The cerebellum plays an important role in depression. Cerebro-cerebellar circuits have been found to show aberrance in bipolar disorder (BD) and major depressive disorder (MDD). However, whether the cerebro-cerebellar connectivity contributes equally to the pathologic mechanisms of BD and MDD remains unknown. We recruited 33 patients with MDD, 32 patients with BD, and 43 healthy controls (HC). We selected six seed regions (three per hemisphere) in the cerebrum, corresponding to the affective, cognitive control, and default mode networks, to establish cerebro-cerebellar functional connectivity maps. Relative to the HC, both the BD and MDD patients exhibited weaker negative connectivity between the right subgenual anterior cingulate cortex and the cerebellar vermis IV_V (p = 0.03, p = 0.001) and weaker positive connectivity between the left precuneus and the left cerebellar lobule IX (p = 0.043, p = 0.000). Moreover, the MDD patients showed weaker positive connectivity in the left precuneus-left cerebellar lobule IX circuit than the BD patients (p = 0.049). In addition, the BD patients showed weaker positive connectivity in the right dorsolateral prefrontal cortex-left cerebellar lobule Crus Ι circuit compared to the HC (p = 0.002) or the MDD patients (p = 0.013). Receiver operating characteristic curves analyses showed that the altered cerebro-cerebellar connectivities could be used to distinguish the patients from the HC with relatively high accuracy. Our findings suggested that differences in connectivity of cerebro-cerebellar circuits, which are involved in affective or cognitive functioning, significantly contributed to BD and MDD.
Disturbed hypothalamus-pituitary-adrenal axis function, which leads to excessive and prolonged hypercortisolemia, is a core feature of major depressive disorder (MDD). However, the relationships between depression, brain structure and function, and cortisol levels are unclear. The current study examined the whole-brain functional connectivity pattern of patients with MDD and evaluated the association between functional connectivity and serum cortisol levels in MDD. A total of 93 unmedicated patients with MDD and 139 healthy control subjects underwent resting-state functional magnetic resonance imaging. Voxel-wise whole-brain connectivity was analyzed by using a graph theory approach: functional connectivity strength (FCS). A seed-based resting-state functional connectivity analysis was further performed to investigate abnormal functional connectivity patterns of those regions with changed FCS. Morning blood samples were drawn for cortisol measurements in some subjects (including 53 MDD patients and 30 controls). The MDD patients had a significantly lower FCS in the left posterior lobes of the cerebellum (mainly lobule Crus II) (p < 0.05, TFCE corrected). The seed-based functional connectivity analysis revealed decreased functional connectivity between the left posterior cerebellum and the left medial orbitofrontal cortex (OFC) (p < 0.05, TFCE corrected). Moreover, the functional connectivity between the left posterior cerebellum and the left medial OFC were significantly positively correlated with the serum cortisol levels in MDD patients. Our results suggest that cerebellar dysconnectivity, in particular distributed cerebellar-OFC functional connectivity, may be associated with serum cortisol levels in MDD patients.
The present study aimed to investigate the neuro-cognitive features in the processing of vocabularies of date in Chinese, using block-design functional magnetic resonance imaging (fMRI). Nineteen normal right-handed volunteers whose native language was Chinese performed judgments of vocabulary of month (JVM), the orientation of digit (JOD) and the meaning of words (JMW) respectively, while the fMRI data were recorded by Signa HDe 1.5T MR machine. All design of three tasks was adapted from previous studies with slight modification. The JOD and JWM were investigated as contrast conditions. JVM asked the subjects to determine whether the month belonged to the first half of the year. JOD was to tell whether the third digit had the same orientation (upright orientation or italic orientation) as the first two, and JMW was to determine whether the two-Chinese-character word was animate. The subjects responded according to the task instruction with a button pressing. Statistical parametric mapping (SPM2) was employed to process data and localize functional areas. We compared the average activation intensity of each activated brain regions in the same task against the rest and the activation intensity of the same regions in different tasks respectively. The activations in inferior parietal (BA40) and inferior occipital (BA18/19) were found in the JVM and JOD. The same areas in middle frontal (BA6), fusiform (BA18), posterior in right cerebellum areas were activated during the JVM and JMW. When the activation of the JMW was subtracted from the JVM, many areas concerning numerical processing, such as left anterior cingulate (BA32), post central (BA2), and the right superior temporal (BA39), superior parietal (BA7), as well as the inferior parietal (BA40), precuneus (BA7/19) of the bilateral hemispheres, were significantly activated. When the activation of the JOD was subtracted from the JVM, the left inferior occipital and the fusiform (BA18) of the bilateral hemispheres, which were also involved in the linguistic processing according to previous studies, were significantly activated. The above results prove that the processing of vocabulary of months in Chinese involves not only linguistic processing but also numerical processing; and these results further indicate that Chinese people might gain access to the cognitive experience of number during the process of acquisition of native language.
Spike encoding at GABAergic neurons plays an important role in maintaining the homeostasis of brain functions for well-organized behaviors. The rise of intracellular Ca2+ in GABAergic neurons causes synaptic plasticity. It is not clear how intracellular Ca2+ influences their spike encoding. We have investigated this issue at GFP-labeled GABAergic cortical neurons and cerebellar Purkinje cells by whole-cell recording in mouse brain slices. Our results show that an elevation of intracellular Ca2+ by infusing adenophostin-A lowers spike encoding at GABAergic cortical neurons and enhances encoding ability at cerebellar Purkinje cells. These differential effects of cytoplasmic Ca2+ on spike encoding are mechanistically associated with Ca2+-induced changes in the refractory periods and threshold potentials of sequential spikes, as well as with various expression ratios of CaM-KII to calcineurin in GABAergic cortical neurons and cerebellar Purkinje cells.
Ischemia-induced excitotoxicity at cerebellar Purkinje cells is presumably due to a persistent glutamate action. To the fact that they are more vulnerable to ischemia than other glutamate-innervated neurons, we studied whether additional mechanisms are present and whether cytoplasm Ca(2+) plays a key role in their ischemic excitotoxicity. Ischemic changes in the excitability of Purkinje cells were measured by whole-cell recording in cerebellar slices of rats with less glutamate action. The role of cytoplasm Ca(2+) was examined by two-photon cellular imaging and BAPTA infusion in Purkinje cells. Lowering perfusion rate to cerebellar slices deteriorated spike timing and raised spike capacity of Purkinje cells. These changes were associated with the reduction of spike refractory periods and threshold potentials, as well as the loss of their control to spike encoding. Ischemia-induced functional deterioration at Purkinje neurons was accompanied by cytoplasm Ca(2+) rise and prevented by BAPTA infusion. Therefore, the ischemia destabilizes the spike encoding of Purkinje cells via raising cytoplasm Ca(2+) without a need for glutamate, which subsequently causes their excitotoxic death.
It is difficult to diagnose cerebellopontine angle area tumor because of many sorts and origins of the tumor. This study was to explore magnetic resonance imaging (MRI) diagnosis of occupied lesions in cerebellopontine angle area. MRI records of 78 patients with pathologically confirmed occupied lesions in cerebellopontine angle area were analyzed. Of the 78 cases, 48 (61.5%) were unilateral acoustic neuroma, 5(6.4%) were bilateral acoustic neuroma, 12 (15.4%) were meningioma, 4 (5.1%) were trigeminal neuroma, 3 (3.8%) were hemangioblastoma, 3 (3.8%) were lipoma, 2 (2.6%) were melanoma, 1 (1.3%) was medulloblastoma. According to the anatomic site, tumor lesion character, and MRI signal character, the majority of cerebellopontine angle area tumors were diagnosed accurately. MRI plays an important role in diagnosis of occupied lesions in cerebellopontine angle area.
Purpose To investigate the whole-brain intrinsic functional connectivity patterns of patients with bipolar disorder (BD). Materials and Methods This prospective study was approved by the research ethics committee, and all participants provided informed consent. Thirty-seven patients with nonmedicated BD II depression and 37 healthy control participants underwent resting-state functional magnetic resonance (MR) imaging. Whole-brain connectivity was analyzed by using a graph theory approach: functional connectivity strength (FCS). Clinical state was assessed by using the 24-item Hamilton Depression Rating Scale and the Young Mania Rating Scale. Two-sample t test and nonparametric correlation analysis were used. Results Compared with healthy control participants, patients with BD II showed decreased FCS in the default mode network (ie, the bilateral medial prefrontal cortex, bilateral middle temporal gyrus, left precuneus, and right posterior cingulate cortex), right supramarginal gyrus and angular gyrus, right superior frontal gyrus, and right superior parietal gyrus and increased FCS in the bilateral temporal pole (including the parahippocampal gyrus and amygdale), left anterior cingulate cortex, left superior temporal gyrus, right lingual gyrus, and left anterior lobe of the cerebellum (P < .05; AlphaSim corrected). Conclusion These results suggest that patients with BD have disrupted intrinsic functional connectivity mainly in the default mode network and limbic system, which might be associated with the pathophysiologic structure of BD. (©) RSNA, 2016.
Depression in the context of bipolar disorder (BD) is often misdiagnosed as unipolar depression (UD), leading to mistreatment and poor clinical outcomes. However, little is known about the similarities and differences in cerebellum between BD and UD. Patients with BD (n=35) and UD (n=30) during a depressive episode as well as 40 healthy controls underwent diffusional kurtosis imaging (DKI) and three dimensional arterial spin labeling (3D ASL). The DKI parameters including mean kurtosis (MK), axial kurtosis (Ka), radial kurtosis (Kr),fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (Da) and radial diffusivity (Dr) and 3D ASL parameters (i.e. cerebral blood flow) was measured by using regions-of-interest (ROIs) analysis in the superior cerebellar peduncles (SCP), middle cerebellar peduncles (MCP) and dentate nuclei (DN) of cerebellum. Patients with UD exhibited significant differences from controls for DKI measures in bilateral SCP and MCP and cerebral blood flow (CBF) in bilateral SCP and left DN. Patients with BD exhibited significant differences from controls for DKI measures in the right MCP and left DN and CBF in the left DN. Patients with UD showed significantly lower MD values compared with patients with BD in the right SCP. Correlation analysis showed there were negative correlations between illness duration and MD and Dr values in the right SCP in UD. This study was cross-sectional and the sample size was not large. Parts of the patients included were under medication prior to MRI scanning. Our findings provide new evidence of microstructural changes in cerebellum in BD and UD. The two disorders may have overlaps in microstructural abnormality in MCP and DN during the depressive period. Microstructural abnormality in SCP may be a key neurobiological feature of UD.
All neurodegenerative diseases are associated with oxidative stress-induced neuronal death. Forkhead box O3a (FOXO3a) is a key transcription factor involved in neuronal apoptosis. However, how FOXO3a forms complexes and functions in oxidative stress processing remains largely unknown. In the present study, we show that histone deacetylase 2 (HDAC2) forms a physical complex with FOXO3a, which plays an important role in FOXO3a-dependent gene transcription and oxidative stress-induced mouse cerebellar granule neuron (CGN) apoptosis. Interestingly, we also found that HDAC2 became selectively enriched in the promoter region of the p21 gene, but not those of other target genes, and inhibited FOXO3a-mediated p21 transcription. Furthermore, we found that oxidative stress reduced the interaction between FOXO3a and HDAC2, leading to an increased histone H4K16 acetylation level in the p21 promoter region and upregulated p21 expression in a manner independent of p53 or E2F1. Phosphorylation of HDAC2 at Ser 394 is important for the HDAC2-FOXO3a interaction, and we found that cerebral ischemia/reperfusion reduced phosphorylation of HDAC2 at Ser 394 and mitigated the HDAC2-FOXO3a interaction in mouse brain tissue. Our study reveals the novel regulation of FOXO3a-mediated selective gene transcription via epigenetic modification in the process of oxidative stress-induced cell death, which could be exploited therapeutically.
Depression in the context of bipolar disorder (BD) is often misdiagnosed as unipolar depression (UD), leading to mistreatment and poor clinical outcomes. However, little is known about the similarities and differences in interhemispheric functional connectivity between BD and UD. Patients with bipolar II disorder (n = 36) and UD (n = 32) during a depressive episode as well as 40 healthy controls underwent resting-state functional magnetic resonance imaging. The functional connectivity between any pair of symmetric interhemispheric voxels (i.e., functional homotopy) was measured by voxel-mirrored homotopic connectivity (VMHC). The three groups showed significant VMHC differences in the posterior cingulate cortex (PCC), fusiform and lingual gyrus, anterior lobe of the cerebellum (CeAL), and posterior lobe of the cerebellum (CePL). In the BD group, the VMHC decreases in the fusiform/lingual gyrus, CeAL, and CePL were shown relative to controls. In the UD group, the VMHC decreases in the PCC, fusiform/lingual gyrus, and CePL were shown relative to controls. No regions of increased VMHC were detected in either patient group. There was no significant difference in the VMHC values in any brain region between the BD group and the UD group. Depressive episodes in BD and UD have similar impairments of interhemispheric coordination, which might imply an overlap in the neuropathology of depression.
This study aimed to investigate the resting-state brain network related to visuospatial working memory (VSWM) in patients with right temporal lobe epilepsy (rTLE). The functional mechanism underlying the cognitive impairment in VSWM was also determined. Fifteen patients with rTLE and 16 healthy controls matched for age, gender, and handedness underwent a 6-min resting-state functional MRI session and a neuropsychological test using VSWM_Nback. The VSWM-related brain network at rest was extracted using multiple independent component analysis; the spatial distribution and the functional connectivity (FC) parameters of the cerebral network were compared between groups. Behavioral data were subsequently correlated with the mean Z-value in voxels showing significant FC difference during intergroup comparison. The distribution of the VSWM-related resting-state network (RSN) in the group with rTLE was virtually consistent with that in the healthy controls. The distribution involved the dorsolateral prefrontal lobe and parietal lobe in the right hemisphere and the partial inferior parietal lobe and posterior lobe of the cerebellum in the left hemisphere (p<0.05, AlphaSim corrected). Between-group differences suggest that the group with rTLE had a decreased FC within the right superior frontal lobe (BA8), right middle frontal lobe, and right ventromedial prefrontal lobe compared with the controls (p<0.05, AlphaSim corrected). The regions of increased FC in rTLE were localized within the right superior frontal lobe (BA11), right superior parietal lobe, and left posterior lobe of the cerebellum (p<0.05, AlphaSim corrected). Moreover, patients with rTLE performed worse than controls in the VSWM_Nback test, and there were negative correlations between ACCmeanRT (2-back) and the mean Z-value in the voxels showing decreased or increased FC in rTLE (p<0.05). The results suggest that the alteration of the VSWM-related RSN might underpin the VSWM impairment in patients with rTLE and possibly implies a functional compensation by enlarging the FC within the ipsilateral cerebral network.
Few studies demonstrated neural circuits related to disgust were influenced by internal sexual orientation in male. Here we used fMRI to study the neural responses to disgust in homosexual and heterosexual men to investigate that issue. Thirty-two healthy male volunteers (sixteen homosexual and sixteen heterosexual) were scanned while viewing alternating blocks of three types of erotic film: heterosexual couples (F-M), male homosexual couples (M-M), and female homosexual couples (F-F) engaged in sexual activity. All the participants rated their level of disgust and sexual arousal as well. The F-F and M-M stimuli induced disgust in homosexual and heterosexual men, respectively. The common activations related to disgusting stimuli included: bilateral frontal gyrus and occipital gyrus, right middle temporal gyrus, left superior temporal gyrus, right cerebellum, and right thalamus. Homosexual men had greater neural responses in the left medial frontal gyrus than did heterosexual men to the sexual disgusting stimuli; in contrast, heterosexual men showed significantly greater activation than homosexual men in the left cuneus. ROI analysis showed that negative correlation were found between the magnitude of MRI signals in the left medial frontal gyrus and scores of disgust in homosexual subjects (p<0.05). This study indicated that there were regions in common as well as regions specific for each type of erotic stimuli during disgust of homosexual and heterosexual men.
Several recent studies have reported a strong association between the cerebellar structural and functional abnormalities and psychiatric disorders. However, there are no studies to investigate possible changes in cerebellar functional connectivity in bipolar disorder. This study aimed to examine the whole-brain functional connectivity pattern of patients with remitted bipolar disorder II, in particular in the cerebellum. A total of 25 patients with remitted bipolar disorder II and 25 controls underwent resting-state functional magnetic resonance imaging and neuropsychological tests. Voxel-wise whole-brain connectivity was analyzed using a graph theory approach: functional connectivity strength. A seed-based resting-state functional connectivity analysis was further performed to investigate abnormal functional connectivity pattern of those regions with changed functional connectivity strength. Remitted bipolar disorder II patients had significantly decreased functional connectivity strength in the bilateral posterior lobes of cerebellum (mainly lobules VIIb/VIIIa). The seed-based functional connectivity analyses revealed decreased functional connectivity between the right posterior cerebellum and the default mode network (i.e. right posterior cingulate cortex/precuneus and right superior temporal gyrus), bilateral hippocampus, right putamen, left paracentral lobule and bilateral posterior cerebellum and decreased functional connectivity between the left posterior cerebellum and the right inferior parietal lobule and bilateral posterior cerebellum in patients with remitted bipolar disorder II. Our results suggest that cerebellar dysconnectivity, in particular distributed cerebellar-cerebral functional connectivity, might be associated with the pathogenesis of bipolar disorder.
The aim of this study was to investigate the relationship among childhood trauma, executive impairments, and altered resting-state brain function in young healthy adults. Twenty four subjects with childhood trauma and 24 age- and gender-matched subjects without childhood trauma were recruited. Executive function was assessed by a series of validated test procedures. Localized brain activity was evaluated by fractional amplitude of low frequency fluctuation (fALFF) method and compared between two groups. Areas with altered fALFF were further selected as seeds in subsequent functional connectivity analysis. Correlations of fALFF and connectivity values with severity of childhood trauma and executive dysfunction were analyzed as well. Subjects with childhood trauma exhibited impaired executive function as assessed by Wisconsin Card Sorting Test and Stroop Color Word Test. Traumatic individuals also showed increased fALFF in the right precuneus and decreased fALFF in the right superior temporal gyrus. Significant correlations of specific childhood trauma severity with executive dysfunction and fALFF value in the right precuneus were found in the whole sample. In addition, individuals with childhood trauma also exhibited diminished precuneus-based connectivity in default mode network with left ventromedial prefrontal cortex, left orbitofrontal cortex, and right cerebellum. Decreased default mode network connectivity was also associated with childhood trauma severity and executive dysfunction. The present findings suggest that childhood trauma is associated with executive deficits and aberrant default mode network functions even in healthy adults. Moreover, this study demonstrates that executive dysfunction is related to disrupted default mode network connectivity.
Avian encephalomyelitis (AE) is an important infectious poultry disease worldwide that is caused by avian encephalomyelitis virus (AEV). However, to date, the dynamic distribution of AEV in quails has not been well described. Quantitative real-time polymerase chain reaction (qPCR) and immunohistochemistry (IHC) assays were used to investigate the dynamic distribution and tissue tropism of AEV in experimentally infected Korean quail. AEV was detected in the cerebrum, cerebellum, proventriculus, intestine, liver, pancreas, spleen, bursa, lung and kidney as early as 3 days post-infection (dpi). The viral loads in the proventriculus, intestine, spleen and bursa were relatively higher than in other tissues. According to the qPCR results, AEV XY/Q-1410 infection lasted for at least 60 days in infected Korean quail. Immunohistochemistry-positive staining signals of AEV antigen were analysed by Image-Pro Plus software. A positive correlation between qPCR and IHC results was identified in most tissues. Our results provide an insight into the dynamic distribution of AEV in various tissues after infection. The distinct dynamic distribution of the viral genome in Korean quail in the early and late stages of infection suggests that AEV replication is affected by antibody levels and the maturity of the immune system of the host.
Identifying brain differences and similarities between bipolar disorder (BD) and major depressive disorder (MDD) is necessary for increasing our understanding of the pathophysiology and for developing more effective treatments. However, the features of whole-brain intrinsic functional connectivity underlying BD and MDD have not been directly compared. We collected resting-state fMRI data from 48 BD patients, 48 MDD patients, and 51 healthy subjects. We constructed voxel-wise whole-brain functional networks and computed regional functional connectivity strength (FCS) using graph-theory and further divided the regional FCS into long-range FCS (lFCS) and short-range FCS (sFCS). Relative to the controls, both the BD and MDD patients showed decreased sFCS in the bilateral precuneus. In addition, the BD patients showed increased and the MDD patients showed decreased lFCS and sFCS in the bilateral cerebellum. The BD patients also showed increased lFCS in the right middle temporal gyrus and increased sFCS in the bilateral thalamus compared to either the MDD patients or the controls. These findings suggest that BD and MDD may have some shared as well as a greater number of specific impairments in their functional connectivity patterns, providing new evidence for the pathophysiology of BD and MDD at the large-scale whole brain connectivity level.
Childhood trauma confers great risk for the development of multiple psychiatric disorders; however, the neural basis for this association is still unknown. The present resting-state functional magnetic resonance imaging study aimed to detect the effects of childhood trauma on brain function in a group of young healthy adults. In total, 24 healthy individuals with childhood trauma and 24 age- and sex-matched adults without childhood trauma were recruited. Each participant underwent resting-state functional magnetic resonance imaging scanning. Intra-regional brain activity was evaluated by regional homogeneity method and compared between groups. Areas with altered regional homogeneity were further selected as seeds in subsequent functional connectivity analysis. Statistical analyses were performed by setting current depression and anxiety as covariates. Adults with childhood trauma showed decreased regional homogeneity in bilateral superior temporal gyrus and insula, and the right inferior parietal lobule, as well as increased regional homogeneity in the right cerebellum and left middle temporal gyrus. Regional homogeneity values in the left middle temporal gyrus, right insula and right cerebellum were correlated with childhood trauma severity. In addition, individuals with childhood trauma also exhibited altered default mode network, cerebellum-default mode network and insula-default mode network connectivity when the left middle temporal gyrus, right cerebellum and right insula were selected as seed area, respectively. The present outcomes suggest that childhood trauma is associated with disturbed intrinsic brain function, especially the default mode network, in adults even without psychiatric diagnoses, which may mediate the relationship between childhood trauma and psychiatric disorders in later life.
GABAergic neurons play a critical role in the central nervous system, such as well-organized behaviors. The ischemic cell death is presumably initiated by neuronal excitotoxicity resulted from the dysfunction of GABAergic neurons. It is not clear how ischemia influences different types of GABAergic neurons and whether intracellular Ca plays a key role in the ischemic excitotoxicity. We have investigated this issue at cortical GABAergic neurons and cerebellar Purkinje cells by whole-cell recording in mouse brain slices, and the roles of intracellular Ca are examined by BABTA infusion. Compare with the data from a group of control, ischemia causes by lowering purfusion rate lowers spike encoding at cortical GABAergic neurons and enhances encoding ability at cerebellar Purkinje cells. These differential effects of ischemia on spike encoding are mechanistically associated with the changes in the refractory periods and threshold potentials of sequential spikes. These ischemia-induced dysfunction of spike encoding at two types of GABAergic cells are prevented by BABTA infusion. Therefore, the ischemia destabilizes the spike encoding of GABAergic cells via raising intracellular Ca. Our findings indicate that ischemia preferentially causes the dysfunction of spike encoding at GABAergic neurons by the up-regulation of intracellular Ca level, which leads to neuronal excitotoxicity.