flow (rCBF) and glucose metabolism using positron emission tomography (PET) (Nugent et al., 2008), single photon emission computed tomography (SPECT) (Talbot and Cooper, 2006) and arterial spin labeling (ASL) with functional magnetic resonance imaging (fMRI) (Roiser et al., 2009). Two of these studies reported no significant difference in resting state activation in any brain regions (Nugent et al., 2008, Roiser et al., 2009). However, these studies examined regional activity using regions of interest (ROI) analysis, which selects the regions to be analyzed a priori according to previous findings regarding serotonergic projections. One study investigated changes in resting state regional activity following ATD using SPECT in healthy subjects with whole brain analysis (Talbot and Cooper, 2006). The study demonstrated that rCBF in the dorsal anterior cingulate cortex (ACC) was decreased and rCBF in the cuneus was increased following ATD.
Recently, there has been great interest in resting-state fMRI (R-fMRI), which can detect resting state activation in brain regions such as the posterior cingulate cortex (PCC), precuneus, lateral parietal cortex, and medial prefrontal cortex (MPFC). The functional network of these regions in low-frequency spontaneous blood oxygenation-level dependent (BOLD) fluctuations is called a default mode network (DMN). The DMN is suggested to be involved in the processes of self-referential mental activity and introspectively oriented mode (Fransson, 2005), and deactivation during behavioral/cognitive tasks (Fox and Raichle, 2007, Raichle et al., 2001). Several studies have been conducted to investigate resting state neuronal activity in MDD using R-fMRI (Anand et al., 2005, Anand et al., 2009, Cullen et al., 2009, Greicius et al., 2007, Yao et al., 2009). In a regional activity study, patients with MDD showed abnormal activities in the OFC, ventral and dorsal ACC, PCC, fusiform cortex, lentiform nucleus, and insula (Yao et al., 2009). In functional connectivity studies, patients with MDD showed decreased functional connectivity between the ACC and the limbic-prefrontal regions (Anand et al., 2005, Anand et al., 2009, Cullen et al., 2009) and increased subgenual ACC and thalamic functional connectivity with the default mode network (Greicius et al., 2007). R-fMRI studies provide cross-modality confirmation of resting state studies using PET and SPECT. Nevertheless, no study has yet investigated the effects of tryptophan depletion on the regional activity of spontaneous BOLD fluctuations using R-fMRI.
The objective of the current study was to investigate the effects of ATD on the regional intensity of spontaneous fluctuations using R-fMRI and the association between ATD-induced mood changes and regional activity changes. We measured the fractional amplitude of low-frequency fluctuation (fALFF), which provides information on the regional intensity of spontaneous BOLD fluctuations. This approach can detect regional activity and abnormalities (Zou et al., 2008).
Section snippets
Subjects
Healthy right-handed males 20–27 years of age gave informed written consent to participate in the experiment, which was conducted with the approval of the ethics committees of Hiroshima University. On the screening day, trained psychiatrists interviewed each volunteer and screened for previous psychiatric problems using the Structured Clinical Interview for DSM-IV (First et al., 2002). We excluded volunteers with any previous psychiatric disorders and with family history of mood disorder. In
Results
ATD significantly lowered the mean plasma free tryptophan (7.39 ± 3.74 nmol/ml and 1.69 ± 0.54 nmol/ml before and after tryptophan depletion, respectively; t(20) = −5.93, p < .001), and the sham-depletion condition significantly increased the mean plasma free tryptophan (7.61 ± 2.58 and 14.50 ± 6.80 nmol/ml before and after sham depletion, respectively; t(20) = 7.32, p < .001). The mood rating scores measured before scanning did not differ significantly between conditions (Table 1).
The regional activities of both
Discussion
This study has two main findings. First, ATD decreased fALFF in the middle OFC and precuneus, while ATD increased fALFF in the superior parietal lobule, paracentral lobule, and precentral gyrus. Second, the ATD-induced change in depressive mood was negatively correlated with the change in fALFF in the middle OFC; ATD-induced change in anger was positively correlated with the change in fALFF in the superior parietal lobule; and ATD-induced change in vigor was negatively correlated with the
Conclusion
This study was the first to examine the effects of tryptophan depletion on fALFF during the resting state. Serotonin depletion induced a decrease in the activity of the OFC and precuneus, and an increase in the activity of parietal–precentral regions. The decreased activity of the OFC correlated with increased depressive mood following serotonin depletion. These results help to elucidate the mechanisms of ATD-induced relapse in remitted MDD patients. Further study will be needed to examine the
Acknowledgements
This work was supported by Grant-in-Aid for Scientific Research on Priority Areas-2—from the Ministry of Education, Culture, Sports, Science and Technology of Japan and Grant-in-Aid for Scientific Research (B). The authors would like to thank the MRI staff at the Hiroshima University Medical Hospital for use of facilities and technical support. Special thanks are due to Y. Akiyama for his contribution to the project. We also thank S Harada for conducting the tryptophan depletion procedure.
References (38)
- et al.
Resting state corticolimbic connectivity abnormalities in unmedicated bipolar disorder and unipolar depression
Psychiatry Res.
(2009) - et al.
Activity and connectivity of brain mood regulating circuit in depression: a functional magnetic resonance study
Biol. Psychiatry
(2005) - et al.
Serotoninergic regulation of emotional and behavioural control processes
Trends Cogn. Sci.
(2008) - et al.
A preliminary study of functional connectivity in comorbid adolescent depression
Neurosci. Lett.
(2009) - et al.
The resting state questionnaire: an introspective questionnaire for evaluation of inner experience during the conscious resting state
Brain Res. Bull.
(2010) - et al.
Resting-state functional connectivity in major depression: abnormally increased contributions from subgenual cingulate cortex and thalamus
Biol. Psychiatry
(2007) - et al.
Effects of acute tryptophan depletion on memory, attention and executive functions: a systematic review
Neurosci. Biobehav. Rev.
(2009) - et al.
Serotonin transporter genotype and depressive phenotype determination by discriminant analysis of glucose metabolism under acute tryptophan depletion
Neuroimage
(2008) The assessment and analysis of handedness: the Edinburgh inventory
Neuropsychologia
(1971)- et al.
Sex differences in the effect of acute tryptophan depletion on declarative episodic memory: a pooled analysis of nine studies
Neurosci. Biobehav. Rev.
(2007)
Relapse of depression after rapid depletion of tryptophan
Lancet
Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain
Neuroimage
Regional homogeneity in depression and its relationship with separate depressive symptom clusters: a resting-state fMRI study
J. Affect. Disord.
An improved approach to detection of amplitude of low-frequency fluctuation (ALFF) for resting-state fMRI: fractional ALFF
J. Neurosci. Methods
Positron emission tomography measurement of cerebral metabolic correlates of tryptophan depletion-induced depressive relapse
Arch. Gen. Psychiatry
Regional brain metabolic correlates of {alpha}-methylparatyrosine-induced depressive symptoms: implications for the neural circuitry of depression
JAMA
The precuneus: a review of its functional anatomy and behavioural correlates
Brain
Orbitofrontal cortex function and structure in depression
Ann. N.Y. Acad. Sci.
Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition (SCID-I/P)
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