Medication-free Major Depressive Disorder Research Articles

Neural responses to facial emotions and subsequent clinical outcomes in difficult-to-treat depression.

Amygdala and dorsal anterior cingulate cortex responses to facial emotions have shown promise in predicting treatment response in medication-free major depressive disorder (MDD). Here, we examined their role in the pathophysiology of clinical outcomes in more chronic, difficult-to-treat forms of MDD. Forty-five people with current MDD who had not responded to ⩾2 serotonergic antidepressants (n = 42, meeting pre-defined fMRI minimum quality thresholds) were enrolled and followed up over four months of standard primary care. Prior to medication review, subliminal facial emotion fMRI was used to extract blood-oxygen level-dependent effects for sad v. happy faces from two pre-registered a priori defined regions: bilateral amygdala and dorsal/pregenual anterior cingulate cortex. Clinical outcome was the percentage change on the self-reported Quick Inventory of Depressive Symptomatology (16-item). We corroborated our pre-registered hypothesis (NCT04342299) that lower bilateral amygdala activation for sad v. happy faces predicted favorable clinical outcomes (rs[38] = 0.40, p = 0.01). In contrast, there was no effect for dorsal/pregenual anterior cingulate cortex activation (rs[38] = 0.18, p = 0.29), nor when using voxel-based whole-brain analyses (voxel-based Family-Wise Error-corrected p < 0.05). Predictive effects were mainly driven by the right amygdala whose response to happy faces was reduced in patients with higher anxiety levels. We confirmed the prediction that a lower amygdala response to negative v. positive facial expressions might be an adaptive neural signature, which predicts subsequent symptom improvement also in difficult-to-treat MDD. Anxiety reduced adaptive amygdala responses.

Relationship of prefrontal cortex activity with anhedonia and cognitive function in major depressive disorder: an fNIRS study.

Major depressive disorder (MDD) is associated with deficits in cognitive function, thought to be related to underlying decreased hedonic experiences. Further research is needed to fully elucidate the role of functional brain activity in this relationship. In this study, we investigated the neurofunctional correlate of the interplay between cognitive function and hedonic experiences in medication-free MDD using functional near-infrared spectroscopy (fNIRS). We examine differences of brain activation corresponding to the verbal fluency test (VFT) between MDD patients and healthy controls (HCs). Fifty-six MDD patients and 35 HCs underwent fMRI scanning while performing the VFT. In exploratory analyses, cognitive performance, as assessed by the Cambridge Neuropsychological Test Automated Battery (CANTAB), four dimensions of hedonic processing (desire, motivation, effort, and consummatory pleasure) measured by the Dimensional Anhedonia Rating Scale (DARS), and relative changes in oxygenated hemoglobin concentration during the VFT were compared across groups. Patients with MDD demonstrated impairments in sustained attention and working memory, accompanied by lower total and subscale scores on the DARS. Compared to healthy controls, MDD patients exhibited reduced activation in the prefrontal cortex (PFC) during the VFT task (t = 2.32 to 4.77, p < 0.001 to 0.02, FDR corrected). DARS motivation, desire, and total scores as well as sustained attention, were positively correlated with activation in the dorsolateral PFC and Broca's area (p < 0.05, FDR corrected). These findings indicate that changes in prefrontal lobe oxygenated hemoglobin levels, a region implicated in hedonic motivation and cognitive function, may serve as potential biomarkers for interventions targeting individuals with MDD. Our results corroborate the clinical consensus that the prefrontal cortex is a primary target for non-invasive neuromodulatory treatments for depression.

Changes in Regional Homogeneity of Medication-Free Major Depressive Disorder Patients With Different Onset Ages.

Background: Neurobiological mechanisms underlying the development of major depressive disorder (MDD) may differ depending on onset ages. Our aim was to determine whether regional homogeneity (ReHo) changes in early-onset depression (EOD) and late-onset depression (LOD) are different, which could also delineate EOD and LOD.Methods: Ninety-one MDD patients and 115 healthy controls (HCs) were recruited, and resting-state functional magnetic resonance imaging data were collected. The ReHo comparison was conducted using analysis of variance.Results: Compared with HCs, MDD patients showed decreased ReHo in the left precentral gyrus and the left middle cingulum area, and increased ReHo in the left middle orbital frontal gyrus and superior temporal gyrus. Compared with LOD patients, young HC separately, EOD patients had significantly increased ReHo in the right inferior frontal triangular gyrus and the left postcentral gyrus. However, compared with young HC, EOD patients showed decreased ReHo in the right superior frontal gyrus/supplementary motor area and the right medial frontal gyrus. ReHo in the right inferior frontal triangular gyrus was negatively correlated with the severity of cognitive disturbance in LOD patients (r = −0.47, p = 0.002), but not in EOD patients (r = 0.21, p = 0.178).Conclusion: MDD patients with different onset ages may have different pathophysiological mechanisms; the EOD patients had more abnormal ReHo than LOD patients in the prefrontal lobe, especially the right inferior frontal triangular gyrus.

Altered Local Gyrification Index and Corresponding Functional Connectivity in Medication Free Major Depressive Disorder.

A lot of previous studies have documented that major depressive disorder (MDD) is a developmental disorder. The cortical surface measure, local gyrification index (LGI), can well reflect the fetal and early postnatal neurodevelopmental processes. Thus, LGI may provide new insight for the neuropathology of MDD. The previous studies only focused on the surface structural abnormality, but how the structural abnormality lead to functional connectivity changes is unexplored. In this study, we investigated LGI and corresponding functional connectivity difference in 28 medication-free MDD patients. We found significantly decreased LGI in left lingual gyrus (LING) and right posterior superior temporal sulcus (bSTS), and the changed LGI in bSTS was negatively correlated with disease onset age and anxiety scores. The following functional connectivity analyses identified decreased functional connectivities between LING and right LING, precentral gyrus, and middle temporal gyrus. The decreased functional connectivities were correlated with disease duration, onset, and depression symptoms. Our findings revealed abnormal LGI in LING and bSTS indicating that the abnormal developmental of visual and social cognition related brain areas may be an early biomarker for depression.

Concurrent alterations of white matter microstructure and functional activities in medication-free major depressive disorder.

Although numerous studies have revealed the structural and functional alterations in major depressive disorder (MDD) using unimodal diffusion magnetic resonance imaging (MRI) or functional MRI, however, the potential associations between changed microstructure and corresponding functional activities in the MDD has been largely uninvestigated. Herein, 27 medication-free MDD patients and 54 gender-, age-, and educational level-matched healthy controls (HC) were used to investigate the concurrent alterations of white matter microstructure and functional activities using tract-based spatial statistics (TBSS) analyses, fractional amplitude of low-frequency fluctuation (fALFF), and degree centrality (DC). The TBSS analyses revealed significantly decreased fractional anisotropy (FA) in the superior longitudinal fasciculus (SLF I) in the MDD patients compared to HC. Correlation analyses showed that decreased FA in the SLF I was significantly correlated with fALFF in left pre/postcentral gyrus and binary, weighted DC in right posterior cerebellum. Moreover, the fALFF in left pre/postcentral gyrus significantly reduced in MDD patients while binary and weighted DC in right posterior cerebellum significantly increased in MDD patients. Our results revealed concurrent structural and functional changes in MDD patients suggesting that the underlying structural disruptions are an important indicator of functional abnormalities.

Altered whole brain functional connectivity pattern homogeneity in medication-free major depressive disorder

BackgroundMany previous studies have revealed abnormal functional connectivity patterns between brain areas underlying the onset of major depressive disorder (MDD) using resting-state functional magnetic resonance imaging (rs-fMRI). However, how to exactly characterize the voxel-wise whole brain functional connectivity pattern changes in MDD remains unclear, which will provide more convincing evidence for localizing the exactly functional connectivity abnormality in MDD. MethodsIn this study, we employed our newly developed whole brain functional connectivity homogeneity (FcHo) method to identify the voxel-wise changes of functional connectivity patterns in 27 medication-free MDD patients and 34 gender-, age-, and education level-matched healthy controls (HC). Furthermore, seed-based functional connectivity analysis was then used to identify the alteration of corresponding functional connectivity. ResultsSignificantly decreased FcHo values in right ventral anterior insula (INS) and medial prefrontal cortex (MPFC) were identified in MDD patients. The ensuing functional connectivity analyses identified decreased functional connectivity between MPFC and left angular gyrus (AG) in MDD patients. Moreover, both decreased FcHo values in INS, MPFC and functional connectivity between MPFC and left AG showed significant negative correlations with Hamilton depression rating scale (HDRS) scores. The FcHo values in INS were also negatively correlated with disease duration. Finally, meta-analysis based functional characterization found that these brain areas are mainly involved in emotion, theory of mind and reward processing. ConclusionsOur findings revealed abnormal whole brain FcHo in INS and MPFC and functional interactions between MPFC and AG in MDD and suggested that dysfunctions of INS and MPFC play an important role in the neuropathology of MDD.

Increased Functional Connectivity Between Medulla and Inferior Parietal Cortex in Medication-Free Major Depressive Disorder.

Emerging evidence has documented the abnormalities of primary brain functions in major depressive disorder (MDD). The brainstem has shown to play an important role in regulating basic functions of the human brain, but little is known about its role in MDD, especially the roles of its subregions. To uncover this, the present study adopted resting-state functional magnetic resonance imaging with fine-grained brainstem atlas in 23 medication-free MDD patients and 34 matched healthy controls (HC). The analysis revealed significantly increased functional connectivity of the medulla, one of the brainstem subregions, with the inferior parietal cortex (IPC) in MDD patients. A positive correlation was further identified between the increased medulla-IPC functional connectivity and Hamilton anxiety scores. Functional characterization of the medulla and IPC using a meta-analysis revealed that both regions primarily participated in action execution and inhibition. Our findings suggest that increased medulla-IPC functional connectivity may be related to over-activity or abnormal control of negative emotions in MDD, which provides a new insight for the neurobiology of MDD.

Abnormal Global Functional Connectivity Patterns in Medication-Free Major Depressive Disorder.

Mounting studies have applied resting-state functional magnetic resonance imaging (rs-fMRI) to study major depressive disorder (MDD) and have identified abnormal functional activities. However, how the global functional connectivity patterns change in MDD is still unknown. Using rs-fMRI, we investigated the alterations of global resting-state functional connectivity (RSFC) patterns in MDD using weighted global brain connectivity (wGBC) method. First, a whole brain voxel-wise wGBC map was calculated for 23 MDD patients and 34 healthy controls. Two-sample t-tests were applied to compare the wGBC and RSFC maps and the significant level was set at p < 0.05, cluster-level correction with voxel-level p < 0.001. MDD patients showed significantly decreased wGBC in left temporal pole (TP) and increased wGBC in right parahippocampus (PHC). Subsequent RSFC analyses showed decreased functional interaction between TP and right posterior superior temporal cortex and increased functional interaction between PHC and right inferior frontal gyrus in MDD patients. These results revealed the abnormal global FC patterns and its corresponding disrupted functional connectivity in MDD. Our findings present new evidence for the functional interruption in MDD.

Spectral Dynamics of Resting State fMRI Within the Ventral Tegmental Area and Dorsal Raphe Nuclei in Medication-Free Major Depressive Disorder in Young Adults.

Background: Dorsal raphe nucleus (DRN) and ventral tegmental area (VTA) are major brainstem monamine nuclei consisting of serotonin and dopamine neurons respectively. Animal studies show that firing patterns in both nuclei are altered when animals exhibit depression like behaviors. Functional MRI studies in humans have shown reduced VTA activation and DRN connectivity in depression. This study for the first time aims at investigating the functional integrity of local neuronal firing concurrently in both the VTA and DRN in vivo in humans using spectral analysis of resting state low frequency fluctuation fMRI.Method: A total of 97 medication-free subjects—67 medication-free young patients (ages 18–30) with major depressive disorder and 30 closely matched healthy controls were included in the study to detect aberrant dynamics in DRN and VTA. For the investigation of altered localized dynamics we conducted power spectral analysis and above this spectral cross correlation between the two groups. Complementary to this, spectral dependence of permutation entropy, an information theoretical measure, was compared between groups.Results: Patients displayed significant spectral slowing in VTA vs. controls (p = 0.035, corrected). In DRN, spectral slowing was less pronounced, but the amount of slowing significantly correlated with 17-item Hamilton Depression Rating scores of depression severity (p = 0.038). Signal complexity as assessed via permutation entropy showed spectral alterations inline with the results on spectral slowing.Conclusion: Our results indicate that altered functional dynamics of VTA and DRN in depression can be detected from regional fMRI signal. On this basis, impact of antidepressant treatment and treatment response can be assessed using these markers in future studies.

Prefrontal cortical GABA abnormalities are associated with reduced hippocampal volume in major depressive disorder

Hippocampal volume reduction has been related to treatment-resistant depression (TRD) and is hypothesized to reflect impaired amino-acid neurotransmission. To better understand the role of amino acid neurotransmission in hippocampal volume deficits, and subsequent resistance to treatment, this study investigated the relationship between hippocampal volumes and GABA levels in the anterior cingulate cortex (ACC), previously associated with TRD. Thirty-three medication-free major depressive disorder (MDD; 14 TRD and 19 non-TRD) and 26 healthy controls (HC) subjects were studied. Participants underwent high-resolution magnetic resonance imaging (MRI) to estimate hippocampal volume and proton MR spectroscopy (1H MRS) to measure ACC GABA levels. MDD patients, with known ACC GABA levels, were divided into two groups: MDD Low GABA and MDD High GABA. We found a significant reduction in hippocampal volume in the MDD Low GABA group compared to MDD High GABA (p<0.001) and HC (p=0.01). The relationship between hippocampal volume and cortical GABA was population (i.e. MDD group) and region specific (i.e. prefrontal cortex). Comparing TRD, non-TRD and HC groups, there was a main effect of group on hippocampal volume (p=0.04), which post hoc analysis revealed as smaller hippocampal volume in TRD subjects than in non-TRD (p=0.05) and HC groups (p=0.03). No hippocampal volume differences between non-TRD and HC groups. The data provides insight into the role of prefrontal neurochemical deficits in the limbic structural abnormalities observed in MDD. In addition, it replicates the relationship between TRD and smaller hippocampal volumes.

Cerebrospinal fluid neuropeptide Y levels in major depression and reported childhood trauma.

Background:Neuropeptide Y (NPY) may enhance resilience to chronic stress. Low brain NPY reported in major depression may normalize in response to antidepressants.Methods:In this study, we examined the relationship of reported childhood trauma to cerebrospinal fluid (CSF) NPY–like immunoreactivity (NPY-LI) in 61 medication-free major depressive disorder (MDD) patients and 20 matched healthy volunteers.Results:Higher CSF NPY-LI was found in MDD compared to the healthy volunteer group (p = 0.01). A positive correlation of CSF NPY-LI with more adverse childhood trauma (p = 0.001) may be indicative of an intact but insufficient NPY-related stress response.Conclusions:We hypothesize that differences in published results may be explained by the existence of two groups of MDD in terms of CSF NPY levels: MDD with low CSF NPY prior to stress or in response to stress, and those with robust NPY responses to stress. Future studies should confirm the two groups and seek the molecular mechanism for their differences.

The Relationship between Age and Affective Reactivity in Depressed and Healthy Females Across the Lifespan

Objective: Depression-related differences in processing emotional information have been observed in prior research, though the influence of age upon affective reactivity of negative, neutral, and positive stimuli may partially explain these differences. We examined the extent to which age influences affective reactivity to positive, neutral, and negative stimuli in depressed and healthy participants. Methods: The study enrolled 129 right-handed females between 16 to 63 years old who met either DSM-IV criteria for current, medication-free Major Depressive Disorder (n=59) or no current or lifetime diagnoses (n=70). All participants completed a structured clinical interview for DSM-IV Axis I disorders, a clinical interview to determine depression severity, and an affective reactivity task. Results: There were no significant main effects of depression status or interaction effects between depression status and age on ratings of positive, negative, and neutral stimuli. Additionally, there was no significant main effect of age on ratings of positive stimuli. However, there were main effects of age on ratings of negative and neutral stimuli suggesting that depressed and healthy participants differed in their evaluation of negative and neutral information as a function of age. Specifically, participants rated neutral information as more positive over the lifespan, and negative information as less negative across the lifespan. Conclusion: Reactions to neutral information appear to become more positive with older age and reactions to negative information appear to decline with age unrelated to depression status.

Whole-brain functional connectivity during emotional word classification in medication-free Major Depressive Disorder: Abnormal salience circuitry and relations to positive emotionality

Major Depressive Disorder (MDD) has been associated with biased processing and abnormal regulation of negative and positive information, which may result from compromised coordinated activity of prefrontal and subcortical brain regions involved in evaluating emotional information. We tested whether patients with MDD show distributed changes in functional connectivity with a set of independently derived brain networks that have shown high correspondence with different task demands, including stimulus salience and emotional processing. We further explored if connectivity during emotional word processing related to the tendency to engage in positive or negative emotional states. In this study, 25 medication-free MDD patients without current or past comorbidity and matched controls (n = 25) performed an emotional word-evaluation task during functional MRI. Using a dual regression approach, individual spatial connectivity maps representing each subject's connectivity with each standard network were used to evaluate between-group differences and effects of positive and negative emotionality (extraversion and neuroticism, respectively, as measured with the NEO-FFI). Results showed decreased functional connectivity of the medial prefrontal cortex, ventrolateral prefrontal cortex, and ventral striatum with the fronto-opercular salience network in MDD patients compared to controls. In patients, abnormal connectivity was related to extraversion, but not neuroticism. These results confirm the hypothesis of a relative (para)limbic–cortical decoupling that may explain dysregulated affect in MDD. As connectivity of these regions with the salience network was related to extraversion, but not to general depression severity or negative emotionality, dysfunction of this network may be responsible for the failure to sustain engagement in rewarding behavior.

Amygdala hyperactivation and prefrontal hypoactivation in subjects with cognitive vulnerability to depression

The hopelessness theory (HT) of depression is a diathesis-stress theory which construes cognitive vulnerability (CV) to depression. Neuroimaging studies examining depression have implicated the amygdala as an important potential locus of dysfunction in the processing of salient threatening stimuli. However, little is known about neural activation in the brain of subjects with CV to depression. Medication-free major depressive disorder (MDD) subjects ( N = 29), never depressed subjects with CV ( N = 26), and demographically matched never depressed healthy control (HC) subjects ( N = 31) were scanned using functional magnetic resonance imaging (fMRI) while performing an emotional matching task. The MDD subjects showed elevated left amygdala responses and reduced left dorsolateral prefrontal cortex (dlPFC) activation levels relative to HC subjects. Similarly, CV subjects had greater activity in the amygdala bilaterally and lesser activation in the dlPFC bilaterally, relative to HC subjects. The present findings raise the possibility that cognitive vulnerability to depression might be characterized by hypoactivation of the prefrontal cortex and hyperactivation of the amygdala in response to emotional stimuli; our observations might provide a potential interpretation to explain the abnormalities in neural networks mediating cognitive modulation of emotions in individuals with cognitive vulnerability to depression.

Smaller Hippocampus Volume Is Associated with Short Variant of 5-HTTLPR Polymorphism in Medication-Free Major Depressive Disorder Patients

Aim: Serotonin is known for its importance in the pathophysiology of major depressive disorder. Although the hippocampus is one of the key regions in which neurogenesis occurs, and serotonin plays an important role in neurogenesis, results of studies that investigate effect of the 5-HTTLPR polymorphism on hippocampal volumes in major depressive disorder are inconclusive. Method: We looked for a relationship between the 5-HTTLPR polymorphism and hippocampal volumes in 44 depressed patients (mean age ± SD 33.6 ± 9.5 years) and 43 healthy controls (30.4 ± 6.7 years). Region of interest analysis was conducted on the images acquired via MRI. Results: Although hippocampal volumes were similar in healthy and patient groups, there was a significant interaction between genotype and diagnosis on hippocampus volumes. Post-hoc ANCOVA showed that hippocampal volumes of S/S homozygous depressed patients were smaller compared to healthy controls in both hemispheres. Conclusion: The 5-HTTLPR polymorphism has an effect on hippocampal volumes of depressed patients, which is apparent only in S/S genotype. It seems that decreased neurogenesis by effects of reduced serotoninergic transmission may be responsible for smaller hippocampal volumes observed in S/S homozygous depressed patients.

Regional brain metabolic correlates of self-reported depression severity contrasted with clinician ratings

Background We compared brain-map correlations of relative cerebral glucose metabolism (rCMRglu) with psychopathologic factors derived from the self-rated Beck Depression Inventory (BDI) and factors from the clinician-rated Hamilton Depression Rating Scale (HDRS) factors, seeking an anatomic basis for differences in self and clinician ratings. Methods [ 18F]-FDG Positron Emission Tomography generated rCMRglu, SPM-estimated, voxel-level, brain correlation maps with BDI factor scores and HDRS factor scores in medication-free major depressive disorder. Results Regional brain correlates of BDI are more extensive than HDRS, even when adjusting for variance accounted for by the HDRS. Factors comprising the BDI were associated with distinct cortical and subcortical regions. The degree of overlap in factor correlation brain maps is explained by the variance shared by BDI and HDRS factor scores. Conclusion Self and clinician-rated aspects of depression have common and distinct neuroanatomic correlates that reflect correlations between rating scales, but correlations between glucose metabolism and self-rated depression were anatomically more extensive in this sample. Findings highlight the importance and biological underpinnings of these subjective features of major depression.