Association of thalamic hyperactivity with treatment-resistant depression and poor response in early treatment for major depression: a resting-state fMRI study using fractional amplitude of low-frequency fluctuations.
ABSTRACT: Despite novel antidepressant development, 10-30% of patients with major depressive disorder (MDD) have antidepressant treatment-resistant depression (TRD). Although new therapies are needed, lack of knowledge regarding the neural mechanisms underlying TRD hinders development of new therapeutic options. We aimed to identify brain regions in which spontaneous neural activity is not only altered in TRD but also associated with early treatment resistance in MDD. Sixteen patients with TRD, 16 patients with early-phase non-TRD and 26 healthy control (HC) subjects underwent resting-state functional magnetic resonance imaging. To identify brain region differences in spontaneous neural activity between patients with and without TRD, we assessed fractional amplitude of low-frequency fluctuations (fALFF). We also calculated correlations between the percent change in the Hamilton Rating Scale for Depression (HRSD17) scores and fALFF values in brain regions with differing activity for patients with and without TRD. Patients with TRD had increased right-thalamic fALFF values compared with patients without TRD. The percent change in HRSD17 scores negatively correlated with fALFF values in patients with non-TRD. In addition, patients with TRD showed increased fALFF values in the right inferior frontal gyrus (IFG), inferior parietal lobule (IPL) and vermis, compared with patients with non-TRD and HC subjects. Our results show that spontaneous activity in the right thalamus correlates with antidepressant treatment response. We also demonstrate that spontaneous activity in the right IFG, IPL and vermis may be specifically implicated in the neural pathophysiology of TRD.
Project description:The glutamate N-methyl-D-aspartate receptor antagonist ketamine has demonstrated antidepressant effects in individuals with treatment-resistant major depressive disorder (TRD) within 24?h of a single dose. The current study utilized functional magnetic resonance imaging (fMRI) and two separate emotion perception tasks to examine the neural effects of ketamine in patients with TRD. One task used happy and neutral facial expressions; the other used sad and neutral facial expressions. Twenty patients with TRD free of concomitant antidepressant medication underwent fMRI at baseline and 24?h following administration of a single intravenous dose of ketamine (0.5?mg?kg(-1)). Adequate data were available for 18 patients for each task. Twenty age- and sex-matched healthy volunteers were scanned at one time point for baseline comparison. Whole-brain, voxel-wise analyses were conducted controlling for a family-wise error rate (FWE) of P<0.05. Compared with healthy volunteers, TRD patients showed reduced neural responses to positive faces within the right caudate. Following ketamine, neural responses to positive faces were selectively increased within a similar region of right caudate. Connectivity analyses showed that greater connectivity of the right caudate during positive emotion perception was associated with improvement in depression severity following ketamine. No main effect of group was observed for the sad faces task. Our results indicate that ketamine specifically enhances neural responses to positive emotion within the right caudate in depressed individuals in a pattern that appears to reverse baseline deficits and that connectivity of this region may be important for the antidepressant effects of ketamine.
Project description:Purpose:The present study combined fractional amplitude of low-frequency fluctuations (fALFF), regional homogeneity (ReHo), and functional connectivity (FC) to explore brain functional abnormalities in acute tinnitus patients (AT) with hearing loss. Methods:We recruited twenty-eight AT patients and 31 healthy controls (HCs) and ran resting-state functional magnetic resonance imaging (fMRI) scans. fALFF, ReHo, and FC were conducted and compared between AT patients and HCs. After that, we calculated correlation analyses among abnormal fALFF, ReHo, FC, and clinical data in AT patients. Results:Compared with HCs, AT showed increased fALFF values in the right inferior temporal gyrus (ITG). In contrast, significantly decreased ReHo values were observed in the cerebellar vermis, the right calcarine cortex, the right precuneus, the right supramarginal gyrus (SMG), and the right middle frontal gyrus (MFG). Based on the differences in the fALFF and ReHo maps, the latter of which we defined as region-of-interest (ROI) for FC analysis, the right ITG exhibited increased connectivity with the right precentral gyrus. In addition, the right MFG demonstrated decreased connectivity with both the bilateral anterior cingulate cortex (ACC) and the left precentral gyrus. Conclusion:By combining ReHo, fALFF, and FC analyses, our work indicated that AT with hearing loss had abnormal intraregional neural activity and disrupted connectivity in several brain regions which mainly involving the non-auditory area, and these regions are major components of default mode network (DMN), attention network, visual network, and executive control network. These findings will help us enhance the understanding of the neuroimaging mechanism in tinnitus populations. Moreover, these abnormalities remind us that we should focus on the early stages of this hearing disease.
Project description:Aging is known to be associated with changes in cerebral morphometry and in regional activations during resting or cognitive challenges. Here, we investigated the effects of age on cerebral gray matter (GM) volumes and fractional amplitude of low-frequency fluctuation (fALFF) of blood oxygenation level-dependent signals in 111 healthy adults, 18-72 years of age. GM volumes were computed using voxel-based morphometry as implemented in Statistical Parametric Mapping, and fALFF maps were computed for task-residuals as described in Zhang and Li (Neuroimage 49:1911-1918, 2010) for individual participants. Across participants, a simple regression against age was performed for GM volumes and fALFF, respectively, with quantity of recent alcohol use as a covariate. At cluster level p < 0.05, corrected for family-wise error of multiple comparisons, GM volumes declined with age in prefrontal/frontal regions, bilateral insula, and left inferior parietal lobule (IPL), suggesting structural vulnerability of these areas to aging. FALFF was negatively correlated with age in the supplementary motor area (SMA), pre-SMA, anterior cingulate cortex, bilateral dorsal lateral prefrontal cortex (DLPFC), right IPL, and posterior cingulate cortex, indicating that spontaneous neural activities in these areas during cognitive performance decrease with age. Notably, these age-related changes overlapped in the prefrontal/frontal regions including the pre-SMA, SMA, and DLPFC. Furthermore, GM volumes and fALFF of the pre-SMA/SMA were negatively correlated with the stop signal reaction time, in accord with our earlier work. Together, these results describe anatomical and functional changes in prefrontal/frontal regions and how these changes are associated with declining inhibitory control during aging.
Project description:It is unclear whether abnormal spontaneous neural activation patterns found in chronic schizophrenia patients (CSP) are part of the pathogenesis of disease, consequences of chronic illness, or effects of antipsychotic treatment. We performed a longitudinal resting-state functional magnetic resonance imaging (fMRI) study in 42 treatment-naïve first-episode schizophrenia patients (FESP) at baseline and then after 8-weeks of risperidone monotherapy, and compared the findings to 38 healthy volunteers. Spontaneous brain activity was quantified using the fractional amplitude of low-frequency fluctuations (fALFF) and regional homogeneity (ReHo) and compared between patients and controls. Pretreatment, patients exhibited higher fALFF in left caudate compared with controls. After treatment, patients had elevated fALFF in bilateral putamen and right caudate, and increased ReHo in right caudate and left putamen. Greater increase of fALFF in the left putamen correlated with less improvement in positive symptoms. Thus, abnormalities of spontaneous neural activity in chronic schizophrenia is at least partly due to a medication effect. The observed post-treatment increase in striatal intrinsic activity may reflect counter-therapeutic functional adaptation to dopamine D2 receptor occupancy required for medication effects on psychosis.
Project description:Objective:Studies on alterations in the regional neural activity in the brain of patients with bipolar disorder (BD) have provided conflicting results because of different medications used and study designs. A low bone mineral density (BMD) is also observed in patients with BD. This study aimed to further explore regional neural activities in unmedicated patients with BD and their association with BMD. Methods:In this study, 40 patients with BD and 42 healthy controls were scanned through resting-state functional magnetic resonance imaging (fMRI). Imaging data were analyzed with regional homogeneity (ReHo) and pattern classification. Pearson's correlation analyses were performed to explore the correlations between abnormal ReHo and BMD. Results:A significant increase in ReHo values in the left inferior frontal gyrus (IFG)/temporal pole, left cerebellum vermis I/vermis II/parahippocampal gyrus/brainstem, and right superior temporal gyrus (STG) and a decrease in ReHo in the occipital gyrus (OG; left middle OG/superior OG/bilateral cuneus) were found in the patients with BD (p < 0.05) compared with those in the healthy controls. No significant correlation was observed between the abnormal ReHo values in any of the brain regions of the patients with BMD.Support vector machine (SVM) analyses revealed that the ReHo values in the right STG for distinguishing patients from healthy controls showed an accuracy of 91.89%, a sensitivity of 75.68%, and a specificity of 83.78%. The ReHo values in the left cerebellum vermis I/vermis II/parahippocampal gyrus/brainstem indicated an accuracy of 78.38%, a sensitivity of 75.68%, and a specificity of 81.08%. Conclusion:This study further confirms the abnormal brain activities in extensive regions, and these brain regions are primarily located in the fronto-temporal-occipital circuit and the cerebellum vermis of patients with BD. The regional neural activity in the right STG and the left cerebellum vermis I/vermis II/parahippocampal gyrus/brainstem may serve as potential imaging markers to distinguish patients with BD from healthy controls.
Project description:The present study examined neural substrates underlying turn-based cooperation and competition in a real two-person situation. We simultaneously measured pairs of participants' activations in their bilateral frontal, temporal, and parietal regions using a 96-channel near-infrared spectroscopy (NIRS) system, when participants played a turn-taking disk-game on a computer. NIRS data demonstrated significant inter-brain neural synchronization (INS) across participant pairs' right posterior superior temporal sulcus (pSTS) in both the cooperation and competition conditions, and the competition condition also involved significant INS in the right inferior parietal lobule (IPL). In addition, competitive dyads' INS in the bilateral inferior frontal gyrus (IFG) may play as a role of mediation in relationship between their empathy score and disk-manipulation latency, but cooperative dyads' INS did not. These results suggest that first the right pSTS may be commonly involved in both cooperation and competition due to task demands of joint attention and intention understanding, while the right IPL may be more important for competition due to additional requirements of mentalizing resources in competing contexts. Second, participants' empathy may promote INS in the bilateral IFG across competitors, and in turn affect their competitive performance.
Project description:Background: The National Institute on Aging-Alzheimer's Association (NIA-AA) has proposed a biological definition of Alzheimer's disease (AD): individuals with both abnormal amyloid and tau biomarkers (A+T+) would be defined as AD. It remains unclear why different cognitive status is present in subjects with biological AD. Resting-state functional magnetic resonance imaging (rsfMRI) has provided an opportunity to reveal the brain activity patterns in a biologically-defined AD cohort. Accordingly, we aimed to investigate distinct brain activity patterns in subjects with existed AD pathology but in the different cognitive stages. Method: We selected individuals with AD pathology (A+T+) and healthy controls (HC, A-T-) based on the cerebrospinal fluid (CSF) biomarkers. According to the cognitive stage, we divided the A+T+ cohort into three groups: (1) preclinical AD; (2) prodromal AD; and (3) AD with dementia (d-AD). We compared spontaneous brain activity measured by a fractional amplitude of low-frequency fluctuation (fALFF) approach among four groups. Results: The analysis of covariance (ANCOVA) results showed significant differences in fALFF in the posterior cingulate cortex/precuneus (PCC/PCu). Further, compared to HC, we found increased fALFF values in the right inferior frontal gyrus (IFG) in the preclinical AD stage, whereas prodromal AD patients showed reduced fALFF in the bilateral precuneus, right middle frontal gyrus (MFG), right precentral gyrus, and postcentral gyrus. Within the d-AD group, both hyperactivity (right fusiform gyrus, right parahippocampal gyrus (PHG)/hippocampus, and inferior temporal gyrus) and hypoactivity (bilateral precuneus, left posterior cingulate cortex, left cuneus and superior occipital gyrus) were detected. Conclusion: We found the distinct brain activity patterns in different cognitive stages among the subjects defined as AD biologically. Our findings may be helpful in understanding mechanisms leading to cognitive changes in the AD pathophysiological process.
Project description:Although Type 2 diabetes mellitus (T2DM) is a well-recognized risk factor for dementia, the neural mechanisms that underlie cognitive impairment in T2DM remain unclear. This study uses resting-state functional magnetic resonance imaging (fMRI) to examine attention network alterations in T2DM and their relationships to impaired cognitive performance. Data-driven independent component analysis was applied to resting-state fMRI data from 38 T2DM patients and 32 healthy controls to identify the dorsal attention network (DAN) and ventral attention network (VAN). Correlations were then determined among the resting-state functional connectivity (rsFC), clinical data, and neuropsychological scores. The T2DM patients exhibited decreased rsFC in the left middle frontal gyrus (MFG) and bilateral inferior parietal lobe (IPL) of the DAN, as well as the left IPL and right MFG/IFG of the VAN. In addition, the rsFC of the left MFG was inversely correlated with the Trail Making Test-B scores; the rsFC of the left IPL was positively correlated with the Digit Span Test scores but negatively correlated with HbA1c; and the rsFC in the right precuneus was positively associated with cognitive performance (without Bonferroni correction). In conclusion, T2DM affects resting-state attentional networks, which may be related to reduced attention and a hyperglycemic state.
Project description:Tinnitus, a phantom ringing, buzzing, or hissing sensation with potentially debilitating consequences, is thought to arise from aberrant spontaneous neural activity at one or more sites within the central nervous system; however, the location and specific features of these oscillations are poorly understood with respect to specific tinnitus features. Recent resting-state functional magnetic resonance imaging (fMRI) studies suggest that aberrant fluctuations in spontaneous low-frequency oscillations (LFO) of the blood oxygen level-dependent (BOLD) signal may be an important factor in chronic tinnitus; however, the role that frequency-specific components of LFO play in subjective tinnitus remains unclear. A total of 39 chronic tinnitus patients and 41 well-matched healthy controls participated in the resting-state fMRI scans. The LFO amplitudes were investigated using the amplitude of low-frequency fluctuation (ALFF) and fractional ALFF (fALFF) in two different frequency bands (slow-4: 0.027-0.073 Hz and slow-5: 0.01-0.027 Hz). We observed significant differences between tinnitus patients and normal controls in ALFF/fALFF in the two bands (slow-4 and slow-5) in several brain regions including the superior frontal gyrus (SFG), inferior frontal gyrus, middle temporal gyrus, angular gyrus, supramarginal gyrus, and middle occipital gyrus. Across the entire subject pool, significant differences in ALFF/fALFF between the two bands were found in the midbrain, basal ganglia, hippocampus and cerebellum (Slow 4 > Slow 5), and in the middle frontal gyrus, supramarginal gyrus, posterior cingulate cortex, and precuneus (Slow 5 > Slow 4). We also observed significant interaction between frequency bands and patient groups in the orbitofrontal gyrus. Furthermore, tinnitus distress was positively correlated with the magnitude of ALFF in right SFG and the magnitude of fALFF slow-4 band in left SFG, whereas tinnitus duration was positively correlated with the magnitude of ALFF in right SFG and the magnitude of fALFF slow-5 band in left SFG. Resting-state fMRI provides an unbiased method for identifying aberrant spontaneous LFO occurring throughout the central nervous system. Chronic tinnitus patients have widespread abnormalities in ALFF and fALFF slow-4 and slow-5 band which are correlated with tinnitus distress and duration. These results provide new insights on the neuropathophysiology of chronic tinnitus; therapies capable of reversing these aberrant patterns may reduce tinnitus distress.
Project description:Purpose:The utility of transcranial magnetic stimulation (TMS) has been growing rapidly in both neurocognitive studies and clinical applications in decades. However, it remains unclear how the responses of the stimulated site and the site-related functional network to the external TMS manipulation dynamically change over time. Methods:A multi-session combining TMS-fMRI experiment was conducted to explore the spatiotemporal effects of TMS within the fronto-limbic network. Ten healthy volunteers were modulated by intermittent theta-burst stimulation (iTBS) at a precise site within the left dorsolateral prefrontal cortex (DLPFC, MNI coordinate [-44 36 20]), navigated by individual structural MRI image. Three-session resting-state fMRI images were acquired before iTBS (TP1), immediately after iTBS (TP2), and 15 min after iTBS (TP3) for each participant. Seventy-four regions of interests (ROIs) within the fronto-limbic network were chosen including the bilateral superior frontal gyrus (SFG), middle frontal gyrus (MidFG), inferior frontal gyrus (IFG), orbital gyrus (OrG), cingulate gyrus (CG), and subcortical nuclei (hippocampus and amygdala). Regional fractional amplitude of low-frequency fluctuation (fALFF) and ROI-to-ROI functional connectivity (FC) were compared among TP1, TP2, and TP3. Results:The immediate iTBS effect was observed at the stimulated site. FC between the left dorsolateral SFG and left dorsal IFG and between the left rostral IFG and right MidFG increased at TP2 as compared to at TP1 (all FDR-p < 0.05), while FC within the left OrG decreased. The relatively long-term iTBS effect transmitted with decreased FC between the left IFG and right amygdala, increased FC between the left MidFG and left OrG, and decreased FC between bilateral IFG and OrG at TP3 than at TP1 (all FDR-p < 0.05). Meanwhile, mean fALFF values over the left SFG, MidFG, ventral CG, and IFG were significantly increased at TP3 as compared to those at TP2 (all p < 0.05 with Bonferroni correction). Conclusion:By combining TMS and fMRI, it becomes possible to track the spatiotemporal dynamics of TMS after-effects within the fronto-limbic network. Our findings suggested that the iTBS effect dynamically changed over time from the local neural activation at the stimulated site to its connected remote regions within the fronto-limbic network.