Article

Clinical, cognitive, and functional connectivity correlations of resting-state intrinsic brain activity alterations in unmedicated depression

October 2014
Journal of Affective Disorders 172

October 2014
172

DOI:10.1016/j.jad.2014.10.017

Authors:

Shaolin Yang

University of Illinois at Chicago

Olusola Ajilore

University of Illinois at Chicago

Differentiating Melancholic and Non-melancholic Major Depressive Disorder Using Fractional Amplitude of Low-Frequency Fluctuations

Article

Full-text available

Feb 2022

Background Melancholic major depressive disorder (MDD) is a network-based brain disorder. However, whether or not network-based changes can be applied to differentiate melancholic (MEL) from non-melancholic (NMEL) MDD remains unclear. Methods Thirty-one MEL patients, 28 NMEL patients, and 32 matched healthy controls (HCs) were scanned using resting-state functional magnetic resonance imaging. Patients were assessed by the Chinese version of Snaith–Hamilton Pleasure Scale (SHAPS-C) and Temporal Experience of Pleasure Scale (TEPS). Fractional amplitude of low-frequency fluctuations (fALFF) and correlation analysis were used to analyze the data. Results Compared with HCs, the MEL group had significantly higher fALFF values in the bilateral inferior frontal gyrus and right supplementary motor area (SMA) and significantly lower fALFF values in the right inferior occipital gyrus (IOG), right middle temporal gyrus (MTG)/left IOG, and bilateral superior occipital gyrus (SOG)/MTG. On the other hand, the NMEL group showed significantly higher fALFF values in the bilateral SMA and significantly lower fALFF values in the bilateral posterior cingulate cortex/precuneus relative to HCs. Compared with the NMEL group, the MEL group showed significantly lower fALFF values in the left anterior cingulate cortex (ACC). A correlation was found between the fALFF values of the right SMA and the SHAPS-C in the MEL group. In addition, correlations were observed between the fALFF values of the left ACC and the TEPS contextual consummatory and total scores in all patients. Conclusion Our study uncovered that MDD exhibited altered brain activity in extensive brain networks, including the default-mode network, frontal-striatal network, reward system, and frontal-limbic network. Decreased fALFF in the left ACC might be applied to differentiate the two subtypes of MDD.

From anatomy to function: the role of the somatosensory cortex in emotional regulation

Article

Full-text available

Dec 2018

: Since the pioneering work of Penfield and his colleagues in the 1930s, the somatosensory cortex, which is located on the postcentral gyrus, has been known for its central role in processing sensory information from various parts of the body. More recently, a converging body of literature has shown that the somatosensory cortex also plays an important role in each stage of emotional processing, including identification of emotional significance in a stimulus, generation of emotional states, and regulation of emotion. Importantly, studies conducted in individuals suffering from mental disorders associated with abnormal emotional regulation, such as major depression, bipolar disorder, schizophrenia, post-traumatic stress disorder, anxiety and panic disorders, specific phobia, obesity, and obsessive-compulsive disorder, have found structural and functional changes in the somatosensory cortex. Common observations in the somatosensory cortices of individuals with mood disorders include alterations in gray matter volume, cortical thickness, abnormal functional connectivity with other brain regions, and changes in metabolic rates. These findings support the hypothesis that the somatosensory cortex may be a treatment target for certain mental disorders. In this review, we discuss the anatomy, connectivity, and functions of the somatosensory cortex, with a focus on its role in emotional regulation.

The landscape of functional brain network impairments in late-onset GM2 gangliosidosis

Preprint

Full-text available

Sep 2022

Late-onset GM2 gangliosidosis (LOGG) is an ultra-rare neurological disease with motor, cognitive and psychiatric manifestations. It is caused by mutations in the HEXA or HEXB genes. Although cerebellar structural and metabolic impairments have been established, global brain functional impairments in this disease remain unknown. In this first functional MRI (fMRI) report on LOGG (N=14), we took an exploratory, multi-pronged approach by assessing impairments in several resting-state fMRI signal characteristics: fMRI signal strength, neurovascular coupling, static and time-varying functional connectivity, and network topology. Contrary to the predominance of cerebellar aberrations in prior non-functional studies, we found more widespread cortical aberrations (p<0.05, FDR-corrected) mainly in cognitive control networks but also in the default mode and somatomotor networks. There was reduced fMRI signal strength, enhanced neurovascular coupling, pathological hyper-connectivity, and altered temporal variability of connectivity in the LOGG cohort. We also observed an imbalance between functional segregation and integration as seen in other psychiatric/neurological disorders, with heightened segregation and suppressed integration (i.e., inefficient brain-wide communication). Some of these imaging markers were significantly associated with clinical measures, as well as with HEXA and HEXB gene expression. These aberrations might contribute to psychiatric symptoms (psychosis, mood disturbances), cognitive impairments (memory, attention, executive function), and oculomotor disturbances commonly seen in LOGG. Future LOGG imaging studies should probe brain function in addition to structure/metabolism while looking for mechanistic insights beyond the cerebellum.

Time-Frequency Characterization of Resting Brain in Bipolar Disorder during Euthymia-A Preliminary Study

Article

Full-text available

May 2021
BSRCCS

The goal of this paper is to investigate the baseline brain activity in euthymic bipolar disorder (BD) patients by comparing it to healthy controls (HC) with the use of a variety of resting state functional magnetic resonance imaging (rs-fMRI) analyses, such as amplitude of low frequency fluctuations (ALFF), fractional ALFF (f/ALFF), ALFF-based functional connectivity (FC), and r egional homogeneity (ReHo). We hypothesize that above-mentioned techniques will differentiate BD from HC indicating dissimilarities between the groups within different brain structures. Forty-two participants divided into two groups of euthymic BD patients (n = 21) and HC (n = 21) underwent rs-fMRI evaluation. Typical band ALFF, slow-4, slow-5, f/ALFF, as well as ReHo indexes were analyzed. Regions with altered ALFF were chosen as ROI for seed-to-voxel analysis of FC. As opposed to HC, BD patients revealed: increased ALFF in left insula; increased slow-5 in left middle temporal pole; increased f/ALFF in left superior frontal gyrus, left superior temporal gyrus, left middle oc-cipital gyrus, right putamen, and bilateral thalamus. There were no significant differences between BD and HC groups in slow-4 band. Compared to HC, the BD group presented higher ReHo values in the left superior medial frontal gyrus and lower ReHo values in the right supplementary motor area. FC analysis revealed significant hyper-connectivity within the BD group between left insula and bilateral middle frontal gyrus, right superior parietal gyrus, right supramarginal gyrus, left inferior parietal gyrus, left cerebellum, and left supplementary motor area. To our best knowledge, this is the first rs-fMRI study combining ReHo, ALFF, f/ALFF, and subdivided frequency bands (slow-4 and slow-5) in euthymic BD patients. ALFF, f/ALFF, slow-5, as well as REHO analysis revealed significant differences between two studied groups. Although results obtained with the above methods enable to identify group-specific brain structures, no overlap between the brain regions was detected. This indicates that combination of foregoing rs-fMRI methods may complement each other, revealing the bigger picture of the complex resting state abnormalities in BD. Citation: Chrobak, A.A.; Bohaterewicz, B.; Sobczak, A.M.; Marszał-Wiśniewska, M.; Tereszko, A.; Krupa, A.; Ceglarek, A.; Fafrowicz, M.; Bryll, A.; Marek, T.; Dudek.; Siwek, M. Time-Frequency Characterization of Resting Brain in Bipolar Disorder during Euthymia-A Preliminary Study. Brain Sci. 2021,

Cognitive remediation therapy modulates intrinsic neural activity in patients with major depression

Article

Sep 2019

Background Cognitive impairment is a core feature of major depressive disorder (MDD). Cognitive remediation may improve cognition in MDD, yet so far, the underlying neural mechanisms are unclear. This study investigated changes in intrinsic neural activity in MDD after a cognitive remediation trial. Methods In a longitudinal design, 20 patients with MDD and pronounced cognitive deficits and 18 healthy controls (HC) were examined using resting-state functional magnetic resonance imaging. MDD patients received structured cognitive remediation therapy (CRT) over 5 weeks. The whole-brain fractional amplitude of low-frequency fluctuations was computed before the first and after the last training session. Univariate methods were used to address regionally-specific effects, and a multivariate data analysis strategy was employed to investigate functional network strength (FNS). Results MDD patients significantly improved in cognitive function after CRT. Baseline comparisons revealed increased right caudate activity and reduced activity in the left frontal cortex, parietal lobule, insula, and precuneus in MDD compared to HC. In patients, reduced FNS was found in a bilateral prefrontal system at baseline ( p < 0.05, uncorrected). In MDD, intrinsic neural activity increased in right inferior frontal gyrus after CRT ( p < 0.05, small volume corrected). Left inferior parietal lobule, left insula, left precuneus, and right caudate activity showed associations with cognitive improvement ( p < 0.05, uncorrected). Prefrontal network strength increased in patients after CRT, but this increase was not associated with improved cognitive performance. Conclusions Our findings support the role of intrinsic neural activity of the prefrontal cortex as a possible mediator of cognitive improvement following CRT in MDD.

Detection of low-frequency oscillations in neonatal piglets with speckle contrast diffuse correlation tomography

Article

May 2023

Disrupted functional connectivity associated with cognitive impairment in generalized anxiety disorder (GAD) and comorbid GAD and depression: a follow-up fMRI study

Article

Nov 2023

Background: Impaired functional connectivity between the bilateral hemispheres may serve as the neural substrate for anxiety and depressive disorders, yet its role in comorbid generalized anxiety disorder (GAD) and depression, as well as the effect of treatment on this connectivity, remains unclear. We sought to examine functional connectivity between homotopic regions of the 2 hemispheres (voxel-mirrored homotopic connectivity [VMHC]) among people with GAD with and without comorbid depression at baseline and after a 4-week paroxetine treatment. Methods: Drug-naïve patients with GAD, with or without comorbid depression and healthy controls underwent functional magnetic resonance imaging and clinical assessments at baseline and after treatment. We compared VMHC and seed-based functional connectivity across the 3 groups. We performed correlation analysis and support vector regression (SVR) to examine the intrinsic relationships between VMHC and symptoms. Results: Both patient groups (n = 40 with GAD only, n = 58 with GAD and depression) showed decreased VMHC in the precuneus, posterior cingulate cortex and lingual gyrus compared with healthy controls (n = 54). Moreover, they showed decreased VMHC in different brain regions compared with healthy controls. However, we did not observe any significant differences between the 2 patient groups. Seeds from abnormal VMHC clusters in patient groups had decreased functional connectivity. Voxel-mirrored homotopic connectivity in the precuneus, posterior cingulate cortex and lingual gyrus was negatively correlated with cognitive impairment among patients with GAD only and among all patients. The SVR analysis based on abnormal VMHC showed significant positive correlations (p < 0.0001) between predicted and actual treatment responses. However, we did not observe significant differences in VMHC or functional connectivity after treatment. Limitations: A notable dropout rate and intergroup somatic symptom variations may have biased the results. Conclusion: Patients with GAD with or without comorbid depression exhibited shared and distinct abnormal VMHC patterns, which might be linked to their cognitive deficits. These patterns have the potential to serve as prognostic biomarkers for GAD.Clinical trial registration: ClinicalTrials.gov NCT03894085.

Hyperthymic temperament predicts neural responsiveness for nonmonetary reward

Article

Full-text available

Sep 2023

Aim Hyperthymic temperament is a cheerful action orientation that is suggested to have a protective effect on depressive symptoms. We recently reported that hyperthymic temperament can positively predict activation of reward‐related brain areas in anticipation of monetary rewards, which could serve as a biomarker of hyperthymic temperament. However, the relationship between hyperthymic temperament and neural responsiveness to nonmonetary rewards (i.e., feedback indicating success in a task) remains unclear. Methods Healthy participants performed a modified monetary incentive delay task inside a functional magnetic resonance imaging scanner. To examine the effect of nonmonetary positive feedback, the participants performed feedback and no‐feedback trials. We explored brain regions whose neural responsiveness to nonmonetary rewards was predicted by hyperthymic temperament. Results There was premotor area activation in anticipation of a nonmonetary reward, which was negatively predicted by hyperthymic temperament. Moreover, brain areas located mainly in the primary somatosensory area and somatosensory association area were activated by performance feedback, which was positively predicted by hyperthymic temperament. Conclusion We found that hyperthymic temperament is related to neural responsiveness to both monetary and nonmonetary rewards. This may be related to the process of affective regulation in the somatosensory area.

Neural correlates of severity in major depressive disorder: A combined structural and resting-state functional MRI study

Article

Full-text available

Sep 2023

Repetitive Negative Thinking-Specific and Nonspecific White Matter Tracts Engaged by Historical Psychosurgical Targets for Depression

Article

Full-text available

Mar 2023
BIOL PSYCHIAT

Background: Repetitive negative thinking (RNT) is a frequent symptom of depression (MDD) associated to poor outcomes and treatment resistance. While most studies on RNT have focused on structural and functional characteristics of gray matter, this study aimed to examine the association between white matter (WM) tracts and interindividual variability in RNT. Methods: A probabilistic tractography approach was used to characterize differences in the size and anatomical trajectory of WM fibers traversing psychosurgery targets historically useful in the treatment of MDD (anterior capsulotomy, anterior cingulotomy, and subcaudate tractotomy), in patients with MDD and low (n = 53) or high RNT (n = 52), and healthy controls (HC, n = 54). MDD samples were propensity matched on depression and anxiety severity and demography. Results: WM tracts traversing left-hemisphere targets and reaching the ventral anterior body of the corpus callosum (thus extending to contralateral regions) were larger in MDD and high RNT compared to low RNT (effect size D = 0.27, p = 0.042) and HC (D = 0.23, p = 0.02). MDD was associated to greater size of tracts that converge onto the right medial orbitofrontal cortex, regardless of RNT intensity. Other RNT-nonspecific findings in MDD involved tracts reaching the left primary motor and the right primary somatosensory cortices. Conclusions: This study provides the first evidence that WM connectivity patterns, which could become targets of intervention, differ between high- and low-RNT MDD participants. These WM differences extend to circuits that are not specific to RNT, possibly subserving reward mechanisms and psychomotor activity.

Resting-state functional alterations in patients with brain arteriovenous malformations involving language areas

Article

Full-text available

Feb 2023
HUM BRAIN MAPP

Brain arteriovenous malformations (AVMs) may involve language areas but usually do not lead to aphasia. This study evaluated resting-state functional alterations and investigated the language reorganization mechanism in AVM patients. Thirty-nine patients with AVMs involving language areas and 32 age- and sex-matched healthy controls were prospectively enrolled. The AVM patients were categorized into three subgroups according to lesion location: the frontal (15 patients), temporal (14 patients), and parietal subgroups (10 patients). All subjects underwent resting-state functional magnetic resonance imaging (rs-fMRI), and the amplitude of low-frequency fluctuation (ALFF) approach was applied to analyze rs-fMRI data. Language abilities were normal in all participants based on the Western Aphasia Battery. Compared with those of healthy subjects, ALFF values significantly increased (FDR corrected p < .01) in the anterior part of the right putamen in the frontal AVM subgroup, in the posterior part of the right inferior and middle temporal gyrus in the temporal AVM subgroup, and in the inferior lateral part of the left cerebellar hemisphere (lobule VIII) and the right inferior parietal lobule in the parietal AVM subgroup. Functional annotation using Neurosynth indicated that the ALFF t-map was only significantly positively associated with the language-related domain (FDR corrected p < .01). In patients with AVMs involving the language cortex, language network reorganization occurs to maintain normal language abilities. The brain areas recruited into the reorganized language network were located in the right cerebral and left cerebellar hemispheres, both of which are nondominant hemispheres. Differences in lesion location led to distinct reorganization patterns.

The thalamus is the causal hub of intervention in patients with major depressive disorder: Evidence from the Granger causality analysis

Article

Full-text available

Dec 2022

Major depressive disorder (MDD) is the leading mental disorder and afflicts more than 350 million people worldwide. The underlying neural mechanisms of MDD remain unclear, hindering the accurate treatment. Recent brain imaging studies have observed functional abnormalities in multiple brain regions in patients with MDD, identifying core brain regions is the key to locating potential therapeutic targets for MDD. The Granger causality analysis (GCA) measures directional effects between brain regions and, therefore, can track causal hubs as potential intervention targets for MDD. We reviewed literature employing GCA to investigate abnormal brain connections in patients with MDD. The total degree of effective connections in the thalamus (THA) is more than twice that in traditional targets such as the superior frontal gyrus and anterior cingulate cortex. Altered causal connections in patients with MDD mainly included enhanced bottom-up connections from the thalamus to various cortical and subcortical regions and reduced top-down connections from these regions to the THA, indicating excessive uplink sensory information and insufficient downlink suppression information for negative emotions. We suggest that the thalamus is the most crucial causal hub for MDD, which may serve as the downstream target for non-invasive brain stimulation and medication approaches in MDD treatment.

Resting state functional connectivity as a marker of internalizing disorder onset in high-risk youth

Article

Full-text available

Dec 2022

While research has linked alterations in functional connectivity of the default mode (DMN), cognitive control (CCN), and salience networks (SN) to depression and anxiety, little research has examined whether these alterations may be premorbid vulnerabilities. This study examined resting state functional connectivity (RSFC) of the CCN, DMN, and SN as markers of risk for developing an onset of a depressive or anxiety disorder in adolescents at high familial risk for these disorders. At baseline, 135 participants aged 11–17 completed resting‑state functional magnetic resonance imaging, measures of internalizing symptoms, and diagnostic interviews to assess history of depressive and anxiety disorders. Diagnostic assessments were completed again at 9‑ or 18‑month follow‑up for 112 participants. At baseline, increased CCN connectivity to areas of the visual network, and decreased connectivity between the left SN and the precentral gyrus, predicted an increased likelihood of a new onset at follow‑up. Increased connectivity between the right SN and postcentral gyrus at baseline predicted first episode onsets at follow‑up. Altered connectivity between these regions may represent a risk factor for developing a clinically significant onset of an internalizing disorder. Results may have implications for understanding the neural bases of internalizing disorders for early identification and prevention efforts.

Neural activity changes in first-episode, drug-naïve patients with major depressive disorder after transcutaneous auricular vagus nerve stimulation treatment: A resting-state fMRI study

Article

Full-text available

Oct 2022

Introduction Major depressive disorder (MDD) is a disease with prominent individual, medical, and economic impacts. Drug therapy and other treatment methods (such as Electroconvulsive therapy) may induce treatment-resistance and have associated side effects including loss of memory, decrease of reaction time, and residual symptoms. Transcutaneous auricular vagus nerve stimulation (taVNS) is a novel and non-invasive treatment approach which stimulates brain structures with no side-effects. However, it remains little understood whether and how the neural activation is modulated by taVNS in MDD patients. Herein, we used the regional homogeneity (ReHo) to investigate the brain activity in first-episode, drug-naïve MDD patients after taVNS treatment. Materials and methods Twenty-two first-episode, drug-naïve MDD patients were enrolled in the study. These patients received the first taVNS treatment at the baseline time, and underwent resting-state MRI scanning twice, before and after taVNS. All the patients then received taVNS treatments for 4 weeks. The severity of depression was assessed by the 17-item Hamilton Depression Rating Scale (HAMD) at the baseline time and after 4-week’s treatment. Pearson analysis was used to assess the correlation between alterations of ReHo and changes of the HAMD scores. Two patients were excluded due to excessive head movement, two patients lack clinical data in the fourth week, thus, imaging analysis was performed in 20 patients, while correlation analysis between clinical and imaging data was performed in only 18 patients. Results There were significant differences in the ReHo values in first-episode, drug-naïve MDD patients between pre- or post- taVNS. The primary finding is that the patients exhibited a significantly lower ReHo in the left/right median cingulate cortex, the left precentral gyrus, the left postcentral gyrus, the right calcarine cortex, the left supplementary motor area, the left paracentral lobule, and the right lingual gyrus. Pearson analysis revealed a positive correlation between changes of ReHo in the right median cingulate cortex/the left supplementary motor area and changes of HAMD scores after taVNS. Conclusion The decreased ReHo were found after taVNS. The sensorimotor, limbic and visual-related brain regions may play an important role in understanding the underlying neural mechanisms and be the target brain regions in the further therapy.

Intrinsic brain abnormalities in female major depressive disorder patients with childhood trauma: A resting-state functional magnetic resonance imaging study

Article

Full-text available

Aug 2022

Objective Childhood trauma is a strong predictor of major depressive disorder (MDD). Women are more likely to develop MDD than men. However, the neural basis of female MDD patients with childhood trauma remains unclear. We aimed to identify the specific brain regions that are associated with female MDD patients with childhood trauma. Methods We recruited 16 female MDD patients with childhood trauma, 16 female MDD patients without childhood trauma, and 20 age- and education level-matched healthy controls. All participants underwent resting-state functional magnetic resonance imaging (MRI). Regional brain activity was evaluated as the amplitude of low-frequency fluctuation (ALFF). Furthermore, functional connectivity (FC) analyses were performed on areas with altered ALFF to explore alterations in FC patterns. Results There was increased ALFF in the left middle frontal gyrus (MFG) and the right postcentral gyrus (PoCG) in MDD with childhood trauma compared with MDD without childhood trauma. The areas with significant ALFF discrepancies were selected as seeds for the FC analyses. There was increased FC between the left MFG and the bilateral putamen gyrus. Moreover, ALFF values were correlated with childhood trauma severity. Conclusion Our findings revealed abnormal intrinsic brain activity and FC patterns in female MDD patients with childhood trauma, which provides new possibilities for exploring the pathophysiology of this disorder in women.

The neural correlates of amplitude of low-frequency fluctuation: a multimodal resting-state MEG and fMRI–EEG study

Article

Mar 2022

The amplitude of low-frequency fluctuation (ALFF) describes the regional intensity of spontaneous blood-oxygen-level-dependent signal in resting-state functional magnetic resonance imaging (fMRI). How the fMRI–ALFF relates to the amplitude in electrophysiological signals remains unclear. We here aimed to investigate the neural correlates of fMRI–ALFF by comparing the spatial difference of amplitude between the eyes-closed (EC) and eyes-open (EO) states from fMRI and magnetoencephalography (MEG), respectively. By synthesizing MEG signal into amplitude-based envelope time course, we first investigated 2 types of amplitude in MEG, meaning the amplitude of neural activities from delta to gamma (i.e. MEG–amplitude) and the amplitude of their low-frequency modulation at the fMRI range (i.e. MEG–ALFF). We observed that the MEG–ALFF in EC was increased at parietal sensors, ranging from alpha to beta; whereas the MEG–amplitude in EC was increased at the occipital sensors in alpha. Source-level analysis revealed that the increased MEG–ALFF in the sensorimotor cortex overlapped with the most reliable EC–EO differences observed in fMRI at slow-3 (0.073–0.198 Hz), and these differences were more significant after global mean standardization. Taken together, our results support that (i) the amplitude at 2 timescales in MEG reflect distinct physiological information and that (ii) the fMRI–ALFF may relate to the ALFF in neural activity.

Altered Brain Function and Causal Connectivity Induced by Repetitive Transcranial Magnetic Stimulation Treatment for Major Depressive Disorder

Article

Full-text available

Mar 2022

Objective Repetitive transcranial magnetic stimulation (rTMS) can effectively improve depression symptoms in patients with major depressive disorder (MDD); however, its mechanism of action remains obscure. This study explored the neuralimaging mechanisms of rTMS in improving depression symptoms in patients with MDD. Methods In this study, MDD patients with first-episode, drug-naive (n = 29) and healthy controls (n = 33) were enrolled. Depression symptoms before and after rTMS treatment were assessed using the Hamilton Depression Rating Scale (HAMD-17). Resting-state functional magnetic resonance imaging (rs-fMRI) data were collected both before and after the treatment. Changes in the brain function after the treatment were compared using the following two indices: the amplitude of the low-frequency fluctuation (ALFF) and regional homogeneity (ReHo), which are sensitive for evaluating spontaneous neuronal activity. The brain region with synchronous changes was selected as the seed point, and the differences in the causal connectivity between the seed point and whole brain before and after rTMS treatment were investigated via Granger causality analysis (GCA). Results Before treatment, patients with MDD had significantly lower ALFF in the left superior frontal gyrus (p < 0.01), higher ALFF in the left middle frontal gyrus and left precuneus (p < 0.01), and lower ReHo in the left middle frontal and left middle occipital gyri (p < 0.01) than the values observed in healthy controls. After the rTMS treatment, the ALFF was significantly increased in the left superior frontal gyrus (p < 0.01) and decreased in the left middle frontal gyrus and left precuneus (p < 0.01). Furthermore, ReHo was significantly increased in the left middle frontal and left middle occipital gyri (p < 0.01) in patients with MDD. Before treatment, GCA using the left middle frontal gyrus (the brain region with synchronous changes) as the seed point revealed a weak bidirectional causal connectivity between the middle and superior frontal gyri as well as a weak causal connectivity from the inferior temporal to the middle frontal gyri. After treatment, these causal connectivities were strengthened. Moreover, the causal connectivity from the inferior temporal gyrus to the middle frontal gyri negatively correlated with the total HAMD-17 score (r = −0.443, p = 0.021). Conclusion rTMS treatment not only improves the local neural activity in the middle frontal gyrus, superior frontal gyrus, and precuneus but also strengthens the bidirectional causal connectivity between the middle and superior frontal gyri and the causal connectivity from the inferior temporal to the middle frontal gyri. Changes in these neuroimaging indices may represent the neural mechanisms underlying rTMS treatment in MDD. Clinical Trial Registration This study was registered in the Chinese Clinical Trial Registry (Registration number: ChiCTR1800019761).

Intrinsic Brain Activity in Temporal Lobe Epilepsy With and Without Depression: Insights From EEG Microstates

Article

Full-text available

Jan 2022

Background: Depression is the most common psychiatric comorbidity of temporal lobe epilepsy (TLE). In the recent years, studies have focused on the common pathogenesis of TLE and depression. However, few of the studies focused on the dynamic characteristics of TLE with depression. We tested the hypotheses that there exist abnormalities in microstates in patients with TLE with depression. Methods: Participants were classified into patients with TLE with depression (PDS) (n = 19) and patients with TLE without depression (nPDS) (n = 19) based upon the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V). Microstate analysis was applied based on 256-channel electroencephalography (EEG) to detect the dynamic changes in whole brain. The coverage (proportion of time spent in each state), frequency of occurrence, and duration (average time of each state) were calculated. Results: Patients with PDS showed a shorter mean microstate duration with higher mean occurrence per second compared to patients with nPDS. There was no difference between the two groups in the coverage of microstate A–D. Conclusion: This is the first study to present the temporal fluctuations of EEG topography in comorbid depression in TLE using EEG microstate analysis. The temporal characteristics of the four canonical EEG microstates were significantly altered in patients with TLE suffer from comorbid depression.

Capturing Neuroplastic Changes after iTBS in Patients with Post-Stroke Aphasia: A Pilot fMRI Study

Article

Full-text available

Oct 2021
BSRCCS

Intermittent theta-burst stimulation (iTBS) is a high-efficiency transcranial magnetic stimulation (TMS) paradigm that has been applied to post-stroke aphasia (PSA). However, its efficacy mechanisms have not been clarified. This study aimed to explore the immediate effects of iTBS of the primary motor cortex (M1) of the affected hemisphere, on the functional activities and connectivity of the brains of PSA patients. A total of 16 patients with aphasia after stroke received iTBS with 800 pulses for 300 s. All patients underwent motor, language, and cognitive assessments and resting-state functional MRI scans immediately before and after the iTBS intervention. Regional, seed-based connectivity, and graph-based measures were used to test the immediate functional effects of the iTBS intervention, including the fractional amplitude of low-frequency fluctuation (fALFF), degree centrality (DC), and functional connectivity (FC) of the left M1 area throughout the whole brain. The results showed that after one session of iTBS intervention, the fALFF, DC, and FC values changed significantly in the patients’ brains. Specifically, the DC values were significantly higher in the right middle frontal gyrus and parts of the left parietal lobe (p < 0.05), while fALFF values were significantly lower in the right medial frontal lobe and parts of the left intracalcarine cortex (p < 0.05), and the strength of the functional connectivity between the left M1 area and the left superior frontal gyrus was reduced (p < 0.05). Our findings provided preliminary evidences that the iTBS on the ipsilesional M1 could induce neural activity and functional connectivity changes in the motor, language, and other brain regions in patients with PSA, which may promote neuroplasticity and functional recovery.

Altered frontal connectivity after sleep deprivation predicts sustained attentional impairment: A resting-state functional magnetic resonance imaging study

Article

Full-text available

Mar 2021

A series of studies have shown that sleep loss impairs one’s capability for sustained attention. However, the underlying neurobiological mechanism linking sleep loss with sustained attention has not been elucidated. The present study aimed to investigate the effect of sleep deprivation on the resting‐state brain and explored whether the magnitude of vigilance impairment after acute sleep deprivation can be predicted by measures of spontaneous fluctuations and functional connectivity. We implemented resting‐state functional magnetic resonance imaging with 42 participants under both normal sleep and 24‐hr sleep‐deprivation conditions. The amplitude of low‐frequency fluctuations (ALFF) and functional connectivity was used to investigate the neurobiological change caused by sleep deprivation, and the psychomotor vigilance task (PVT) was used to measure sustained attention in each state. Correlation analysis was used to investigate the relationship between the change in ALFF/functional connectivity and vigilance performance. Sleep deprivation induced significant reductions in ALFF in default mode network nodes and frontal‐parietal network nodes, while inducing significant increments of ALFF in the bilateral thalamus, motor cortex, and visual cortex. The increased ALFF in the visual cortex was correlated with increased PVT lapses. Critically, decreased frontal‐thalamus connectivity was correlated with increased PVT lapses, while increased frontal‐visual connectivity was correlated with increased PVT lapses. The findings indicated that acute sleep deprivation induced a robust alteration in the resting brain, and sustained attentional impairment after sleep deprivation could be predicted by altered frontal connectivity with crucial neural nodes of stimulus input, such as the thalamus and visual cortex.

Gray Matter and Regional Brain Activity Abnormalities in Subclinical Hypothyroidism

Article

Full-text available

Feb 2021

Background Subclinical hypothyroidism (SCH) brain structure and resting state of functional activity have remained unexplored.PurposeTo investigate gray matter volume (GMV) and regional brain activity with the fractional amplitude of low-frequency fluctuations (fALFF) in subclinical hypothyroidism (SCH) patients before and after treatment.Material and Methods We enrolled 54 SCH and 41 age-, sex-, and education-matched controls. GMV and fALFF of SCH were compared with controls and between pre- and post-treatment within SCH group. Correlations of GMV and fALFF in SCH with thyroid function status and mood scales were assessed by multiple linear regression analysis.ResultsCompared to controls, GMV in SCH was significantly decreased in Orbital part of inferior frontal, superior frontal, pre-/postcentral, inferior occipital, and temporal pole gyrus. FALFF values in SCH were significantly increased in right angular, left middle frontal, and left superior frontal gyrus. After treatment, there were no significant changes in GMV and the local brain function compared to pre-treatment, however the GMV and fALFF of the defective brain areas were improved. Additionally, decreased values of fALFF in left middle frontal gyrus were correlated with increased mood scales.Conclusion In this study we found that patients with SCH, the gray matter volume in some brain areas were significantly reduced, and regional brain activity was significantly increased. After treatment, the corresponding structural and functional deficiencies had a tendency for improvement. These changes may reveal the neurological mechanisms of mood disorder in SCH patients.

Altered neuronal spontaneous activity correlates with glutamate concentration in medial prefrontal cortex of major depressed females: An fMRI-MRS study Journal of Affective Disorders

Article

Full-text available

Apr 2016

Background: Major depressive disorder (MDD) is twice more prevalent in females than in males. Yet, there have only been a few studies on the functional brain activity in female MDD patients and the detailed mechanisms underlying their neurobiology merit further investigations. In the present work, we used combined fMRI-MRS methods to investigate the altered intrinsic neuronal activity and its association with neurotransmitter concentration in female MDD patients. Methods: The whole brain amplitude of low frequency fluctuation (ALFF) analysis using resting state functional magnetic resonance imaging (fMRI) was performed to explore the alteration of intrinsic neuronal signals in MDD females (n¼ 11) compared with female healthy controls (n¼ 11). With a specific interest in the medial prefrontal cortex (mPFC) area, we quantified the concentration of amino acid neurotransmitters including GABA ((r-aminobutyric acid)), Glu (Glutamate), and Glx (Glutamate þ Glutamine) using 1 H-MRS technology. Moreover, we conducted Pearson correlation analysis between the ALFF value and neurotransmitter concentration to find out the functional-biochemical relation in mPFC area. The relationship between the meta-bolites concentration and MDD symptomatology was also examined through Spearman correlation analysis. Results: We found that the female MDD patients showed increased neuronal spontaneous activity in left medial prefrontal cortex (mPFC) and left middle frontal cortex, with decreased ALFF level in right putamen and right middle temporal cortex (po0.01, Alphasim corrected). The ALFF in mPFC was shown positively correlated with Glu concentration in female MDD patients (r¼0.67, p¼0.023). The Glu concentration in mPFC was positively correlated with patients HAMA scores (r¼0.641, p¼ 0.033). Limitations: The relatively small sample size, metabolite information acquired only in mPFC and not all patients were unmedicated are the major limitations of our study. Conclusions: Using combined fMRI-MRS methods, we found increased spontaneous neuronal activity was correlated with Glu concentration in mPFC of female MDD patients. Other regions including left middle frontal gyrus, right putamen and middle temporal gyrus also showed altered spontaneous neuronal activities. The abnormal intrinsic neuronal activities in fronto-cortical regions shed light on the pathogenesis underlying MDD females. The multimodal resting-state neuroimaging technique served as a useful tool for functional-biochemical investigation of MDD pathophysiology.

Sequential multi-locus transcranial magnetic stimulation for treatment of obsessive-compulsive disorder with comorbid major depression: A case series

Article

Full-text available

Oct 2020
BRAIN STIMUL

Obsessive-compulsive disorder (OCD) and major depressive disorder (MDD) are highly comorbid [1], with depressive symptoms amplifying the chronicity and severity of OCD symptoms. Comorbid illness decreases quality of life and daily functioning [2] and is associated with greater suicidality and more frequent inpatient hospitalizations [3]. Furthermore, comorbid OCD/depression is associated with poorer response to OCD-focused psychological and pharmacological treatments [4]. Epidemiologic studies have shown that OCD symptoms generally precedes the occurrence of depression, suggesting a causal interacting model in which OCD predisposes to development of depressive symptoms [5]. In line with that causal model, Tadayonnejad et al. showed aberrant effective (directional) connectivity between OCD and MDD circuits may be a potential network mechanism of depressive symptom genesis or worsening in OCD-MDD [6]. The challenging nature of this comorbidity necessitates the development of novel, more effective treatments.

Beyond the low frequency fluctuations morning and evening differences in human brain

Preprint

Jun 2019

Human performance, alertness, and most biological functions express rhythmic fluctuations across a 24-hour-period. This phenomenon is believed to originate from differences in both circadian and homeostatic sleep-wake regulatory processes. Interactions between these processes result in time-of-day modulations of behavioral performance as well as brain activity patterns. Although the basic mechanism of the 24-hour clock is conserved across evolution, there are interindividual differences in the timing of sleep-wake cycles, subjective alertness and functioning throughout the day. The study of circadian typology differences has increased during the last few years, especially research on extreme chronotypes, which provide a unique way to investigate the effects of sleep-wake regulation on cerebral mechanisms. Using functional magnetic resonance imaging (fMRI), we assessed the influence of chronotype and time-of-day on resting-state functional connectivity. 29 extreme morning- and 34 evening-type participants underwent two fMRI sessions: about one hour after wake-up time (morning) and about ten hours after wake-up time (evening), scheduled according to their declared habitual sleep-wake pattern on a regular working day. Analysis of obtained neuroimaging data disclosed only an effect of time of day on resting-state functional connectivity; there were different patterns of functional connectivity between morning and evening sessions. The results of our study showed no differences between extreme morning-type and evening-type individuals. We demonstrate that circadian and homeostatic influences on the resting-state functional connectivity have a universal character, unaffected by circadian typology.

FMRI hemodynamic response function (HRF) as a novel marker of brain function: applications for understanding obsessive-compulsive disorder pathology and treatment response

Article

Full-text available

Jun 2021
BRAIN IMAGING BEHAV

The hemodynamic response function (HRF) represents the transfer function linking neural activity with the functional MRI (fMRI) signal, modeling neurovascular coupling. Since HRF is influenced by non-neural factors, to date it has largely been considered as a confound or has been ignored in many analyses. However, underlying biophysics suggests that the HRF may contain meaningful correlates of neural activity, which might be unavailable through conventional fMRI metrics. Here, we estimated the HRF by performing deconvolution on resting-state fMRI data from a longitudinal sample of 25 healthy controls scanned twice and 44 adults with obsessive-compulsive disorder (OCD) before and after 4-weeks of intensive cognitive-behavioral therapy (CBT). HRF response height, time-to-peak and full-width at half-maximum (FWHM) in OCD were abnormal before treatment and normalized after treatment in regions including the caudate. Pre-treatment HRF predicted treatment outcome (OCD symptom reduction) with 86.4% accuracy, using machine learning. Pre-treatment HRF response height in the caudate head and time-to-peak in the caudate tail were top-predictors of treatment response. Time-to-peak in the caudate tail, a region not typically identified in OCD studies using conventional fMRI activation or connectivity measures, may carry novel importance. Additionally, pre-treatment response height in caudate head predicted post-treatment OCD severity (R = -0.48, P = 0.001), and was associated with treatment-related OCD severity changes (R = -0.44, P = 0.0028), underscoring its relevance. With HRF being a reliable marker sensitive to brain function, OCD pathology, and intervention-related changes, these results could guide future studies towards novel discoveries not possible through conventional fMRI approaches like standard BOLD activation or connectivity.

Is there any difference in the fractional amplitude of low-frequency fluctuations between first episode major depressive disorder patients and subclinical depressive subjects?

Preprint

Full-text available

Jul 2020

Background To explore the differences in the fractional amplitude of low-frequency fluctuations (fALFF) at the whole-brain level between young adults with major depressive disorder (MDD) and those with Subclinical depression (SD). Methods Thirty-nine first-episode MDD patients, 30 SD subjects, and 37 healthy controls (HCs) were recruited. All participants underwent resting-state fMRI (Rs-fMRI) scans on a 3T MR scanner. We used the fALFF to explore spontaneous neuronal activity between groups. Results Significant differences in the fALFF were observed among the three groups. Compared with the HCs, an increased fALFF was found in the left cerebellum in MDD patients. When MDD patients were compared with SD subjects, we observed increased fALFF values in the bilateral fusiform gyrus and decreased fALFF values in the right inferior frontal gyrus, right superior frontal gyrus, right middle frontal gyrus, left cuneus and right precuneus. Compared with the HCs, the SD group demonstrated increased fALFF values in the precuneus. Additionally, a positive correlated was revealed between the fALFF values and Hamilton Anxiety Scale (HAMA)score in the right fusiform gyrus in MDD patients. Moreover, the fALFF value were negatively correlated with the Beck Depression Inventory (BDI) score in the right inferior frontal gyrus and with the age in the left fusiform gyrus in SD subjects. Conclusions Our findings suggest that alterations of cognitive and executive networks, default mode networks and visual recognition circuits may contribute to the different neural mechanisms between MDD and SD in young adult subjects.

Amplitude of low-frequency fluctuations on Alzheimer’s disease with depression: evidence from resting-state fMRI

Article

Full-text available

Jul 2020

Background The prevalence of Alzheimer’s disease (AD) comorbid with depression is common. However, the mechanisms of AD with depression remain unclear. Aims To investigate the regional alterations of brain activity of AD with depression in resting-state functional magnetic resonance imaging (rs-fMRI). Methods 154 patients with AD who met the inclusion criteria were recruited from the Zhejiang Provincial People’s Hospital from October 2014 to October 2016. According to whether the core symptoms of depression were present, patients were divided into two groups, 22 patients with AD with depression (AD-D) and 52 patients with AD without depression (AD-nD). The amplitude of low frequency fluctuations (ALFF) was compared between two groups by performing independent-samples t -test. Results Compared with the AD-D group, increased ALFF values in the bilateral superior frontal gyrus, left middle frontal gyrus and left inferior frontal gyrus were observed in the AD-nD group. The brain activity in the AD-nD group in the bilateral superior frontal gyrus, left middle frontal gyrus and the left inferior frontal gyrus was higher than the AD-D group. Conclusions Resting-state brain functional alterations may be closely bound up with the pathophysiologic features of patients with AD with depressive symptoms.

Altered brain function and clinical features in patients with first-episode, drug naïve major depressive disorder: A resting-state fMRI study

Article

Jun 2020
PSYCHIAT RES-NEUROIM

Major depressive disorder (MDD) is characterized by heterogeneous clinical performance and neurocognitive impairment. It is important to explore the correlation between global functioning and regional homogeneity (ReHo)/amplitude of low-frequency fluctuation (ALFF) values in MDD patients. 67 first-episode, drug naïve MDD patients and 69 healthy subjects were enrolled in the study. The MATRICS Consensus Cognitive Battery (MCCB) and the Functioning Assessment Short Test (FAST) were used to assess functional impairment in patients. Brain activity was assessed using ReHo and ALFF measurements. The relationship between the clinical features and altered brain function was evaluated using correlation analysis. There were significant differences in the ReHo and ALFF values between MDD patients and healthy subjects. The reduction in ReHo in the left calcarine/lingual gyrus/cuneus was negatively correlated with occupational functioning and the total FAST scores. The reduction in ALFF in the right calcarine/lingual gyrus was positively correlated with the verbal learning aspects of the MCCB. These findings suggest that the altered brain function in the default mode network (DMN) may be related to functional impairments in patients with first-episode, drug naïve major depressive disorder.

Reducing Inter-Site Variability for Fluctuation Amplitude Metrics in Multisite Resting State BOLD-fMRI Data

Article

Full-text available

Jan 2021

It has been reported that resting state fluctuation amplitude (RSFA) exhibits extremely large inter-site variability, which limits its application in multisite studies. Although global normalization (GN) based approaches are efficient in reducing the site effects, they may cause spurious results. In this study, our purpose was to find alternative strategies to minimize the substantial site effects for RSFA, without the risk of introducing artificial findings. We firstly modified the ALFF algorithm so that it is conceptually validated and insensitive to data length, then found that (a) global mean amplitude of low-frequency fluctuation (ALFF) covaried only with BOLD signal intensity, while global mean fractional ALFF (fALFF) was significantly correlated with TRs across different sites; (b) The inter-site variations in raw RSFA values were significant across the entire brain and exhibited similar trends between gray matter and white matter; (c) For ALFF, signal intensity rescaling could dramatically reduce inter-site variability by several orders, but could not fully removed the globally distributed inter-site variability. For fALFF, the global site effects could be completely removed by TR controlling; (d) Meanwhile, the magnitude of the inter-site variability of fALFF could also be reduced to an acceptable level, as indicated by the detection power of fALFF in multisite data quite close to that in monosite data. Thus our findings suggest GN based harmonization methods could be replaced with only controlling for confounding factors including signal scaling, TR and full-band power.

Beyond the Low Frequency Fluctuations: Morning and Evening Differences in Human Brain

Article

Full-text available

Aug 2019
FRONT HUM NEUROSCI

Human performance, alertness, and most biological functions express rhythmic fluctuations across a 24-h-period. This phenomenon is believed to originate from differences in both circadian and homeostatic sleep-wake regulatory processes. Interactions between these processes result in time-of-day modulations of behavioral performance as well as brain activity patterns. Although the basic mechanism of the 24-h clock is conserved across evolution, there are interindividual differences in the timing of sleep-wake cycles, subjective alertness and functioning throughout the day. The study of circadian typology differences has increased during the last few years, especially research on extreme chronotypes, which provide a unique way to investigate the effects of sleep-wake regulation on cerebral mechanisms. Using functional magnetic resonance imaging (fMRI), we assessed the influence of chronotype and time-of-day on resting-state functional connectivity. Twenty-nine extreme morning- and 34 evening-type participants underwent two fMRI sessions: about 1 h after wake-up time (morning) and about 10 h after wake-up time (evening), scheduled according to their declared habitual sleep-wake pattern on a regular working day. Analysis of obtained neuroimaging data disclosed only an effect of time of day on resting-state functional connectivity; there were different patterns of functional connectivity between morning (MS) and evening (ES) sessions. The results of our study showed no differences between extreme morning-type and evening-type individuals. We demonstrate that circadian and homeostatic influences on the resting-state functional connectivity have a universal character, unaffected by circadian typology.

EEG Resting-State Large-Scale Brain Network Dynamics Are Related to Depressive Symptoms

Article

Full-text available

Aug 2019

Background: The few previous studies on resting-state electroencephalography (EEG) microstates in depressive patients suggest altered temporal characteristics of microstates compared to those of healthy subjects. We tested whether resting-state microstate temporal characteristics could capture large-scale brain network dynamic activity relevant to depressive symptomatology. Methods: To evaluate a possible relationship between the resting-state large-scale brain network dynamics and depressive symptoms, we performed EEG microstate analysis in 19 patients with moderate to severe depression in bipolar affective disorder, depressive episode, and recurrent depressive disorder and in 19 healthy controls. Results: Microstate analysis revealed six classes of microstates (A–F) in global clustering across all subjects. There were no between-group differences in the temporal characteristics of microstates. In the patient group, higher depressive symptomatology on the Montgomery–Åsberg Depression Rating Scale correlated with higher occurrence of microstate A (Spearman’s rank correlation, r = 0.70, p < 0.01). Conclusion: Our results suggest that the observed interindividual differences in resting-state EEG microstate parameters could reflect altered large-scale brain network dynamics relevant to depressive symptomatology during depressive episodes. Replication in larger cohort is needed to assess the utility of the microstate analysis approach in an objective depression assessment at the individual level.

Alterations of amplitude of low-frequency fluctuation in treatment-resistant versus non-treatment-resistant depression patients

Article

Full-text available

Jul 2019

Purpose: We used parcellation based on 264 putative functional areas to explore the difference of amplitude of low-frequency fluctuation (ALFF) between refractory depression and non-refractory depression patients. Patients and methods: Sixty first episode drug-naive patients with major depressive disorder (MDD) and 20 healthy controls (HCs) were recruited in this study; the MDD group was divided into a refractory depression (TRD) group (n=15) and a non-refractory depression (non-TRD) group (n=18) according to the treatment effect following up for 2 years. All the subjects underwent magnetic resonance imaging scanning and performed the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and all the patients with MDD finished the 17-item Hamilton Depression Rating Scale (HAMD17). We used a parcellation based on 264 putative functional areas to explore the difference of ALFF measures in the three groups. The correlation between the abnormal ALFF value and characteristics of MDD was examined. Results: RBANS total scores and index scores in the HCs were significantly different from that of the MDD group. HAMD-17 in the TRD group was significantly higher than that of non-TRD group. Relative to HCs, MDD groups showed significantly lower ALFF within the right default mode network, which was positively correlated with the immediate memory and language in the MDD group. Compared with the non-TRD group, the TRD group showed higher ALFF in the right sensory/somatomotor hand, right auditory and left default mode network. Conclusion: Dysfunction of the somatosensory areas, right auditory and left default mode network may be a marker for specific psychopathology symptoms of TRD.

Abnormal Alterations of Regional Spontaneous Neuronal Activity in Inferior Frontal Orbital Gyrus and Corresponding Brain Circuit Alterations: A Resting-State fMRI Study in Somatic Depression

Article

Full-text available

Apr 2019

Background: Major depressive disorders often involve somatic symptoms and have been found to have fundamental differences from non-somatic depression (NSD). However, the neural basis of this type of somatic depression (SD) is unclear. The aim of this study is to use the amplitude of low-frequency fluctuation (ALFF) and functional connectivity (FC) analyses to examine the abnormal, regional, spontaneous, neuronal activity and the corresponding brain circuits in SD patients. Methods: 35 SD patients, 25 NSD patients, and 27 matched healthy controls were selected to complete this study. The ALFF and seed-based FC analyses were employed, and the Pearson correlation was determined to observe possible clinical relevance. Results: Compared with NSD, the SD group showed a significant ALFF increase in the right inferior temporal gyrus; a significant ALFF decrease in left hippocampus, right inferior frontal orbital gyrus and left thalamus; and a significant decrease in the FC value between the right inferior frontal orbital gyrus and the left inferior parietal cortex (p < 0.05, corrected). Within the SD group, the mean ALFF value of the right inferior frontal orbital gyrus was associated with the anxiety factor scores (r = –0.431, p = 0.010, corrected). Conclusions: Our findings suggest that abnormal differences in the regional spontaneous neuronal activity of the right inferior frontal orbital gyrus were associated with dysfunction patterns of the corresponding brain circuits during rest in SD patients, including the limbic-cortical systems and the default mode network. This may be an important aspect of the underlying mechanisms for pathogenesis of SD at the neural level.

EEG resting-state large-scale brain network dynamics are related to depressive symptoms

Preprint

Full-text available

Apr 2019

Background: The few previous studies on resting-state EEG microstates in depressive patients suggest altered temporal characteristics of microstates compared to those of healthy subjects. We tested whether resting-state microstate temporal characteristics could capture large-scale brain network dynamic activity relevant to depressive symptomatology. Methods: To evaluate a possible relationship between the resting-state large-scale brain network dynamics and depressive symptoms, we performed EEG microstate analysis in patients with moderate to severe depression within bipolar affective disorder, depressive episode, and periodic depressive disorder, and in healthy controls. Results: Microstate analysis revealed six classes of microstates (A-F) in global clustering across all subjects. There were no between-group differences in the temporal characteristics of microstates. In the patient group, higher symptomatology on the Montgomery-Asberg Depression Rating Scale, a questionnaire validated as measuring severity of depressive episodes in patients with mood disorders, correlated with higher occurrence of microstate A (Spearman rank correlation, r = 0.70, p < 0.01). Conclusion: Our results suggest that the observed interindividual differences in resting-state EEG microstate parameters could reflect altered large-scale brain network dynamics relevant to depressive symptomatology during depressive episodes. These findings suggest the utility of the microstate analysis approach in an objective depression assessment.

Structural alterations of the brain preceded functional alterations in major depressive disorder patients: Evidence from multimodal connectivity

Article

Apr 2019
J AFFECT DISORDERS

Background: Recent studies showed that major depressive disorder (MDD) has been involved in abnormal functional and structural connections in specific brain regions. However, comprehensive researches on MDD-related alterations in the topological organization of brain functional and structural networks are still limited. Methods: Functional network (FN) was constructed from resting-state functional MRI temporal series correlations and structural network (SN) was established by Diffusion tensor imaging (DTI) data in 58 MDD patients and 71 healthy controls (HC). The measurements of the network properties were calculated for two networks respectively. Correlations were conducted between altered network parameters and Hamilton depression scale (HAMD) score. Additionally, network resilient analysis were conducted on FN and SN. Results: The losses of small-worldness charateristics and the decline of nodal efficiency across FN and SN were found in MDD patients. Based on network-based statistic (NBS) approach, the decreased connections in MDD patients were mainly found in the superior occipital gyrus, superior temporal gyrus for FN and SN, while the increased connections were distributed in putamen, superior frontal gyrus only for SN. Compared with the FN, the SN showed less resilient to targeted or random node failure. Besides, altered edges in NBS and regions with decreased nodal efficiency were negatively associated with HAMD score in MDD patients. Limitations: The samples size is small and most of the MDD patients take different antidepressant medications. Conclusions: Alterations of SN in the brain of MDD patients preceded that of FN to some extent, and reorganization of the brain network was a mechanism which compensated for functional and structural alterations during disease progression.

Electrophysiological brain abnormalities in depression: microstate analysis on resting high-density EEG

Article

Mar 2019
BRAIN STIMUL

Abnormal resting state activity of left middle occipital gyrus and its functional connectivity in female patients with major depressive disorder

Article

Full-text available

Nov 2018
BMC PSYCHIATRY

Background: Women are more susceptible to major depressive disorder (MDD). A possible explanation is that women have a trait tendency to engage in a ruminative response style. Depending on cognitive model of depression, attention bias, memory bias and self-referential bias were closely related among depressed patients. Previous studies have explored the neural mechanism of the cognitive biases by using amplitude of low frequency fluctuations (ALFF) or functional connectivity (FC), and few combined these two metrics, especially focusing on female patients. Methods: We assessed 25 female patients diagnosed with MDD and 13 well matched healthy controls (HCs) using Rs-fMRI. Two metrics ALFF and FC based on abnormal ALFF were explored and made comparisons. Results: Compared with HCs, female patients with MDD showed that one cluster with significantly decreased ALFF in the left middle occipital gyrus(L-MOG). Furtherly we founded depressed female subjects showed significantly lower FC between the L-MOG seed and left orbitofrontal cortex, and significantly higher FC between the L-MOG seed and left medial prefrontal gyrus and left hippocampus. Conclusions: Our results showed L-MOG may act as a connection, which involved in the processing of cognitive biases of MDD by connected with limbic-cortical regions in resting state. These findings may enhance the understanding of the neurobiological mechanism in female patients with MDD.

Individual large-scale functional network mapping for major depressive disorder with electroconvulsive therapy

Article

May 2024
J AFFECT DISORDERS

Rumination and Over-Recruitment of Cognitive Control Circuits in Depression

Article

May 2024

Aberrant dynamic functional connectivity of thalamocortical circuitry in major depressive disorder

Article

Feb 2024
J ZHEJIANG UNIV-SC B

Thalamocortical circuitry has a substantial impact on emotion and cognition. Previous studies have demonstrated alterations in thalamocortical functional connectivity (FC), characterized by region-dependent hypo- or hyper-connectivity, among individuals with major depressive disorder (MDD). However, the dynamical reconfiguration of the thalamocortical system over time and potential abnormalities in dynamic thalamocortical connectivity associated with MDD remain unclear. Hence, we analyzed dynamic FC (dFC) between ten thalamic subregions and seven cortical subnetworks from resting-state functional magnetic resonance images of 48 patients with MDD and 57 healthy controls (HCs) to investigate time-varying changes in thalamocortical FC in patients with MDD. Moreover, dynamic laterality analysis was conducted to examine the changes in functional lateralization of the thalamocortical system over time. Correlations between the dynamic measures of thalamocortical FC and clinical assessment were also calculated. We identified four dynamic states of thalamocortical circuitry wherein patients with MDD exhibited decreased fractional time and reduced transitions within a negative connectivity state that showed strong correlations with primary cortical networks, compared with the HCs. In addition, MDD patients also exhibited increased fluctuations in functional laterality in the thalamocortical system across the scan duration. The thalamo-subnetwork analysis unveiled abnormal dFC variability involving higher-order cortical networks in the MDD cohort. Significant correlations were found between increased dFC variability with dorsal attention and default mode networks and the severity of symptoms. Our study comprehensively investigated the pattern of alteration of the thalamocortical dFC in MDD patients. The heterogeneous alterations of dFC between the thalamus and both primary and higher-order cortical networks may help characterize the deficits of sensory and cognitive processing in MDD.

Deciphering Neural Codes: A Resource Search Network Perspective on Brain Connectivity

Conference Paper

Feb 2024

Aishwarya Vijayan

Associations between frequent nightmares, nightmare distress and depressive symptoms in adolescent psychiatric patients

Article

Mar 2023
SLEEP MED

Background: Nightmares are common in patients with psychiatric disorders. Patients with psychiatric disorders often experience depressive symptoms. Nightmares have been associated with depressive symptoms among adolescents. Previous studies have explored the mediating role of nightmare distress in the relationship between frequent nightmares and depressive symptoms in the general adolescent population. We aimed to explore the associations between frequent nightmares, nightmare distress, and depressive symptoms in Chinese adolescent patients with psychiatric disorders. Methods: A total of 408 adolescents participated in this study. A self-administered questionnaire was used to measure nightmare frequency, nightmare distress, depressive symptoms, and covariates. Linear regressions and mediation analyses were performed to examine the associations between nightmare frequency, nightmare distress, and depressive symptoms. Results: The mean age of participants was 15.31 ± 1.88 years, and 152 (37.3%) were boys. The prevalence of frequent nightmares in adolescent patients with psychosis was 49.3%. Girls reported more frequent nightmares and had significantly higher scores of depressive symptoms and nightmare distress. Patients with frequent nightmares had higher scores of nightmare distress and depressive symptoms. Frequent nightmares and nightmare distress were significantly associated with depressive symptoms. Nightmare distress had a full mediating effect on the correlation between frequent nightmares and depressive symptoms. Conclusions: In Chinese adolescent patients with psychiatric disorders, frequent nightmares and nightmare distress were associated with depressive symptoms, whereas the association between frequent nightmares and depressive symptoms was mediated by nightmare distress. Interventions for nightmare distress may be more useful in reducing depressive symptoms in adolescent patients with psychiatric disorders.

Increased subcortical brain activity in anxious but not depressed individuals

Article

Feb 2023
J PSYCHIATR RES

Background: Anxiety and depressive symptoms usually co-occur. Neuroimaging abnormalities in patients with depression and anxiety disorders are therefore related to a combination of symptoms. Here, we used a large population study to select individuals with anxiety, depressive, or both anxiety and depressive symptoms to identify whether neuroimaging differences are unique or shared between anxiety and depressive symptoms. Methods: We selected four groups of 200 individuals (anxiety, depression, anxiety and depression, controls) from the UK Biobank, matched for age, sex, intelligence, and educational attainment (total N = 800). We extracted the amplitude of low frequency fluctuations (ALFF) from resting-state functional magnetic resonance imaging data, which indexes spontaneous neuronal activity. Group differences were assessed using permutation testing to correct for multiple comparisons, with age, sex, IQ, and head motion as covariates. Results: Compared to controls, anxious individuals had higher ALFF values in many subcortical brain regions including the striatum, thalamus, medial temporal lobe, midbrain, pons, as well as the cerebellum. Anxious individuals also showed higher ALFF in the hippocampus, parahippocampal gyrus, cerebellum, and pons compared to individuals with depressive symptoms. No significant differences were found for the depression and combined anxiety/depression groups. Post-hoc tests with largest possible samples showed comparable results in the anxiety group and in the combined group, but still no significant differences for the depression group. Conclusions: Anxiety but not depressive symptoms were associated with increased subcortical activity during rest. This suggest that anxiety symptoms may have the largest contribution to the neuroimaging differences in individuals with depression and anxiety disorders.

Use of right orbitofrontal repetitive Transcranial Magnetic Stimulation (rTMS) augmentation for treatment-refractory Obsessive-Compulsive Disorder with comorbid Major Depressive Disorder

Article

Sep 2022
PSYCHIAT RES

We examined the safety and efficacy of repetitive Transcranial Magnetic Stimulation (rTMS) of the right orbitofrontal cortex (OFC) in patients with refractory obsessive-compulsive disorder (OCD) and comorbid Major Depressive Disorder. All participants (n = 26) received excitatory stimulation of the left dorsolateral prefrontal cortex followed by inhibitory stimulation of bilateral supplementary motor area for 10 sessions. In 18 patients with poor early OCD response, treatment was augmented with OFC inhibitory stimulation after the tenth treatment session. Augmentation with OFC stimulation was well-tolerated, and associated with further alleviation of both OCD and depression symptoms, particularly in individuals with more severe illnesses.

Partial resistance to citalopram in a Wistar–Kyoto rat model of depression: An evaluation using resting-state functional MRI and graph analysis

Article

Apr 2022
J PSYCHIATR RES

Wistar–Kyoto (WKY) rats as an endogenous depression model partially lack a response to classic selective serotonin reuptake inhibitors (SSRIs). Thus, this strain has the potential to be established as a model of treatment-resistant depression (TRD). However, the SSRI resistance in WKY rats is still not fully understood. In this study, WKY and control rats were subjected to a series of tests, namely, a forced swim test (FST), a sucrose preference test (SPT), and an open field test (OFT), and were scanned in a 7.0-T MRI scanner before and after three-week citalopram or saline administration. Behavioral results demonstrated that WKY rats had increased immobility in the FST and decreased sucrose preference in the SPT and central time spent in the OFT. However, citalopram did not improve immobility in the FST. The amplitude of low-frequency fluctuation (ALFF) analysis showed regional changes in the striatum and hippocampus of WKY rats. However, citalopram partially reversed the ALFF value in the dorsal part of the two regions. Functional connectivity (FC) analysis showed that FC strengths were decreased in WKY rats compared with controls. Nevertheless, citalopram partially increased FC strengths in WKY rats. Based on FC, global graph analysis demonstrated decreased network efficiency in WKY + saline group compared with control + saline group, but citalopram showed weak network efficiency improvement. In conclusion, resting-state fMRI results implied widely affected brain function at both regional and global levels in WKY rats. Citalopram had only partial effects on these functional changes, indicating a potential treatment resistance mechanism.

Altered regional brain activity and functional connectivity patterns in major depressive disorder: A function of childhood trauma or diagnosis?

Article

Jan 2022
J PSYCHIATR RES

Childhood trauma (CT) is a non-specific risk factor for major depressive disorder (MDD). However, the neurobiological mechanisms of MDD with CT remain unclear. In the present study, we sought to determine the specific brain regions associated with CT and MDD etiology. Fractional amplitude of low-frequency fluctuation (fALFF) and functional connectivity (FC) analyses were performed to assess alterations of intrinsic brain activity in MDD with CT, MDD without CT, healthy controls with CT, and healthy controls without CT. Two-by-two factorial analyses were performed to examine the effects of the factors “MDD” and “CT” on fALFF and FC. Moderator analysis was used to explore whether the severity of depression moderated the relationship between CT and aberrant fALFF. We found that the etiological effects of MDD and CT exhibited negative impacts on brain dysfunction including altered fALFF in the left postcentral gyrus, left lingual gyrus, left paracentral lobule (PCL), and left cuneus. Decreased FC was observed in the following regions: (i) the left lingual gyrus seed and the left fusiform gyrus as well as the right calcarine cortex; (ii) the left PCL seed and the left supplementary motor area, left calcarine cortex, left precentral gyrus, and right cuneus; (iii) the left postcentral gyrus seed and left superior parietal lobule, right postcentral gyrus, and left precentral gyrus. Furthermore, the severity of depression acted as a moderator in the relationship between CT and aberrant fALFF in the left PCL. These data indicate that MDD patients with and without trauma exposure are clinically and neurobiologically distinct.

Shared and distinct homotopic connectivity changes in melancholic and non-melancholic depression

Article

Mar 2021
J AFFECT DISORDERS

Objective : Previous studies have revealed different neuroimaging features between melancholic and non-melancholic major depressive disorder (MDD). However, homotopic connectivity of melancholic and non-melancholic MDD remains unknown. The present study aimed to explore common and distinct homotopic connectivity patterns of melancholic and non-melancholic MDD and their associations with clinical characteristics. Methods : Sixty-four patients with MDD and thirty-two healthy controls were scanned by resting-state functional magnetic resonance imaging (fMRI). Voxel-mirrored homotopic connectivity (VMHC) and pattern classification were applied to analyze the imaging data. Results : Relative to healthy controls, melancholic patients displayed decreased VMHC in the fusiform gyrus, posterior cingulate cortex (PCC), superior occipital gyrus (SOG), postcentral gyrus and precentral/postcentral gyrus, and non-melancholic patients displayed decreased VMHC in the PCC. Compared with non-melancholic patients, melancholic patients displayed reduced VMHC in the precentral gyrus and precentral/postcentral gyrus. Support vector machine (SVM) results exhibited VMHC in the precentral gyrus could distinguish melancholic patients from non-melancholic patients with more than 0.6 for specificity, sensitivity and accuracy. Conclusion : The study demonstrated common and distinct homotopic connectivity patterns in melancholic and non-melancholic patients. Decreased VMHC in the PCC may be a state-related change for depression, and reduced VMHC in the precentral gyrus and postcentral gyrus may be a distinctive neurobiological feature for melancholic MDD. VMHC in precentral gyrus might be served as potential imaging markers to discriminate melancholic patients from non-melancholic MDD.

Increased ALFF and functional connectivity of the right striatum in bipolar disorder patients

Article

Oct 2020
PROG NEURO-PSYCHOPH

Background Bipolar disorder (BD) is a serious neuropsychiatric disorder characterized by alternating periods of mania, depression, and euthymia. Abnormal spontaneous brain activity within the cortical-striatal neural circuits has been observed in patients with BD. However, whether the abnormality appears in patients with BD while not in a manic mood state is unclear. Methods This study collected resting-state fMRI data from 65 patients with BD who were not in a manic mood state and 85 matched healthy controls. First, we examined differences in amplitude of low-frequency fluctuations (ALFF) between the patients with BD and the healthy controls to identify regions that show abnormal local spontaneous activity in the patients. Based on the ALFF results, we conducted seed-based resting-state functional connectivity (rsFC) analysis to identify the changes in brain networks that are centered on the regions showing abnormal local spontaneous activity in the patients. Finally, we repeated these analyses in a sub-sample comprising euthymic BD patients (N = 37) and between the euthymic BD patients and all the other patients who had at least mild depressive symptoms. Results BD patients exhibited increased ALFF in the right caudate/putamen and increased rsFC in the right caudate/putamen with the right inferior parietal lobe (cluster-level FWE p < 0.05). Further analyses showed that the euthymic BD patients showed similar abnormalities in ALFF and rsFC maps as found in all patients with BD. And the euthymic BD patients were comparable with all the other patients who had at least mild depressive symptoms in ALFF values. Conclusions Our results indicated the important role of the right striatum in the baseline brain function of BD patients and suggested that the abnormality of spontaneous brain activity in the cortical-striatal neural circuits may be a trait-like variant in patients with BD. The results deepen our understanding of the neurobiological mechanisms associated with BD etiology.

Reward Functioning Abnormalities in Adolescents at High Familial Risk for Depressive Disorders

Article

Sep 2020

Background A parental history of major depressive disorder (MDD) is an established risk factor for youth MDD and clarifying the mechanisms related to familial risk transmission is critical. Aberrant reward processing is a promising biomarker of MDD risk; accordingly, the aim of the current study was to test behavioral measures of reward responsiveness and underlying frontostriatal resting activity in healthy adolescents, both with (high-risk) and without (low-risk) a maternal history of MDD. Methods Low-risk and high-risk 12-14-year-old adolescents completed a probabilistic reward task (n = 74 low-risk, n = 27 high-risk) and a resting state MRI scan (n = 61 low-risk, n = 25 high-risk). Group differences in response bias toward reward and resting ventral striatal (VS) and medial prefrontal cortex (mPFC) fractional amplitude of low frequency fluctuations (fALFF) were examined. Computational modeling was applied to dissociate reward sensitivity versus learning rate. Results High-risk adolescents showed a blunted response bias compared to low-risk adolescents. Computational modeling analyses revealed that, relative to low-risk adolescents, high-risk adolescents exhibited reduced reward sensitivity but similar learning rate. Although there were no group differences in VS and mPFC fALFF, groups differed in relationships between mPFC fALFF and response bias. Specifically, among high-risk adolescents, higher mPFC fALFF correlated with a blunted response bias, whereas there was no fALFF-response bias relationship among low-risk youth. Conclusion High-risk adolescents exhibit reward functioning impairments, which is associated with mPFC fALFF. The blunted response bias-mPFC fALFF association may reflect an excessive mPFC-mediated suppression of reward-driven behavior, which may potentiate MDD risk.

Magnetic resonance imaging of neuroinflammation in chronic pain: a role for astrogliosis?

Article

Jan 2020

Non-invasive measures of neuroinflammatory processes in humans could substantially aid diagnosis and therapeutic development for many disorders, including chronic pain. Several proton Magnetic Resonance Spectroscopy (H-MRS) metabolites have been linked with glial activity (i.e. choline and myo-inositol) and found to be altered in chronic pain patients, but their role in the neuroinflammatory cascade is not well known. Our multimodal study evaluated resting fMRI connectivity and H-MRS metabolite concentration in insula cortex in 43 patients suffering from fibromyalgia, a chronic centralized pain disorder previously demonstrated to include a neuroinflammatory component, and 16 healthy controls. Patients demonstrated elevated choline (but not myo-inositol) in anterior insula (p=0.03), with greater choline levels linked with worse pain interference (r=0.41, p=0.01). In addition, reduced resting functional connectivity between anterior insula and putamen was associated with both pain interference (whole brain analysis, pcorrected<0.01) and elevated anterior insula choline (r=-0.37, p=0.03). In fact, anterior insula/putamen connectivity statistically mediated the link between anterior insula choline and pain interference (p<0.01), highlighting the pathway by which neuroinflammation can impact clinical pain dysfunction. In order to further elucidate the molecular substrates of the effects observed, we investigated how putative neuroinflammatory H-MRS metabolites are linked with ex-vivo tissue inflammatory markers in a nonhuman primate model of neuroinflammation. Results demonstrated that cortical choline levels were correlated with glial fibrillary acidic protein, a known marker for astrogliosis (Spearman r=0.49, p=0.03). Choline, a putative neuroinflammatory H-MRS assessed metabolite elevated in fibromyalgia and associated with pain interference, may be linked with astrogliosis in these patients.

Altered baseline brain activity in children with ADHD revealed by resting-state functional MRI

Article

Full-text available

Jan 2006

Article in Press, Corrected Proof

Multimodal Brain Connectivity Analysis in Unmedicated Late-Life Depression

Article

Full-text available

Apr 2014
PLOS ONE

Late-life depression (LLD) is a common disorder associated with emotional distress, cognitive impairment and somatic complains. Structural abnormalities have been suggested as one of the main neurobiological correlates in LLD. However the relationship between these structural abnormalities and altered functional brain networks in LLD remains poorly understood. 15 healthy elderly comparison subjects from the community and 10 unmedicated and symptomatic subjects with geriatric depression were selected for this study. For each subject, 87 regions of interest (ROI) were generated from whole brain anatomical parcellation of resting state fMRI data. Whole-brain ROI-wise correlations were calculated and compared between groups. Group differences were assessed using an analysis of covariance after controlling for age, sex and education with multiple comparison correction using the false discovery rate. Structural connectivity was assessed by tract-based spatial statistics (TBSS). LLD subjects had significantly decreased connectivity between the right accumbens area (rA) and the right medial orbitofrontal cortex (rmOFC) as well as between the right rostral anterior cingulate cortex (rrACC) and bilateral superior frontal gyrus (bsSFG). Altered connectivity of rrACC with the bsSFG was significantly correlated with depression severity in depressed subjects. TBSS analysis showed a 20% reduction in fractional anisotropy (FA) in the right Forceps Minor (rFM) in depressed subjects. rFM FA values were positively correlated with rA-rmOFC and rrACC-bsFG functional connectivity values in our total study sample. Coordinated structural and functional impairment in circuits involved in emotion regulation and reward pathways play an important role in the pathophysiology of LLD.

Alterations in Amplitude of Low Frequency Fluctuation in Treatment-Naive Major Depressive Disorder Measured With Resting-State fMRI

Article

Full-text available

Oct 2014
HUM BRAIN MAPP

There are limited resting-state functional magnetic resonance imaging (fMRI) studies in major depressive disorder (MDD). Of these studies, functional connectivity analyses are mostly used. However, a new method based on the magnitude of low frequency fluctuation (LFF) during resting-state fMRI may provide important insight into MDD. In this study, we examined the amplitude of LFF (ALFF) within the whole brain during resting-state fMRI in 30 treatment-naïve MDD subjects and 30 healthy control (HC) subjects. When compared with HC, MDD subjects showed increased ALFF in the frontal cortex (including the bilateral ventral/dorsal anterior cingulate cortex, orbitofrontal cortex, premotor cortex, ventral prefrontal cortex, left dorsal lateral frontal cortex, left superior frontal cortex), basal ganglia (including the right putamen and left caudate nucleus), left insular cortex, right anterior entorhinal cortex and left inferior parietal cortex, together with decreased ALFF in the bilateral occipital cortex, cerebellum hemisphere, and right superior temporal cortex. These findings may relate to characteristics of MDD, such as excessive self-referential processing and deficits in cognitive control of emotional processing, which may contribute to the persistent and recurrent nature of the disorder. Hum Brain Mapp, 2014. © 2014 Wiley Periodicals, Inc.

First-Episode Medication-Naive Major Depressive Disorder Is Associated with Altered Resting Brain Function in the Affective Network

Article

Full-text available

Jan 2014
PLOS ONE

Major depressive disorder (MDD) has been associated with abnormal structure and function of the brain's affective network, including the amygdala and orbitofrontal cortex (OFC). However, it is unclear if alterations of resting-state function in this affective network are present at the initial onset of MDD. To examine resting-state function of the brain's affective network in first-episode, medication-naive patients with MDD compared to healthy controls (HCs). Resting-state functional magnetic resonance imaging (rs-fMRI) was performed on 32 first-episode, medication-naive young adult patients with MDD and 35 matched HCs. The amplitude of low-frequency fluctuations (ALFF) of the blood oxygen level-dependent (BOLD) signal and amygdala-seeded functional connectivity (FC) were investigated. Compared to HC, MDD patients showed reduced ALFF in the bilateral OFC and increased ALFF in the bilateral temporal lobe extending to the insular and left fusiform cortices. Enhanced anti-correlation of activity between the left amygdala seed and the left OFC was found in MDD patients but not in HCs. Reduced ALFF in the OFC suggests hypo-functioning of emotion regulation in the affective network. Enhanced anti-correlation of activity between the amygdala and OFC may reflect dysfunction of the amygdala-OFC network and additionally represent a pathological process of MDD.

Brain Network Dysfunction in Late-Life Depression: A Literature Review

Article

Full-text available

Dec 2013

As a common psychiatric disorder in the growing geriatric population, late-life depression (LLD) has a negative impact on the cognitive, affective, and somatic domains of the lives of the elderly individuals. Accumulating evidence from the structural and functional imaging studies on LLD supports a "network dysfunction model" rather than a "lesion pathology model" for understanding the underlying biological mechanism in this mental disorder. In this work, we used network dysfunction model as a conceptual framework for reviewing recent neuroimaging findings in LLD. Our focus was on 4 major neurocircuits that have been shown to be involved in LLD: default mood network, cognitive control network, affective/frontolimbic network, and corticostriatal circuits. Findings of LLD-related gray and white matter structural abnormalities and resting-state and task-based functional changes were discussed for each network separately. We extended our review by summarizing the latest works that apply graph theory-based network analysis techniques for testing alterations in whole-brain network properties associated with LLD.

Burden of Depressive Disorders by Country, Sex, Age, and Year: Findings from the Global Burden of Disease Study 2010

Article

Full-text available

Nov 2013
PLOS MED

Depressive disorders were a leading cause of burden in the Global Burden of Disease (GBD) 1990 and 2000 studies. Here, we analyze the burden of depressive disorders in GBD 2010 and present severity proportions, burden by country, region, age, sex, and year, as well as burden of depressive disorders as a risk factor for suicide and ischemic heart disease. Burden was calculated for major depressive disorder (MDD) and dysthymia. A systematic review of epidemiological data was conducted. The data were pooled using a Bayesian meta-regression. Disability weights from population survey data quantified the severity of health loss from depressive disorders. These weights were used to calculate years lived with disability (YLDs) and disability adjusted life years (DALYs). Separate DALYs were estimated for suicide and ischemic heart disease attributable to depressive disorders. Depressive disorders were the second leading cause of YLDs in 2010. MDD accounted for 8.2% (5.9%-10.8%) of global YLDs and dysthymia for 1.4% (0.9%-2.0%). Depressive disorders were a leading cause of DALYs even though no mortality was attributed to them as the underlying cause. MDD accounted for 2.5% (1.9%-3.2%) of global DALYs and dysthymia for 0.5% (0.3%-0.6%). There was more regional variation in burden for MDD than for dysthymia; with higher estimates in females, and adults of working age. Whilst burden increased by 37.5% between 1990 and 2010, this was due to population growth and ageing. MDD explained 16 million suicide DALYs and almost 4 million ischemic heart disease DALYs. This attributable burden would increase the overall burden of depressive disorders from 3.0% (2.2%-3.8%) to 3.8% (3.0%-4.7%) of global DALYs. GBD 2010 identified depressive disorders as a leading cause of burden. MDD was also a contributor of burden allocated to suicide and ischemic heart disease. These findings emphasize the importance of including depressive disorders as a public-health priority and implementing cost-effective interventions to reduce its burden. Please see later in the article for the Editors' Summary.

Toward a Neuroimaging Treatment Selection Biomarker for Major Depressive Disorder

Article

Full-text available

Jun 2013

Importance Currently, fewer than 40% of patients treated for major depressive disorder achieve remission with initial treatment. Identification of a biological marker that might improve these odds could have significant health and economic impact.Objective To identify a candidate neuroimaging “treatment-specific biomarker” that predicts differential outcome to either medication or psychotherapy.Design Brain glucose metabolism was measured with positron emission tomography prior to treatment randomization to either escitalopram oxalate or cognitive behavior therapy for 12 weeks. Patients who did not remit on completion of their phase 1 treatment were offered enrollment in phase 2 comprising an additional 12 weeks of treatment with combination escitalopram and cognitive behavior therapy.Setting Mood and anxiety disorders research program at an academic medical center.Participants Men and women aged 18 to 60 years with currently untreated major depressive disorder.Intervention Randomized assignment to 12 weeks of treatment with either escitalopram oxalate (10-20 mg/d) or 16 sessions of manual-based cognitive behavior therapy.Main Outcome and Measure Remission, defined as a 17-item Hamilton Depression Rating Scale score of 7 or less at both weeks 10 and 12, as assessed by raters blinded to treatment.Results Positive and negative predictors of remission were identified with a 2-way analysis of variance treatment (escitalopram or cognitive behavior therapy) × outcome (remission or nonresponse) interaction. Of 65 protocol completers, 38 patients with clear outcomes and usable positron emission tomography scans were included in the primary analysis: 12 remitters to cognitive behavior therapy, 11 remitters to escitalopram, 9 nonresponders to cognitive behavior therapy, and 6 nonresponders to escitalopram. Six limbic and cortical regions were identified, with the right anterior insula showing the most robust discriminant properties across groups (effect size = 1.43). Insula hypometabolism (relative to whole-brain mean) was associated with remission to cognitive behavior therapy and poor response to escitalopram, while insula hypermetabolism was associated with remission to escitalopram and poor response to cognitive behavior therapy.Conclusions and Relevance If verified with prospective testing, the insula metabolism-based treatment-specific biomarker defined in this study provides the first objective marker, to our knowledge, to guide initial treatment selection for depression.Trial Registration Registered at clinicaltrials.gov (NCT00367341)

Amplitude of Low-Frequency Oscillations in First-Episode, Treatment-Naive Patients with Major Depressive Disorder: A Resting-State Functional MRI Study

Article

Full-text available

Oct 2012
PLOS ONE

Resting-state fMRI is a novel approach to measure spontaneous brain activity in patients with major depressive disorder (MDD). Although most resting-state fMRI studies have focused on the examination of temporal correlations between low-frequency oscillations (LFOs), few studies have explored the amplitude of these LFOs in MDD. In this study, we applied the approaches of amplitude of low-frequency fluctuation (ALFF) and fractional ALFF to examine the amplitude of LFOs in MDD. A total of 36 subjects, 18 first-episode, treatment-naive patients with MDD matched with 18 healthy controls (HCs) completed the fMRI scans. Compared with HCs, MDD patients showed increased ALFF in the right fusiform gyrus and the right anterior and posterior lobes of the cerebellum but decreased ALFF in the left inferior temporal gyrus, bilateral inferior parietal lobule, and right lingual gyrus. The fALFF in patients was significantly increased in the right precentral gyrus, right inferior temporal gyrus, bilateral fusiform gyrus, and bilateral anterior and posterior lobes of the cerebellum but was decreased in the left dorsolateral prefrontal cortex, bilateral medial orbitofrontal cortex, bilateral middle temporal gyrus, left inferior temporal gyrus, and right inferior parietal lobule. After taking gray matter (GM) volume as a covariate, the results still remained. These findings indicate that MDD patients have altered LFO amplitude in a number of regions distributed over the frontal, temporal, parietal, and occipital cortices and the cerebellum. These aberrant regions may be related to the disturbances of multiple emotion- and cognition-related networks observed in MDD and the apparent heterogeneity in depressive symptom domains. Such brain functional alteration of MDD may contribute to further understanding of MDD-related network imbalances demonstrated in previous fMRI studies.

Estimating remission from untreated major depression: a systematic review and meta-analysis

Article

Full-text available

Aug 2012
PSYCHOL MED

Background: Few studies have examined spontaneous remission from major depression. This study investigated the proportion of prevalent cases of untreated major depression that will remit without treatment in a year, and whether remission rates vary by disorder severity. Method: Wait-list controlled trials and observational cohort studies published up to 2010 with data describing remission from untreated depression at ≤ 2-year follow-up were identified. Remission was defined as rescinded diagnoses or below threshold scores on standardized symptom measures. Nineteen studies were included in a regression model predicting the probability of 12-month remission from untreated depression, using logit transformed remission proportion as the dependent variable. Covariates included age, gender, study type and diagnostic measure. Results: Wait-listed compared to primary-care samples, studies with longer follow-up duration and older adult compared to adult samples were associated with lower probability of remission. Child and adolescent samples were associated with higher probability of remission. Based on adult samples recruited from primary-care settings, the model estimated that 23% of prevalent cases of untreated depression will remit within 3 months, 32% within 6 months and 53% within 12 months. Conclusions: It is undesirable to expect 100% treatment coverage for depression, given many will remit before access to services is feasible. Data were drawn from consenting wait-list and primary-care samples, which potentially over-represented mild-to-moderate cases of depression. Considering reported rates of spontaneous remission, a short untreated period seems defensible for this subpopulation, where judged appropriate by the clinician. Conclusions may not apply to individuals with more severe depression.

Is depression a disconnection syndrome? Meta-analysis of diffusion tensor imaging studies in patients with MDD

Article

Full-text available

Jun 2012
J PSYCHIATR NEUROSCI

Background: Many studies using diffusion tensor imaging (DTI) have demonstrated impaired white matter integrity in patients with major depressive disorder (MDD), with significant results found in diverse brain regions. We sought to identify whether there are consistent changes of regional white matter integrity in patients with MDD, as shown by decreased fractional anisotropy in DTI. Method: A systematic search strategy was used to identify relevant whole brain voxel-based DTI studies of patients with MDD in relation to comparison groups. Relevant databases were searched for studies published between January 1994 and February 2011 using combinations of the terms "DTI" or "diffusion tensor;" "whole brain" or "voxel-based;" and "depress*." Using the studies that met our inclusion criteria, we performed a meta-analysis of the coordinates of decreased fractional anisotropy using the activation likelihood estimation (ALE) method, which detects 3-dimensional conjunctions of coordinates from multiple studies, weighted by sample size. We then used DTIquery software for fibre tracking to locate the fascicles involved in each region. Results: We included 11 studies with a combined sample of 231 patients with MDD and 261 comparison participants, providing 50 coordinates of decreased fractional anisotropy. Our meta-analysis identified 4 consistent locations of decreased fractional anisotropy in patients with MDD: white matter in the right frontal lobe, right fusiform gyrus, left frontal lobe and right occipital lobe. Fibre tracking showed that the main fascicles involved were the right inferior longitudinal fasciculus, right inferior fronto-occipital fasciculus, right posterior thalamic radiation and interhemispheric fibres running through the genu and body of the corpus callosum. Limitations: The number of studies included was relatively small, and the DTI data acquisition and analysis techniques were heterogeneous. The ALE method cannot handle studies with no significant group differences. Conclusion: Voxel-based analysis of DTI studies of patients with MDD consistently identified decreased fractional anisotropy in the white matter fascicles connecting the prefrontal cortex within cortical (frontal, temporal and occipital lobes) and subcortical areas (amygdala and hippocampus). This isstrong evidence for the involvement of these neural circuits in the pathology of MDD.

Salience network integrity predicts default mode network function after traumatic brain injury

Article

Full-text available

Mar 2012
P NATL ACAD SCI USA

Efficient behavior involves the coordinated activity of large-scale brain networks, but the way in which these networks interact is uncertain. One theory is that the salience network (SN)--which includes the anterior cingulate cortex, presupplementary motor area, and anterior insulae--regulates dynamic changes in other networks. If this is the case, then damage to the structural connectivity of the SN should disrupt the regulation of associated networks. To investigate this hypothesis, we studied a group of 57 patients with cognitive impairments following traumatic brain injury (TBI) and 25 control subjects using the stop-signal task. The pattern of brain activity associated with stop-signal task performance was studied by using functional MRI, and the structural integrity of network connections was quantified by using diffusion tensor imaging. Efficient inhibitory control was associated with rapid deactivation within parts of the default mode network (DMN), including the precuneus and posterior cingulate cortex. TBI patients showed a failure of DMN deactivation, which was associated with an impairment of inhibitory control. TBI frequently results in traumatic axonal injury, which can disconnect brain networks by damaging white matter tracts. The abnormality of DMN function was specifically predicted by the amount of white matter damage in the SN tract connecting the right anterior insulae to the presupplementary motor area and dorsal anterior cingulate cortex. The results provide evidence that structural integrity of the SN is necessary for the efficient regulation of activity in the DMN, and that a failure of this regulation leads to inefficient cognitive control.

The Cortical Rhythms of Chronic Back Pain

Article

Full-text available

Sep 2011
J NEUROSCI

Chronic pain is maladaptive and influences brain function and behavior by altering the flow and integration of information across brain regions. Here we use a power spectral analysis to investigate impact of presence of chronic pain on brain oscillatory activity in humans. We examine changes in BOLD fluctuations, across different frequencies, in chronic back pain (CBP) patients (n = 15) as compared to healthy controls (n = 15) during resting-state fMRI. While healthy subjects exhibited a specific, frequency band-dependent, large-scale neural organization, patients showed increased high-frequency BOLD oscillations (0.12-0.20 Hz) circumscribed mainly to medial prefrontal cortex (mPFC) and parts of the default mode network. In the patients a correlation analysis related the mPFC aberrant BOLD high-frequency dynamics to altered functional connectivity to pain signaling/modulating brain regions, thus linking BOLD frequency changes to function. We also found that increased frequency fluctuations within the mPFC were temporally synchronous with spontaneous pain changes in patients during a pain-rating task. These observations provide novel insights about the nature of CBP, identifying how it disturbs the resting brain, and link high-frequency BOLD oscillations to perception.

Fractionating the Default Mode Network: Distinct Contributions of the Ventral and Dorsal Posterior Cingulate Cortex to Cognitive Control

Article

Full-text available

Mar 2011
J NEUROSCI

The posterior cingulate cortex (PCC) is a central part of the default mode network (DMN) and part of the structural core of the brain. Although the PCC often shows consistent deactivation when attention is focused on external events, anatomical studies show that the region is not homogeneous, and electrophysiological recordings in nonhuman primates suggest that it is directly involved in some forms of attention. We report a functional magnetic resonance imaging study of an attentionally demanding task (either a zero- or two-back working memory task). Standard subtraction analysis within the PCC shows a relative deactivation as task difficulty increases. In contrast, a dual-regression functional connectivity analysis reveals a clear dissociation between ventral and dorsal parts of the PCC. As task difficulty increases, the ventral PCC shows reduced integration within the DMN and less anticorrelation with the cognitive control network (CCN) activated by the task. The dorsal PCC shows an opposite pattern, with increased DMN integration and more anticorrelation. At rest, the dorsal PCC also shows functional connectivity with both the DMN and attentional networks. As expected, these results provide evidence that the PCC is involved in supporting internally directed thought, as the region is more highly integrated with the DMN at low task demands. In contrast, the task-dependent increases in connectivity between the dorsal PCC and the CCN are consistent with a role for this region in modulating the dynamic interaction between these two networks controlling the efficient allocation of attention.

Frontocingulate Dysfunction in Depression: Toward Biomarkers of Treatment Response

Article

Full-text available

Jan 2011
NEUROPSYCHOPHARMACOL

Diego Pizzagalli

Increased rostral anterior cingulate cortex (rACC) activity has emerged as a promising predictor of treatment response in depression, but neither the reliability of this relationship nor the mechanisms supporting it have been thoroughly investigated. This review takes a three-pronged approach to these issues. First, I present a meta-analysis demonstrating that the relationship between resting rACC activity and treatment response is robust. Second, I propose that the rACC plays a key role in treatment outcome because of its 'hub' position in the default network. Specifically, I hypothesize that elevated resting rACC activity confers better treatment outcomes by fostering adaptive self-referential processing and by helping to recalibrate relationships between the default network and a 'task-positive network' that comprises dorsolateral prefrontal and dorsal cingulate regions implicated in cognitive control. Third, I support this hypothesis by reviewing neuropsychological, electrophysiological, and neuroimaging data on frontocingulate dysfunction in depression. The review ends with a discussion of the limitations of current work and future directions.

The left superior temporal gyrus is a shared substrate for auditory short-term memory and speech comprehension: Evidence from 210 patients with stroke

Article

Full-text available

Nov 2009
BRAIN

Competing theories of short-term memory function make specific predictions about the functional anatomy of auditory short-term memory and its role in language comprehension. We analysed high-resolution structural magnetic resonance images from 210 stroke patients and employed a novel voxel based analysis to test the relationship between auditory short-term memory and speech comprehension. Using digit span as an index of auditory short-term memory capacity we found that the structural integrity of a posterior region of the superior temporal gyrus and sulcus predicted auditory short-term memory capacity, even when performance on a range of other measures was factored out. We show that the integrity of this region also predicts the ability to comprehend spoken sentences. Our results therefore support cognitive models that posit a shared substrate between auditory short-term memory capacity and speech comprehension ability. The method applied here will be particularly useful for modelling structure–function relationships within other complex cognitive domains.

Clinical Applications of Resting State Functional Connectivity

Article

Full-text available

Jun 2010

During resting conditions the brain remains functionally and metabolically active. One manifestation of this activity that has become an important research tool is spontaneous fluctuations in the blood oxygen level-dependent (BOLD) signal of functional magnetic resonance imaging (fMRI). The identification of correlation patterns in these spontaneous fluctuations has been termed resting state functional connectivity (fcMRI) and has the potential to greatly increase the translation of fMRI into clinical care. In this article we review the advantages of the resting state signal for clinical applications including detailed discussion of signal to noise considerations. We include guidelines for performing resting state research on clinical populations, outline the different areas for clinical application, and identify important barriers to be addressed to facilitate the translation of resting state fcMRI into the clinical realm.

Reduced capacity to sustain positive emotion in major depression reflects diminished maintenance of fronto-striatal brain activation

Article

Full-text available

Dec 2009
P NATL ACAD SCI USA

Anhedonia, the loss of pleasure or interest in previously rewarding stimuli, is a core feature of major depression. While theorists have argued that anhedonia reflects a reduced capacity to experience pleasure, evidence is mixed as to whether anhedonia is caused by a reduction in hedonic capacity. An alternative explanation is that anhedonia is due to the inability to sustain positive affect across time. Using positive images, we used an emotion regulation task to test whether individuals with depression are unable to sustain activation in neural circuits underlying positive affect and reward. While up-regulating positive affect, depressed individuals failed to sustain nucleus accumbens activity over time compared with controls. This decreased capacity was related to individual differences in self-reported positive affect. Connectivity analyses further implicated the fronto-striatal network in anhedonia. These findings support the hypothesis that anhedonia in depressed patients reflects the inability to sustain engagement of structures involved in positive affect and reward.

Intrinsic Functional Connectivity As a Tool For Human Connectomics: Theory, Properties, and Optimization

Article

Full-text available

Nov 2010
J NEUROPHYSIOL

Resting state functional connectivity MRI (fcMRI) is widely used to investigate brain networks that exhibit correlated fluctuations. While fcMRI does not provide direct measurement of anatomic connectivity, accumulating evidence suggests it is sufficiently constrained by anatomy to allow the architecture of distinct brain systems to be characterized. fcMRI is particularly useful for characterizing large-scale systems that span distributed areas (e.g., polysynaptic cortical pathways, cerebro-cerebellar circuits, cortical-thalamic circuits) and has complementary strengths when contrasted with the other major tool available for human connectomics-high angular resolution diffusion imaging (HARDI). We review what is known about fcMRI and then explore fcMRI data reliability, effects of preprocessing, analysis procedures, and effects of different acquisition parameters across six studies (n = 98) to provide recommendations for optimization. Run length (2-12 min), run structure (1 12-min run or 2 6-min runs), temporal resolution (2.5 or 5.0 s), spatial resolution (2 or 3 mm), and the task (fixation, eyes closed rest, eyes open rest, continuous word-classification) were varied. Results revealed moderate to high test-retest reliability. Run structure, temporal resolution, and spatial resolution minimally influenced fcMRI results while fixation and eyes open rest yielded stronger correlations as contrasted to other task conditions. Commonly used preprocessing steps involving regression of nuisance signals minimized nonspecific (noise) correlations including those associated with respiration. The most surprising finding was that estimates of correlation strengths stabilized with acquisition times as brief as 5 min. The brevity and robustness of fcMRI positions it as a powerful tool for large-scale explorations of genetic influences on brain architecture. We conclude by discussing the strengths and limitations of fcMRI and how it can be combined with HARDI techniques to support the emerging field of human connectomics.

Brain Imaging Correlates of Cognitive Impairment in Depression

Article

Full-text available

Oct 2009
FRONT HUM NEUROSCI

This review briefly summarises recent research on the neural basis of cognition in depression. Two broad areas are covered: emotional and non-emotional processing. We consider how research findings support models of depression based on disrupted cortico-limbic circuitry, and how modern connectivity analysis techniques can be used to test such models explicitly. Finally we discuss clinical implications of cognitive imaging in depression, and specifically the possible role for these techniques in diagnosis and treatment planning.

Reward Processing After Catecholamine Depletion in Unmedicated, Remitted Subjects with Major Depressive Disorder

Article

Full-text available

Apr 2009

We investigated whether performance on a reward processing task differs between fully remitted patients with major depressive disorder (MDD) and healthy control subjects after catecholamine depletion. Seventeen unmedicated subjects with remitted MDD (RMDD) and 13 healthy control subjects underwent catecholamine depletion with oral alpha-methyl-para-tyrosine (AMPT) in a randomized, placebo-controlled, double-blind crossover study. The main outcome measure was the reaction time on the monetary incentive delay (MID) task. A diagnosis x drug interaction was evident (p = .001), which was attributable to an increase in reaction time across all incentive levels after AMPT in RMDD subjects (p = .001) but no significant AMPT effect on reaction time in control subjects (p = .17). There was no drug x diagnosis interaction on control tasks involving working memory or attention. In the RMDD sample the AMPT-induced depressive symptoms correlated with AMPT-induced changes in reaction time at all incentive levels of the MID task (r values = .58-.82, p < .002). Under catecholamine depletion the RMDD subjects were robustly differentiated from control subjects by development of performance deficits on a reward processing task. These performance deficits correlated directly with the return of depressive symptoms after AMPT administration. The sensitivity of central reward processing systems to reductions in brain catecholamine levels thus seems to represent a trait-like marker in MDD.

Diagnostic validity of a standardized neuropsychological battery derived from Luria's Neuropsychological Tests

Article

Full-text available

Dec 1978

A. R. Luria has devised an extensive set of procedures used for neuropsychological evaluation. His tests permit the full identification of the specific deficits underlying a disorder and can be completed in about 2 hrs. The most significant flaw in the battery is a lack of standard administration and scoring that has precluded an assessment of its validity. The present study attempted to overcome these deficiencies by developing an objective form, combining Luria's procedures with the advantages of a standard test battery. The resultant test, the Luria-South Dakota Neuro-psychological Test Battery, was evaluated using 50 medical patient controls, average age 42.0 yrs, and 50 neurological patients, average age 44.3 yrs. Of the 285 measures in the battery, 253 significantly discriminated at the .05 level, and only 16 failed to discriminate at the .2 level. A discriminant analysis, using the 30 most effective items, yielded a hit rate of 100%. The battery's potential and the future research necessary are discussed. (13 ref)

The brain's default network: Anatomy, function and relevance to disease

Article

Jan 2008

Functional architecture of basal ganglia circuits: Neural substrates of parallel processing

Article

Jan 1989
TRENDS NEUROSCI

Concepts of basal ganglia organization have changed markedly over the past decade, due to significant advances in our understanding of the anatomy, physiology and pharmacology of these structures. Independent evidence from each of these fields has reinforced a growing perception that the functional architecture of the basal ganglia is essentially parallel in nature, regardless of the perspective from which these structures are viewed. This represents a significant departure from earlier concepts of basal ganglia organization, which generally emphasized the serial aspects of their connectivity. Current evidence suggests that the basal ganglia are organized into several structurally and functionally distinct 'circuits' that link cortex, basal ganglia and thalamus, with each circuit focused on a different portion of the frontal lobe. In this review, Garrett Alexander and Michael Crutcher, using the basal ganglia 'motor' circuit as the principal example, discuss recent evidence indicating that a parallel functional architecture may also be characteristic of the organization within each individual circuit.

Wechsler Adult Intelligence Scale–Third Edition

Book

Jan 1997

D Wechsler

Depression rating scale

Article

Jan 1960

M. Hamilton

Development and validation of a geriatric depression scale A preliminary report

Article

Jan 1982
PSYCHIAT RES

Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging

Article

Jan 2007

Causal interactions between fronto-parietal central executive and default-mode networks in humans

Article

Nov 2013
P NATL ACAD SCI USA

Significance Three large-scale neural networks are thought to play important roles in cognitive and emotional information processing in humans. It has been theorized that the “central executive” and “salience” networks achieve this by regulating the “default mode” network. Support for this idea comes from correlational neuroimaging studies; however, direct evidence for this neural mechanism is lacking. We tested this hypothesized mechanism by exciting or inhibiting nodes within the central executive and salience networks using noninvasive brain stimulation and observed the results using simultaneous brain imaging. We found that the default mode network is under inhibitory control specifically from a node in the central executive network, which provides mechanistic insights into prior work that implicates these networks in a range of neuropsychiatric disorders.

Delis-Kaplan executive function system (D-KEFS)

Book

Jan 2001

Subcortical biophysical abnormalities in patients with mood disorders

Article

Jul 2013

Cortical-subcortical circuits have been implicated in the pathophysiology of mood disorders. Structural and biochemical abnormalities have been identified in patients diagnosed with mood disorders using magnetic resonance imaging-related approaches. In this study, we used magnetization transfer (MT), an innovative magnetic resonance approach, to study biophysical changes in both gray and white matter regions in cortical-subcortical circuits implicated in emotional regulation and behavior. Our study samples comprised 28 patients clinically diagnosed with major depressive disorder (MDD) and 31 non-depressed subjects of comparable age and gender. MT ratio (MTR), representing the biophysical integrity of macromolecular proteins within key components of cortical-subcortical circuits-the caudate, thalamic, striatal, orbitofrontal, anterior cingulate and dorsolateral regions-was the primary outcome measure. In our study, the MTR in the head of the right caudate nucleus was significantly lower in the MDD group when compared with the comparison group. MTR values showed an inverse relationship with age in both groups, with more widespread relationships observed in the MDD group. These data indicate that focal biophysical abnormalities in the caudate nucleus may be central to the pathophysiology of depression and critical to the cortical-subcortical abnormalities that underlie mood disorders. Depression may also accentuate age-related changes in the biophysical properties of cortical and subcortical regions. These observations have broad implications for the neuronal circuitry underlying mood disorders across the lifespan.Molecular Psychiatry advance online publication, 23 July 2013; doi:10.1038/mp.2013.84.

Structured clinical interview for DSM-IV Axis-II disorders

Article

Jan 1994

Development and validation of a Geriatric Depression Screening Scale: A preliminary report

Article

Jan 1983
J AM GERIATR SOC

Wechsler Adult Intelligence Scale—Revised UK

Article

Jan 1997

Wechsler DA

Localization of function in anterior cingulate cortex: From psychosurgery to functional neuroimaging

Article

Jan 2013

Philip Gerard Gasquoine

Early localizationists linked anterior cingulate cortex (ACC: Brodmann's area 24 and adjacent regions) with emotional behavior, paving the way for bilateral cingulotomy psychosurgery in severe, treatment resistant, cases of obsessive-compulsive disorder, chronic pain, depression, and substance abuse. Neuropsychological follow-up of such cases demonstrated executive function impairment. Abnormal neuroimaged activity in ACC has been found in many psychiatric conditions, including obsessive-compulsive disorder, chronic pain, substance abuse, and schizophrenia. With healthy participants, increased neuroimaged activity in ACC has been linked with challenging executive function tasks, homeostatically incongruous physical states, and the encoding of the pleasant/averseness of stimuli. There is disagreement on the cortical substrate subsumed by the term ACC, the existence of functionally distinct ACC subregions (e.g., dorsal: cognitive vs. ventral: emotion), and the interpretation of functional neuroimaging studies. Synthesis of neuropsychological and functional neuroimaging studies suggests ACC contributes to behavior by modifying responses especially in reaction to challenging cognitive and physical states that require additional effortful cognitive control. This is accomplished by monitoring the emotional salience of stimuli, exerting control over the autonomic nervous system, and modulating cognitive activity.

Manual for the Wechsler Adult Intelligence Scale-III

Article

Jan 1981

David Wechsler

The revision of the Wechsler-Bellevue Adult Intelligence Scale retains the type of item categories but has numerous changes in the items. Standardization is based on a stratified sample of 1700 adults ages 16 to 64. Additional norms are given for ages above 64 based on a different group of subjects. Reliabilities for verbal, performance and full scale IQ's are .96, .93, and .97, and for the subtests range from .65 to .96. Manual includes directions for administering, IQ tables, and scaled score tables. Officially the title is to be abbreviated WAIS. (PsycINFO Database Record (c) 2012 APA, all rights reserved)

Reversal alterations of amplitude of low-frequency fluctuations in early and late onset, first-episode, drug-naive depression

Article

Aug 2012

Background: It is unclear how patients with early onset depression (EOD) and late onset depression (LOD) differ at the neural level. Using amplitude of low-frequency fluctuations (ALFF) approach, we are to test the hypothesis of the different abnormal neural activities between patients with EOD and LOD. Methods: Fifteen patients with EOD, 15 patients with LOD, 15 young healthy subjects (HS) and 15 old HS were enrolled in the study. ALFF approach was employed to analyze the images. Results: ANOVA analysis revealed widespread differences in ALFF values among the four groups throughout frontal, parietal, temporal, occipital cortex, cerebellum and limbic regions. Compared to LOD group, EOD group had higher ALFF in bilateral precuneus, superior medial frontal gyrus and superior frontal gyrus, and lower ALFF in left brainstem and left superior temporal gyrus. Compared to young HS, lower ALFF in left superior/inferior temporal gyrus, left lingual gyrus and right middle occipital gyrus and higher ALFF in left medial frontal gyrus and bilateral superior frontal gyrus were seen in the EOD group; in contrast, in the LOD group, lower ALFF in bilateral superior frontal gyrus and higher ALFF in left superior temporal gyrus were observed. Further ROC analysis suggested that the mean ALFF values in the bilateral superior frontal gyrus and left superior temporal gyrus could serve as markers to separate patients with EOD from individuals with LOD. Conclusions: Patients with EOD and LOD exhibit reversal pattern of abnormal ALFF in bilateral superior frontal gyrus and left superior temporal gyrus.

Functional Neuroimaging of Major Depressive Disorder: A Meta-Analysis and New Integration of Baseline Activation and Neural Response Data

Article

Apr 2012
AM J PSYCHIAT

Functional neuroimaging investigations of major depressive disorder can advance both the neural theory and treatment of this debilitating illness. Inconsistency of neuroimaging findings and the use of region-of-interest approaches have hindered the development of a comprehensive, empirically informed neural model of major depression. In this context, the authors sought to identify reliable anomalies in baseline neural activity and neural response to affective stimuli in major depressive disorder. The authors applied voxel-wise, whole-brain meta-analysis to neuroimaging investigations comparing depressed to healthy comparison groups with respect to baseline neural activity or neural response to positively and/or negatively valenced stimuli. Relative to healthy subjects, those with major depression had reliably higher baseline activity, bilaterally, in the pulvinar nucleus. The analysis of neural response studies using negative stimuli showed greater response in the amygdala, insula, and dorsal anterior cingulate cortex and lower response in the dorsal striatum and dorsolateral prefrontal cortex in individuals with major depressive disorder than in healthy subjects. The meta-analytic results support an elegant and neuroanatomically viable model of the salience of negative information in major depressive disorder. In this proposed model, high baseline pulvinar activity in depression first potentiates responding of the brain's salience network to negative information; next, and owing potentially to low striatal dopamine levels in depression, this viscerally charged information fails to propagate up the cortical-striatal-pallidalthalamic circuit to the dorsolateral prefrontal cortex for contextual processing and reappraisal.

Functional Connectivity in the Motor Cortex of Resting Human Brain Using Echo-Planar Mri

Article

Oct 1995
MAGN RESON MED

An MRI time course of 512 echo-planar images (EPI) in resting human brain obtained every 250 ms reveals fluctuations in signal intensity in each pixel that have a physiologic origin. Regions of the sensorimotor cortex that were activated secondary to hand movement were identified using functional MRI methodology (FMRI). Time courses of low frequency (<0.1 Hz) fluctuations in resting brain were observed to have a high degree of temporal correlation (P < 10−3) within these regions and also with time courses in several other regions that can be associated with motor function. It is concluded that correlation of low frequency fluctuations, which may arise from fluctuations in blood oxygenation or flow, is a manifestation of functional connectivity of the brain.

A meta-analysis of neurofunctional imaging studies of emotion and cognition in major depression

Article

Apr 2012
NEUROIMAGE

Functional Connectivity in the Cognitive Control Network and the Default Mode Network in Late-life Depression

Article

Mar 2012

Abnormalities have been identified in the Cognitive Control Network (CCN) and the Default Mode Network (DMN) during episodes of late-life depression. This study examined whether functional connectivity at rest (FC) within these networks characterizes late-life depression and predicts antidepressant response. 26 non-demented, non-MCI older adults were studied. Of these, 16 had major depression and 10 had no psychopathology. Depressed patients were treated with escitalopram (target dose 20 mg) for 12 weeks after a 2-week placebo phase. Resting state time series was determined prior to treatment. FC within the CCN was determined by placing seeds in the dACC and the DLPFC bilaterally. FC within the DMN was assessed from a seed placed in the posterior cingulate. Low resting FC within the CCN and high resting FC within the DMN distinguished depressed from normal elderly subjects. Beyond this "double dissociation", low resting FC within the CCN predicted low remission rate and persistence of depressive symptoms and signs, apathy, and dysexecutive behavior after treatment with escitalopram. In contrast, resting FC within the DMN was correlated with pessimism but did not predict treatment response. If confirmed, these findings may serve as a signature of the brain's functional topography characterizing late-life depression and sustaining its symptoms. By identifying the network abnormalities underlying biologically meaningful characteristics (apathy, dysexecutive behavior, pessimism) and sustaining late-life depression, these findings can provide a novel target on which new somatic and psychosocial treatments can be tested.

Gray matter abnormalities in Major Depressive Disorder: A meta-analysis of voxel based morphometry studies

Article

Apr 2011

Voxel-based morphometry (VBM) has been widely used to quantify structural brain changes associated with Major Depressive Disorder (MDD). While some consistent findings have been reported, individual studies have also varied with respect to the key brain regions affected by the illness, and how these abnormalities are related to patients' clinical characteristics. Here, we aimed to identify those brain regions that most consistently showed gray matter anomalies in MDD, and their clinical correlates, using meta-analytic techniques. A systematic search of VBM studies was applied in MDD. Signed differential mapping, a new coordinate based neuroimaging meta-analysis technique, was applied to data collated from a total of 23 studies comparing regional gray matter volumes of 986 MDD patients and 937 healthy controls. Gray matter was significantly reduced in a confined cluster located in the rostral anterior cingulate cortex (ACC). There were also gray matter reductions in dorsolateral and dorsomedial prefrontal cortex and decrease in the latter region was evident in patients with multiple-episodes. Amygdala and parahippocampal gray matter volumes were significantly reduced in studies including patients with comorbid anxiety disorders, as well as in first-episode/drug free samples. Gray matter reduction in rostral ACC was the most consistent finding in VBM studies of MDD. The evidence for reductions in other regions within fronto-subcortical and limbic regions was less consistent. The associations between these gray matter anomalies and clinical characteristics, particularly measures relating to illness duration, suggest that chronic MDD has a robust and deleterious, albeit spatially focal, effect on brain structure.

Transient inhibition of the dorsolateral prefrontal cortex disrupts attention-based modulation of tactile stimuli at early stages of somatosensory processing

Article

Mar 2011

Damage to the dorsolateral prefrontal cortex (DLPFC) impairs gating of irrelevant sensory information at early cortical processing stages. We investigated how transient inhibition of DLPFC impacts early event-related potentials (ERPs) arising from relevant or irrelevant vibrotactile stimuli to the fingertips. Specifically, we hypothesized that suppression of DLPFC using continuous theta burst stimulation (cTBS) would result in reduced attention-based modulation of tactile ERPs generated at early stages of cortical somatosensory processing. Participants received vibrotactile stimulation to the second and fifth digit on the left hand and reported target stimuli on one digit only (as instructed) in one of three groups following: (1) cTBS over DLPFC (40s; 600 pulses of 3 stimuli at 50 Hz repeated at 5 Hz using 80% of resting motor threshold for abductor pollicis brevis), (2) sham stimulation, or (3) no stimulation. ERP amplitudes for the P50, N70, P100, N140 and long latency positivity (LLP) were quantified for attended and non-attended trials at C4, CP4, and CP3 electrodes. There was no effect of attention on the P50 and N70 however the P100, N140 and LLP were modulated with attention. The P100 and LLP were significantly more positive during trials where the stimuli were attended to, while the N140 was enhanced for non-attended stimuli. Comparisons between groups revealed a reduction in P100 attention-based modulation for the cTBS group versus sham and no-stimulation groups. While the P100 was clearly reduced for non-attended stimuli relative to attended stimuli in the sham and no-stimulation groups, this effect was attenuated following cTBS. The reduction in attentional modulation of the P100 following cTBS suggests that the DLPFC contributes to filtering irrelevant somatosensory information at early cortical processing stages. Notably the influence of the DLPFC in attention-based modulation was evident even within digits of the same hand. The present results support the use of cTBS as an effective means of transiently suppressing DLPFC excitability.

Functional Connectivity and Coactivation of the Nucleus Accumbens: A Combined Functional Connectivity and Structure-Based Meta-analysis

Article

Oct 2011
J COGNITIVE NEUROSCI

This article investigates the functional connectivity patterns of the nucleus accumbens (NAcc) in 18 healthy participants using a resting state functional connectivity (rsFC) protocol. Also, a meta-analytic connectivity modeling (MACM) was used to characterize patterns of functional coactivations involving NAcc: The results of a structure-based meta-analyses of 57 fMRI and PET studies were submitted to activation likelihood estimation analysis to estimate consistent activation patterns across the different imaging studies. The results of the combined rsFC and MACM analyses show that spontaneous activity in NAcc predicts activity in regions implicated in reward circuitries, including orbitomedial prefrontal cortex, globus pallidus, thalamus, midbrain, amygdala, and insula. This confirms the key role of NAcc in the mesocorticolimbic system, which integrates inputs from limbic and cortical regions. We also detected activity in brain regions having few or no direct anatomical connections with NAcc, such as sensorimotor cortex, cerebellum, medial and posterior parietal cortex, and medial/inferior temporal cortex, supporting the view that not all functional connections can be explained by anatomical connections but can also result from connections mediated by third areas. Our rsFC findings are in line with the results of the structure-based meta-analysis: MACM maps are superimposable with NAcc rsFC results, and the reward paradigm class is the one that most frequently generates activation in NAcc. Our results overlap considerably with recently proposed schemata of the main neuron systems in the limbic forebrain and in the anterior part of the limbic midbrain in rodents and nonhuman primates.

The Oscillating Brain: Complex and Reliable

Article

Sep 2009
NEUROIMAGE

The human brain is a complex dynamic system capable of generating a multitude of oscillatory waves in support of brain function. Using fMRI, we examined the amplitude of spontaneous low-frequency oscillations (LFO) observed in the human resting brain and the test-retest reliability of relevant amplitude measures. We confirmed prior reports that gray matter exhibits higher LFO amplitude than white matter. Within gray matter, the largest amplitudes appeared along mid-brain structures associated with the "default-mode" network. Additionally, we found that high-amplitude LFO activity in specific brain regions was reliable across time. Furthermore, parcellation-based results revealed significant and highly reliable ranking orders of LFO amplitudes among anatomical parcellation units. Detailed examination of individual low frequency bands showed distinct spatial profiles. Intriguingly, LFO amplitudes in the slow-4 (0.027-0.073 Hz) band, as defined by Buzsáki et al., were most robust in the basal ganglia, as has been found in spontaneous electrophysiological recordings in the awake rat. These results suggest that amplitude measures of LFO can contribute to further between-group characterization of existing and future "resting-state" fMRI datasets.

Neural response to specific components of fearful faces in healthy and schizophrenic adults

Article

Sep 2009
NEUROIMAGE

Perception of fearful faces is associated with functional activation of cortico-limbic structures, which has been found altered in individuals with psychiatric disorders such as schizophrenia, autism and major depression. The objective of this study was to isolate the brain response to the features of standardized fearful faces by incorporating principal component analysis (PCA) into the analysis of neuroimaging data of healthy volunteers and individuals with schizophrenia. At the first stage, the visual characteristics of morphed fearful facial expressions (FEEST, Young et al., 2002) were classified with PCA, which produced seven orthogonal factors, with some of them related to emotionally salient facial features (eyes, mouth, brows) and others reflecting non-salient facial features. Subsequently, these PCA-based factors were included into the functional magnetic resonance imaging (fMRI) analysis of 63 healthy volunteers and 32 individuals with schizophrenia performing a task that involved implicit processing of FEEST stimuli. In healthy volunteers, significant neural response was found to visual characteristics of eyes, mouth or brows. In individuals with schizophrenia, PCA-based analysis enabled us to identify several significant clusters of activation that were not detected by the standard approach. These clusters were implicated in processing of visual and emotional information and were attributable to the perception of eyes and brows. PCA-based analysis could be useful in isolating brain response to salient facial features in psychiatric populations.

Brain Volume Abnormalities in Major Depressive Disorder: A Meta-Analysis of Magnetic Resonance Imaging Studies

Article

Nov 2009
HUM BRAIN MAPP

So far, there have been no attempts to integrate the growing number of all brain volumetric magnetic resonance imaging studies in depression. In this comprehensive meta-analysis the magnitude and extent of brain volume differences between 2,418 patients with major depressive disorder and 1,974 healthy individuals from 64 studies was determined. A systematic research was conducted for volumetric magnetic resonance imaging studies of patients with major depressive disorder in relation to healthy control subjects. Studies had to report sufficient data for computation of effect sizes. For each study, the Cohen's d was calculated. All analyses were performed using the random effects model. Additionally, meta-regression analyses were done to explore the effects of potential sources of heterogeneity. Patients showed large volume reductions in frontal regions, especially in the anterior cingulate and orbitofrontal cortex with smaller reductions in the prefrontal cortex. The hippocampus, the putamen and caudate nucleus showed moderate volume reductions. This is the first comprehensive meta-analysis in major depressive disorder demonstrating structural brain abnormalities, particularly in those brain areas that are involved in emotion processing and stress-regulation.

Functional architecture of basal ganglia circuits: neural substrates of parallel processing

Article

Aug 1990
TRENDS NEUROSCI

Gating of somatosensory input by human prefrontal cortex

Article

Jul 1990
BRAIN RES

Somatosensory evoked potentials (SEPs) to median nerve stimulation were recorded in controls and in patients with focal lesions in dorsolateral prefrontal cortex (PFCx). Unilateral PFCx lesions increased the amplitude of the P26 component generated in postcentral areas 1 and 2. The amplitudes of the N28, P45 and N67 SEP components recorded over post-rolandic and frontal electrodes were also enhanced by PFCx damage. In contrast, the N19 component generated in postcentral area 3b was unaffected by PFCx lesions. The results indicate that PFCx exerts inhibitory modulation on sensory processing that may be mediated by corticocortical PFCx-parietal connections.

Development and Validation of a Geriatric Depression Screening Scale

Article

Nov 1982
J PSYCHIATR RES

A new Geriatric Depression Scale (GDS) designed specifically for rating depression in the elderly was tested for reliability and validity and compared with the Hamilton Rating Scale for Depression (HRS-D) and the Zung Self-Rating Depression Scale (SDS). In constructing the GDS a 100-item questionnaire was administered to normal and severely depressed subjects. The 30 questions most highly correlated with the total scores were then selected and readministered to new groups of elderly subjects. These subjects were classified as normal, mildly depressed or severely depressed on the basis of Research Diagnostic Criteria (RDC) for depression. The GDS, HRS-D and SDS were all found to be internally consistent measures, and each of the scales was correlated with the subject's number of RDC symptoms. However, the GDS and the HRS-D were significantly better correlated with RDC symptoms than was the SDS. The authors suggest that the GDS represents a reliable and valid self-rating depression screening scale for elderly populations.

Subgenual prefrontal cortex abnormalities in mood disorders

Article

May 1997

Pathological disturbances of mood may follow a 'bipolar' course, in which normal moods alternate with both depression and mania, or a 'unipolar' course, in which only depression occurs. Both bipolar and unipolar disorders can be heritable illnesses associated with neurochemical, neuroendocrine and autonomic abnormalities. The neurobiological basis for these abnormalities has not been established. Using positron emission tomographic (PET) images of cerebral blood flow and rate of glucose metabolism to measure brain activity, we have now localized an area of abnormally decreased activity in the prefrontal cortex ventral to the genu of the corpus callosum in both familial bipolar depressives and familial unipolar depressives. This decrement in activity was at least partly explained by a corresponding reduction in cortical volume, as magnetic resonance imaging (MRI) demonstrated reductions in the mean grey matter volume in the same area of 39 and 48% in the bipolar and unipolar samples, respectively. This region has previously been implicated in the mediation of emotional and autonomic responses to socially significant or provocative stimuli, and in the modulation of the neurotransmitter systems targeted by antidepressant drugs.

Clinical, cognitive, and functional connectivity correlations of resting-state intrinsic brain activity alterations in unmedicated depression

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