Modulation of default-mode network activity by acute tryptophan depletion is associated with mood change: A resting state functional magnetic resonance imaging study

Department of Psychiatry and Neurosciences, Division of Frontier Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
Neuroscience Research (Impact Factor: 1.94). 11/2010; 69(2):129-34. DOI: 10.1016/j.neures.2010.11.005
Source: PubMed


Recently, resting-state fMRI (R-fMRI) has attracted interest based on its ability to detect the default mode network. We examined the effect of acute tryptophan depletion (ATD) on the fractional amplitude of low-frequency fluctuation (fALFF) during the resting state, and the correlation between changes of mood and fALFF following ATD. We manipulated the central serotonergic levels of 21 right-handed healthy males (mean age=21.57±1.83 years) following ATD. A within-subjects, double-blind, placebo-controlled, and counter-balanced design was employed. Following ATD or sham depletion, subjects completed the Profile of Mood States (POMS) and underwent 5-min R-fMRI scans. Our findings show that the fALFF of the middle orbitofrontal cortex and precuneus was significantly decreased and the fALFF of the superior parietal lobule, paracentral lobule and precentral gyrus was significantly increased after ATD. The fALFF of the orbitofrontal cortex was negatively correlated with depressive mood. The fALFF of the superior parietal lobule was positively correlated with anger-hostility and the fALFF of the paracentral lobule was negatively correlated with vigor-activity. The middle orbitofrontal cortex plays a key role in serotonin depletion-induced brain changes and individual differences in depressive mood change. These results serve to further elucidate the mechanism of ATD-induced relapse in remitted MDD patients.

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    • "Kunisato et al. performed a resting-state fMRI study with 21 healthy men in which they showed that changes in some subscores of the POMS correlated with changes in orbitofrontal cortex (OFC) activity of the brain under ATD. Less activity of the OFC was associated with an increase of depressive mood during the depletion situation [38]. To the best of our knowledge, there are no imaging studies which investigate the influence of orally administered 5-HTP supplementation on the brain. "
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    ABSTRACT: Background. Fat affects gastric emptying (GE). 5-Hydroxythryptophan (5-HTP) is involved in central and peripheral satiety mechanisms. Influence of 5-HTP in addition to saturated or monounsaturated fatty acids (FA) on GE and hormone release was investigated. Subjects/Methods. 24 healthy individuals (12f : 12m, 22–29 years, BMI 19–25.7 kg/m²) were tested on 4 days with either 5-HTP + short-chain saturated FA (butter), placebo + butter, 5-HTP + monounsaturated FA (olive oil), or placebo + olive oil in double-blinded randomized order. Two hours after FA/5-HTP or placebo intake, a 13C octanoid acid test was conducted. Cortisol, serotonin, cholecystokinin (CCK), and ghrelin were measured, as were mood and GE. Results. GE was delayed with butter and was normal with olive (P < 0.05) but not affected by 5-HTP. 5-HTP supplementation did not affect serotonin levels. Food intake increased plasma CCK (F = 6.136; P < 0.05) irrespective of the FA. Ghrelin levels significantly decreased with oil/5-HTP (F = 9.166; P < 0.001). The diurnal cortisol profile was unaffected by FA or 5-HTP, as were ratings of mood, hunger, and stool urgency. Conclusion. Diverse FAs have different effects on GE and secretion of orexigenic and anorexigenic hormones. Supplementation of 5-HTP had no effect on plasma serotonin and central functions. Further studies are needed to explain the complex interplay.
    Full-text · Article · Aug 2014 · Gastroenterology Research and Practice
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    • "Moreover, 5-HT1A autoreceptor binding has been shown to be anti-correlated with PCC activation, while opposing effects were found for retrosplenial and medial prefrontal DMN regions [20]. A similar regionally-specific effect of serotonergic neurotransmission on DMN activity has been reported in a tryptophan depletion study [85]. Given the spatial co-occurrence between cortical regions of high 5-HTT densities and nodes of the DMN [23], [78] (Text S1 and Figure S8), it is interesting that 5-HT reuptake inhibition with escitalopram or combined 5-HT and norepinephrine inhibition with duloxetine have been demonstrated to decrease DMN coupling in human phMRI studies [16], [86]. "
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    ABSTRACT: The serotonin transporter (5-HTT) is abundantly expressed in humans by the serotonin transporter gene SLC6A4 and removes serotonin (5-HT) from extracellular space. A blood-brain relationship between platelet and synaptosomal 5-HT reuptake has been suggested, but it is unknown today, if platelet 5-HT uptake can predict neural activation of human brain networks that are known to be under serotonergic influence. A functional magnetic resonance study was performed in 48 healthy subjects and maximal 5-HT uptake velocity (Vmax) was assessed in blood platelets. We used a mixed-effects multilevel analysis technique (MEMA) to test for linear relationships between whole-brain, blood-oxygen-level dependent (BOLD) activity and platelet Vmax. The present study demonstrates that increases in platelet Vmax significantly predict default-mode network (DMN) suppression in healthy subjects independent of genetic variation within SLC6A4. Furthermore, functional connectivity analyses indicate that platelet Vmax is related to global DMN activation and not intrinsic DMN connectivity. This study provides evidence that platelet Vmax predicts global DMN activation changes in healthy subjects. Given previous reports on platelet-synaptosomal Vmax coupling, results further suggest an important role of neuronal 5-HT reuptake in DMN regulation.
    Full-text · Article · Mar 2014 · PLoS ONE
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    • "Another group tested healthy males with ATD and showed changes in low frequency (0.01 – 0.08 Hz) cortical functional connectivity measures that were associated with changes in mood behaviors. No raphé or subcortical changes were described (Kunisato et al. 2011). In the depression ATD study (above), the contrast between raphé activation and diminished raphé-thalamic frequency connectivity was paralleled by a neuron modeling paradigm in which optimal amplitudes of high-frequency components of activity were important for optimal processing of low-frequency signal components (Yu et al. 2011). "
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    ABSTRACT: Oscillations in brain activities with periods of minutes to hours may be critical for normal mood behaviors. Ultradian (faster than circadian) rhythms of mood behaviors and associated central nervous system activities are altered in depression. Recent data suggest that ultradian rhythms in serotonin (5HT) function also change in depression. In two separate studies, 5HT metabolites in cerebrospinal fluid (CSF) were measured every 10 m for 24 h before and after chronic antidepressant treatment. Antidepressant treatments were associated with enhanced ultradian amplitudes of CSF metabolite levels. Another study used resting-state functional magnetic resonance imaging (fMRI) to measure amplitudes of dorsal raphé activation cycles following sham or active dietary depletions of the 5HT precursor (tryptophan). During depletion, amplitudes of dorsal raphé activation cycles increased with rapid 6 s periods (about 0.18 Hz) while functional connectivity weakened between dorsal raphé and thalamus at slower periods of 20 s (0.05 Hz). A third approach studied MDMA (ecstasy) users because of their chronically diminished 5HT function compared to non-MDMA polysubstance users (Karageorgiou et al., 2009). Compared to a non-MDMA using cohort, MDMA users showed diminished fMRI intra-regional coherence in motor regions along with altered functional connectivity, again suggesting effects of altered 5HT oscillatory function. These data support a hypothesis that qualities of ultradian oscillations in 5HT function may critically influence moods and behaviors. Dysfunctional 5HT rhythms in depression may be a common endpoint and biomarker for depression, linking dysfunction of slow brain network oscillators to 5HT mechanisms affected by commonly available treatments. 5HT oscillatory dysfunction may define illness subtypes and predict responses to serotonergic agents. Further studies of 5HT oscillations in depression are indicated. Synapse, 2013. © 2013 Wiley Periodicals, Inc.
    Full-text · Article · Nov 2013 · Synapse
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