Pei-Chi Tu

Complexity of spontaneous BOLD activity in default mode network is correlated with cognitive function in normal male elderly: a multiscale entropy analysis

The nonlinear properties of spontaneous fluctuations in blood oxygen level-dependent (BOLD) signals remain unexplored. We test the hypothesis that complexity of BOLD activity is reduced with aging and is correlated with cognitive performance in the elderly. A total of 99 normal older and 56 younger male subjects were included. Cognitive function was assessed using Cognitive Abilities Screening Instrument and Wechsler Digit Span Task. We employed a complexity measure, multiscale entropy (MSE) analysis, and investigated appropriate parameters for MSE calculation from relatively short BOLD signals. We then compared the complexity of BOLD signals between the younger and older groups, and examined the correlation between cognitive test scores and complexity of BOLD signals in various brain regions. Compared with the younger group, older subjects had the most significant reductions in MSE of BOLD signals in posterior cingulate gyrus and hippocampal cortex. For older subjects, MSE of BOLD signals from default mode network areas, including hippocampal cortex, cingulate cortex, superior and middle frontal gyrus, and middle temporal gyrus, were found to be positively correlated with major cognitive functions, such as attention, orientation, short-term memory, mental manipulation, and language. MSE from subcortical regions, such as amygdala and putamen, were found to be positively correlated with abstract thinking and list-generating fluency, respectively. Our findings confirmed the hypothesis that complexity of BOLD activity was correlated with aging and cognitive performance based on MSE analysis, and may provide insights on how dynamics of spontaneous brain activity relates to aging and cognitive function in specific brain regions.

Cortico-striatal disconnection within the cingulo-opercular network in schizophrenia revealed by intrinsic functional connectivity analysis: A resting fMRI study

The cingulo-opercular network (CON) is a newly defined control network responsible for various cognitive processes that have been consistently found to be impaired in schizophrenia. The aim of this study was to use functional connectivity magnetic resonance imaging (fcMRI) to test the hypothesis that schizophrenia is associated with functional disconnection within the CON. Thirty subjects with schizophrenia and thirty healthy controls were enrolled in the study. Each subject received resting fMRI scanning, clinical evaluations and cognitive examinations. The CON of each subject was derived by calculating the functional connectivity map of a seed in the dorsal anterior cingulate (dACC). A between-group comparison was performed using a random effect analysis. Further network analyses with multiple regions of interest (ROIs) were performed to characterize the pattern of functional disconnection within the entire CON. Using the dACC seed in healthy controls, we derived the CON, which includes the following anatomical structures: the dACC; the bilateral anterior prefrontal, inferior parietal and anterior insular cortices; the putamen; the thalamus; and the cerebellum. Compared with healthy controls, schizophrenic patients showed significantly reduced functional connectivity in the bilateral putamens. Further network analysis demonstrated widespread cortico-striatal disconnection within the CON of schizophrenic patients. The disconnections correlated with negative symptom severity. Behavioral regression revealed that cortico-striatal functional connectivity predicted 2-back working memory performance in healthy controls, but not in schizophrenic patients. Our findings suggest that schizophrenia is associated with cortical-striatal disconnection within the CON. The result provides a network basis for the cortico-striatal disconnection hypothesis of schizophrenia.

Regional cortical thinning in patients with major depressive disorder: A surface-based morphometry study

This study uses surfaced-based morphometry to investigate cortical thinning and its functional correlates in patients with major depressive disorder (MDD). Subjects with MDD (N=36) and healthy control subjects (N=36) were enrolled in the study. Each subject received T1 structural magnetic resonance imaging (MRI), clinical evaluations, and neuropsychological examinations of executive functions with the Color Trail Test (CTT) and the Wisconsin Card Sorting Test (WCST). This study used an automated surface-based method (FreeSurfer) to measure cortical thickness and to generate the thickness maps for each subject. Statistical comparisons were performed using a general linear model. Compared with healthy controls, subjects with MDD showed the largest area of cortical thinning in the prefrontal cortex. This study also noted smaller areas of cortical thinning in the bilateral inferior parietal cortex, left middle temporal gyrus, left entorhinal cortex, left lingual cortex, and right postcentral gyrus. Regression analysis demonstrated cortical thinning in several frontoparietal regions, predicting worse executive performance measured by CTT 2, though the patterns of cortical thickness/executive performance correlation differed in healthy controls and MDD subjects. In conclusion, the results provide further evidence for the significant role of a prefrontal structural deficit and an aberrant structural/functional relationship in patients with MDD.

Efficacy of prefrontal theta-burst stimulation in refractory depression: a randomized sham-controlled study

Theta-burst transcranial magnetic stimulation could modulate cortical excitability and has the potential to treat refractory depression. However, there has been a lack of large randomized studies of the antidepressant efficacy of different forms of theta-burst stimulation, such as intermittent and continuous theta-burst stimulation. A randomized sham-controlled study was conducted to investigate antidepressant efficacy of theta-burst stimulation and to compare efficacy among left-prefrontal intermittent theta-burst stimulation, right-prefrontal continuous theta-burst stimulation and a combination of them in patients showing different levels of antidepressant refractoriness. A group of 60 treatment-refractory patients with recurrent major depressive disorder were recruited and randomized to four groups (Group A: continuous theta-burst stimulation; Group B: intermittent theta-burst stimulation; Group C: a combination of continuous and intermittent theta-burst stimulation; and Group D: sham theta-burst stimulation; 15 patients were included in each group). After 2 weeks of theta-burst stimulation treatment, depression improved in all groups. Groups B and C had better antidepressant responses (as reflected by % decreases in depression score) than Groups A and D (P = 0.001, post hoc analysis: B > A, B > D, C > A, and C > D), even after controlling for age and refractoriness scores. The mean antidepressant effect was highest in Group C and followed by that in Group B. Additionally, a significant placebo effect was found in patients with low refractoriness; this disappeared in patients with moderate-to-high refractoriness. A significant correlation existed between refractoriness scores and treatment responses. Treatment refractoriness was a significant factor negatively predicting efficacy of theta-burst stimulation (P = 0.039). This randomized sham-controlled study demonstrated that active theta-burst stimulation is a well-tolerated form of repetitive transcranial magnetic stimulation and has good antidepressant efficacy, particularly in depressed subjects within a certain range of treatment refractoriness.

Comparison of pro-inflammatory cytokines among patients with bipolar disorder and unipolar depression and normal controls.

Research evidence has shown that bipolar disorder (BD) and unipolar depression (UD) are both related to inflammatory dysregulation, but few studies have compared the levels of cytokines between these two disorders.

Impairments in Cognitive Function and Brain Connectivity in Severe Asymptomatic Carotid Stenosis

Background and Purpose— Severe asymptomatic carotid stenosis has been associated with cognitive impairment, but it is unknown whether this association is attributable to effects on brain connectivity. We present cognitive network abnormalities in a group of patients at a presymptomatic stage. Methods— Seventeen patients with ≥70% asymptomatic stenosis of unilateral internal carotid artery were compared with 26 healthy controls utilizing a comprehensive neuropsychological battery, the dizziness handicap inventory, and multimodality neuroimaging including diffusion tensor imaging and resting-state functional connectivity magnetic resonance imaging. Longitudinally, assessments were completed in a subgroup of 10 patients at 3 months after carotid artery stenting. Results— Compared with the healthy controls, the patients had worse dizziness scores, poorer memory, complex visuo-spatial performances, and lower whole-brain mean fractional anisotropy. The Scheltens scores of leukoaraiosis/infarction were not different between groups. Their seed-based functional connectivity magnetic resonance imaging showed marked decrements of interhemispheric and intrahemispheric, ipsilaterally to carotid stenosis, functional connectivity in the frontoparietal network. In the default mode network, the intrahemispheric functional connectivity was bilaterally impaired. Importantly, the disrupted mean fractional anisotropy in the patients significantly correlated with the attention and verbal memory functions. After successful carotid artery stenting, small but measurable increments of the mean fractional anisotropy and little functional connectivity in the default mode network ipsilateral-to-carotid artery stenting were noted. Conclusions— We identified for the first time distinct patterns of network disruption that correlate with cognitive fragility in patients with asymptomatic carotid stenosis. Brain connectivity may provide early and useful biomarkers for brain ischemia and reperfusion.

Impaired Prefronto-Thalamic Functional Connectivity as a Key Feature of Treatment-Resistant Depression: A Combined MEG, PET and rTMS Study

Prefrontal left-right functional imbalance and disrupted prefronto-thalamic circuitry are plausible mechanisms for treatment-resistant depression (TRD). Add-on repetitive transcranial magnetic stimulation (rTMS), effective in treating antidepressant-refractory TRD, was administered to verify the core mechanisms underlying the refractoriness to antidepressants. Thirty TRD patients received a 2-week course of 10-Hz rTMS to the left dorsolateral prefrontal cortex (DLPFC). Depression scores were evaluated at baseline (W0), and the ends of weeks 1, 2, and 14 (W14). Responders were defined as those who showed an objective improvement in depression scores ≥50% after rTMS. Left-right frontal alpha asymmetry (FAA) was measured by magnetoencephalography at each time point as a proxy for left-right functional imbalance. Prefronto-thalamic connections at W0 and W14 were assessed by studying couplings between prefrontal alpha waves and thalamic glucose metabolism (PWTMC, reflecting intact thalamo-prefrontal connectivity). A group of healthy control subjects received magnetoencephalography at W0 (N = 50) to study whether FAA could have a diagnostic value for TRD, or received both magnetoencephalography and positron-emission-tomography at W0 (N = 10) to confirm the existence of PWTMC in the depression-free state. We found that FAA changes cannot differentiate between TRD and healthy subjects or between responders and non-responders. No PWTMC were found in the TRD group at W0, whereas restitution of the PWTMC was demonstrated only in the sustained responders at W14 and euthymic healthy controls. In conclusion, we affirmed impaired prefronto-thalamic functional connections, but not frontal functional imbalance, as a core deficit in TRD.

Different patterns of abnormal gamma oscillatory activity in unipolar and bipolar disorder patients during an implicit emotion task.

This study investigates the distinct patterns of local and long-range gamma oscillations between patients with bipolar disorder (BD) and major depressive disorder (MDD). Twenty BD patients, twenty MDD patients, and twenty normal controls participated in this study. For each participant, the event-related magnetoencephalographic responses while performing an implicit emotional task were recorded and processed with time-frequency analysis. Compared to normal controls, the BD patients exhibited the gamma power decease at the right frontal and prefrontal regions and yet gamma power increase at the right posterior temporal region. The abnormal long-range gamma oscillation between the right frontal and parietal-occipital region was also found. These results indicate that the BD patients may have hyperactivity in perceptual binding of emotional features and tend to be oversensitive to facial features. On the other hand, MDD patients displayed increased early gamma activity at the left anterior temporal region, which may imply their hyperactivated binding process of emotional features at corticolimbic regions. The distinct alterations of gamma patterns between the BD and MDD patients implicate that their impairments of binding processes are located at different regions. Gamma activity in the parietal and left posterior temporal regions may be a potential index to differentiate BD patients from MDD patients.

Major Depressive Disorder and Stroke Risks: A 9-Year Follow-Up Population-Based, Matched Cohort Study

Background and Purpose Major depressive disorder (MDD) is characterized by recurrent depressive episodes and one of the treatment choices is antidepressants. Patients with MDD are at greater risk of developing major metabolic diseases that may in turn lead to stroke. Moreover, both depressive symptoms and taking antidepressant medications are associated with higher risk of stroke. However, whether and how clinical depression increases stroke risk remains an unanswered question. Our aim was to provide answers to this question. Methods A matched cohort study of 5015 subjects (1003 MDD patients and 4012 control subjects) was conducted using a nationwide database. Subjects were followed to a maximum of 9 years to determine rates of newly-developed strokes, and controls and MDD groups with different levels of antidepressant refractoriness were compared to determine the temporal relation between stroke and three major metabolic comorbidities (i.e., diabetes mellitus, hypertension and hyperlipidemia). The levels of depressive symptoms and the antidepressant medications before stroke onset were investigated. Results Patients with MDD had significantly higher rates of stroke (4.3% vs. 2.8%, p<0.05) during the follow-up. Mediation regression analyses revealed that the occurrence of stroke in the MDD subjects was significantly mediated by the development of major metabolic diseases. Greater severity of depression, but not greater use of antidepressants, preceded the occurrence of stroke. Conclusions A clinical diagnosis of major depression leads to stroke indirectly through more intense depressive symptoms and the development of major comorbidities.

Neural Network of Body Representation Differs between Transsexuals and Cissexuals

Body image is the internal representation of an individual’s own physical appearance. Individuals with gender identity disorder (GID), commonly referred to as transsexuals (TXs), are unable to form a satisfactory body image due to the dissonance between their biological sex and gender identity. We reasoned that changes in the resting-state functional connectivity (rsFC) network would neurologically reflect such experiential incongruence in TXs. Using graph theory-based network analysis, we investigated the regional changes of the degree centrality of the rsFC network. The degree centrality is an index of the functional importance of a node in a neural network. We hypothesized that three key regions of the body representation network, i.e., the primary somatosensory cortex, the superior parietal lobule and the insula, would show a higher degree centrality in TXs. Twenty-three pre-treatment TXs (11 male-to-female and 12 female-to-male TXs) as one psychosocial group and 23 age-matched healthy cissexual control subjects (CISs, 11 males and 12 females) were recruited. Resting-state functional magnetic resonance imaging was performed, and binarized rsFC networks were constructed. The TXs demonstrated a significantly higher degree centrality in the bilateral superior parietal lobule and the primary somatosensory cortex. In addition, the connectivity between the right insula and the bilateral primary somatosensory cortices was negatively correlated with the selfness rating of their desired genders. These data indicate that the key components of body representation manifest in TXs as critical function hubs in the rsFC network. The negative association may imply a coping mechanism that dissociates bodily emotion from body image. The changes in the functional connectome may serve as representational markers for the dysphoric bodily self of TXs.