In this study, we aimed to investigate the reactive changes in diffusion tensor imaging (DTI)-derived diffusion metrics of the anterior thalamic nucleus (AN), a relaying center for the Papez circuit, in early idiopathic normal pressure hydrocephalus (iNPH) patients with memory impairment, as well as its correlation with the patients' neuropsychological performances. In total, 28 probable iNPH patients with symptom onset within 1 year and 17 control subjects were prospectively recruited between 2010 and 2013 for this institutional review board-approved study. Imaging studies including DTI and a neuropsychological assessment battery were performed in all subjects. Diffusion metrics were measured from the region of the AN using tract-deterministic seeding method by reconstructing the mammillo-thalamo-cingulate connections within the Papez circuit. Differences in diffusion metrics and memory assessment scores between the patient and control group were examined via the Mann-Whitney U test. Spearman correlation analyses were performed to examine associations between diffusion metrics of AN and neuropsychological tests within the patient group. We discovered that early iNPH patients exhibited marked elevations in fractional anisotropy, pure diffusion anisotropy, and axial diffusivity (all P < 0.01), as well as lower neuropsychological test scores including verbal and nonverbal memory (all P < 0.05) compared with normal control. Spearman rank correlation analyses did not disclose significant correlations between AN diffusion metrics and neuropsychological test scores in the patient group, whereas ranked scatter plots clearly demonstrated a dichotic sample distribution between patient and control samples. In summary, our study highlighted the potential compensatory role of the AN by increasing thalamocortical connectivity within the Papez circuit because memory function declines in early iNPH when early shunt treatment may potentially reverse the memory deficits.

Parkinson's disease (PD) is a common neurodegenerative disorder that may increase the risk of falls, functional limitation, and balance deficits. Tai Chi was used as an option for improving balance in people with PD. The aim of this meta-analysis was to evaluate the effects of Tai Chi on falls, balance, and functional mobility in individuals with PD.

We conducted an observational study to investigate clinical predictors of cognitive decline in patients with mild cognitive impairment (MCI), with a focus on patients with Parkinson's disease (PD) and Alzheimer's disease (AD). The study was performed with detailed neuropsychological testing, a portable device for gait analysis, and a comprehensive geriatric assessment for patients with MCI. Cognitive decline was defined as subjective cognitive impairment with an objective decline in the Mini-Mental State Examination (MMSE) ≥2 points at the one-year follow-up. Participants (n = 74) had a median age of 70 (interquartile range 60-79) years, and 45.9% of them were women. At the end of the study, 17.6% of the patients with MCI had a cognitive decline. Although no differences were observed between groups at the baseline cognitive study, patients with PD-MCI demonstrated more cognitive decline than patients with AD-MCI (28.6% vs. 7.7% p = 0.03). Patients with PD-MCI had more physical disabilities, including scores of instrumental activities of daily living (IADL), Tinetti balance, and gait scores, and some Timed Up and Go components. Initial Clinical Dementia Rating-Sum of Boxes score was a better predictor of future cognitive decline than MMSE in PD-MCI. For predicting the occurrence of cognitive decline in PD-MCI, the prediction accuracy increased from the reduced model (AUC = 0.822, p < 0.001) to the full model (a total of five independent variables, AUC = 0.974, p < 0.001). Given the potentially modifiable predictor, our findings also highlight the importance of identifying sleep quality and the ability to perform IADL.

Numerous studies indicated the physical benefits of regular exercise, but the neurophysiological mechanisms of regular exercise in elders were less investigated. We aimed to compare changes in brain activity during exercise in elderly people and in young adults with and without regular exercise habits. A total of 36 healthy young adults (M/F:18/18) and 35 healthy elderly adults (M/F:20/15) participated in this study. According to exercise habits, each age group were classified into regular and occasional exerciser groups. ECG, EEG, and EMG signals were recorded using V-AMP with a 1-kHz sampling rate. The participants were instructed to perform three 5-min bicycle rides with different exercise loads. The EEG spectral power of elders who exercised regularly revealed the strongest positive correlation with their exercise intensity by using Pearson correlation analysis. The results demonstrate that exercise-induced significant cortical activation in the elderly participants who exercised regularly, and most of the p-values are less than 0.001. No significant correlation was observed between spectral power and exercise intensity in the elders who exercised occasionally. The young participants who exercised regularly had greater cardiac and neurobiological efficiency. Our results may provide a new exercise therapy reference for adult groups with different exercise habits, especially for the elders.

The ability to classify patients with bipolar disorder (BD) is restricted by their heterogeneity, which limits the understanding of their neuropathology. Therefore, we aimed to investigate clinically discernible and neurobiologically distinguishable BD subtypes. T1-weighted and resting-state functional magnetic resonance images of 112 patients with BD were obtained, and patients were segregated according to diagnostic subtype (i.e., types I and II) and clinical patterns, including the number of episodes and hospitalizations and history of suicide and psychosis. For each clinical pattern, fewer and more occurrences subgroups and types I and II were classified through nested cross-validation for robust performance, with minimum redundancy and maximum relevance, in feature selection. To assess the proportion of variance in cognitive performance explained by the neurobiological markers, multiple linear regression between verbal memory and the selected features was conducted. Satisfactory performance (mean accuracy, 73.60%) in classifying patients with a high or low number of episodes was attained through functional connectivity, mostly from default-mode and motor networks. Moreover, these neurobiological markers explained 62% of the variance in verbal memory. The number of episodes is a potentially critical aspect of the neuropathology of BD. Neurobiological markers can help identify BD neuroprogression.

To determine specific resting-state network patterns underlying alterations in chronic migraine, we employed oscillatory connectivity and machine learning techniques to distinguish patients with chronic migraine from healthy controls and patients with other pain disorders. This cross-sectional study included 350 participants (70 healthy controls, 100 patients with chronic migraine, 40 patients with chronic migraine with comorbid fibromyalgia, 35 patients with fibromyalgia, 30 patients with chronic tension-type headache, and 75 patients with episodic migraine). We collected resting-state magnetoencephalographic data for analysis. Source-based oscillatory connectivity within each network, including the pain-related network, default mode network, sensorimotor network, visual network, and insula to default mode network, was examined to determine intrinsic connectivity across a frequency range of 1-40 Hz. Features were extracted to establish and validate classification models constructed using machine learning algorithms. The findings indicated that oscillatory connectivity revealed brain network abnormalities in patients with chronic migraine compared with healthy controls, and that oscillatory connectivity exhibited distinct patterns between various pain disorders. After the incorporation of network features, the best classification model demonstrated excellent performance in distinguishing patients with chronic migraine from healthy controls, achieving high accuracy on both training and testing datasets (accuracy > 92.6% and area under the curve > 0.93). Moreover, in validation tests, classification models exhibited high accuracy in discriminating patients with chronic migraine from all other groups of patients (accuracy > 75.7% and area under the curve > 0.8). In conclusion, oscillatory synchrony within the pain-related network and default mode network corresponded to altered neurophysiological processes in patients with chronic migraine. Thus, these networks can serve as pivotal signatures in the model for identifying patients with chronic migraine, providing reliable and generalisable results. This approach may facilitate the objective and individualised diagnosis of migraine.

Lysyl oxidase-like 2 (LOXL2) is a matrix-remodeling enzyme that has recently been identified as an important regulator of tumor progression and metastasis. This study discovered that LOXL2 expression in oral squamous cell carcinoma (OSCC) tissues was significantly associated with tumor clinical stage, lymph node metastasis and patients' overall survival time. LOXL2-overexpressing human buccal SCC TW2.6 (TW2.6/LOXL2) and hypopharyngeal SCC FaDu (FaDu/LOXL2) cells exhibited enhanced migration, invasion, epithelial-mesenchymal transition (EMT), and cancer stem cell (CSC) phenotypes, independently of its enzymatic activity. Moreover, TW2.6/LOXL2 significantly increased tumor-initiating frequency in SCID mice. We further demonstrated that LOXL2 increased the levels of interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) and IFIT3 in TW2.6/LOXL2 and FaDu/LOXL2 cells. We also identified IFIT1 and IFIT3 as key downstream components of LOXL2 action in migration, invasion, EMT, and CSC phenotypes in TW2.6 and FaDu cells. Furthermore, a significant positive correlation between LOXL2 expression and IFIT1 and IFIT3 overexpression in human OSCC tissues was observed. In addition, TW2.6/LOXL2 and FaDu/LOXL2 cells were 3.3- to 3.6-fold more susceptible to the epidermal growth factor receptor (EGFR) inhibitor gefitinib than were their respective control cells. The antitumor effect of gefitinib on orthotopic TW2.6/LOXL2 xenograft tumor was fourfold higher than that on controls. Our results indicate that LOXL2 expression is a strong prognostic factor for OSCC and may be used as a marker to identify patients most likely to respond to EGFR-targeted therapy.

Memory impairment is commonly noted in stroke survivors, and can lead to delay of functional recovery. Exercise has been proved to improve memory in adult healthy subjects. Such beneficial effects are often suggested to relate to hippocampal synaptic plasticity, which is important for memory processing. Previous evidence showed that in normal rats, low intensity exercise can improve synaptic plasticity better than high intensity exercise. However, the effects of exercise intensities on hippocampal synaptic plasticity and spatial memory after brain ischemia remain unclear. In this study, we investigated such effects in brain ischemic rats. The middle cerebral artery occlusion (MCAO) procedure was used to induce brain ischemia. After the MCAO procedure, rats were randomly assigned to sedentary (Sed), low-intensity exercise (Low-Ex), or high-intensity exercise (High-Ex) group. Treadmill training began from the second day post MCAO procedure, 30 min/day for 14 consecutive days for the exercise groups. The Low-Ex group was trained at the speed of 8 m/min, while the High-Ex group at the speed of 20 m/min. The spatial memory, hippocampal brain-derived neurotrophic factor (BDNF), synapsin-I, postsynaptic density protein 95 (PSD-95), and dendritic structures were examined to document the effects. Serum corticosterone level was also quantified as stress marker. Our results showed the Low-Ex group, but not the High-Ex group, demonstrated better spatial memory performance than the Sed group. Dendritic complexity and the levels of BDNF and PSD-95 increased significantly only in the Low-Ex group as compared with the Sed group in bilateral hippocampus. Notably, increased level of corticosterone was found in the High-Ex group, implicating higher stress response. In conclusion, after brain ischemia, low intensity exercise may result in better synaptic plasticity and spatial memory performance than high intensity exercise; therefore, the intensity is suggested to be considered during exercise training.

In morphometric neuroimaging studies, the relationship between brain structural changes and the antidepressant treatment response in patients with major depressive disorder has been explored to search depression-trait biomarkers. Although patients were treated with serotonin-related drugs, whether the same treatment resulted in remission and non-remission in depressed patients is currently under investigation. We recruited 25 depressed patients and 25 healthy controls and acquired volumetric magnetic resonance imaging of each participant. We used the shape index and curvedness to classify cortical shapes and quantify shape complexities, respectively, in studying the pharmacological effect on brain morphology. The results showed that different regions of structural abnormalities emerged between remitting and non-remitting patients when contrasted with healthy controls. In addition to comparing structural metrics in each cortical parcellation, similar to the traditional voxel-based morphometric method, we highlighted the importance of structural integrity along the serotonin pathway in response to medication treatment. We discovered that disrupted serotonin-related cortical regions might cause non-remission to antidepressant treatment from a pharmacological perspective. The anomalous areas manifested in non-remitting patients were mainly in the frontolimbic areas, which can be used to differentiate remitting from non-remitting participants before medication treatment. Because non-remission is the failure to respond to treatment with serotonin-related drugs, our method may help clinicians choose appropriate medications for non-remitting patients.

Coactivation of primary motor cortex ipsilateral to a unilateral movement (M1(ipsilateral)) has been observed, and the magnitude of activation is influenced by the contracting muscles. It has been suggested that the microstructural integrity of the callosal motor fibers (CMFs) connecting M1 regions may reflect the observed response. However, the association between the structural connectivity of CMFs and functional changes in M1(ipsilateral) remains unclear. The purpose of this study was to investigate the relationship between functional changes within M1(ipsilateral) during unilateral arm or leg movements and the microstructure of the CMFs connecting both homotopic representations (arm or leg).

Bipolar disorder (BD) is a genetically and phenotypically complex psychiatric disease. Although previous studies have suggested that the relatives of BD patients have an increased risk of experiencing affective disturbances, most relatives who have similar genotypes may not manifest the disorder. We aim to identify the neuroimaging alterations-specifically, the cortical folding structures of the anterior limbic network (ALN)-in BD patients and their siblings, compared to healthy controls. The shared alterations in patients and their siblings may indicate the hereditary predisposition of BD, and the altered cortical structures unique to BD patients may be a probe of BD expression. High-resolution, T1-weighted magnetic resonance images for 17 euthymic patients with BD, 17 unaffected siblings of BD patients, and 22 healthy controls were acquired. We categorized the cortical regions within the ALN into sulcal and gyral areas, based on the shape index, followed by the measurement of the folding degree, using the curvedness. Our results revealed that the changes in cortical folding in the orbitofrontal and temporal regions were associated with a hereditary predisposition to BD. Cortical folding structures in multiple regions of the ALN, particularly in the striatal-thalamic circuit and anterior cingulate cortex, could be used to differentiate BD patients from healthy controls and unaffected siblings. We concluded that the cortical folding structures of ALN can provide potential biomarkers for clinical diagnosis of BD and differentiation from the unaffected siblings.

Background: Recent studies have shown that the patients with spinocerebellar ataxia type 3 (SCA3) may not only have disease involvement in the cerebellum and brainstem but also in the cerebral regions. However, the relations between the widespread degenerated brain regions remains incompletely explored. Methods: In the present study, we investigate the topological properties of the brain networks of SCA3 patients (n = 40) constructed based on the correlation of three-dimensional fractal dimension values. Random and targeted attacks were applied to measure the network resilience of normal and SCA3 groups. Results: The SCA3 networks had significantly smaller clustering coefficients (P < 0.05) and global efficiency (P < 0.05) but larger characteristic path length (P < 0.05) than the normal controls networks, implying loss of small-world features. Furthermore, the SCA3 patients were associated with reduced nodal betweenness (P < 0.001) in the left supplementary motor area, bilateral paracentral lobules, and right thalamus, indicating that the motor control circuit might be compromised. Conclusions: The SCA3 networks were more vulnerable to targeted attacks than the normal controls networks because of the effects of pathological topological organization. The SCA3 revealed a more sparsity and disrupted structural network with decreased values in the largest component size, mean degree, mean density, clustering coefficient, and global efficiency and increased value in characteristic path length. The cortico-cerebral circuits in SCA3 were disrupted and segregated into occipital-parietal (visual-spatial cognition) and frontal-pre-frontal (motor control) clusters. The cerebellum of SCA3 were segregated from cerebellum-temporal-frontal circuits and clustered into a frontal-temporal cluster (cognitive control). Therefore, the disrupted structural network presented in this study might reflect the clinical characteristics of SCA3.

Paroxysmal kinesigenic dyskinesia (PKD) is conventionally regarded as a movement disorder (MD) and characterized by episodic hyperkinesia by sudden movements. However, patients of PKD often have sensory aura and respond excellently to antiepileptic agents. PRRT2 mutations, the most common genetic etiology of PKD, could cause epilepsy syndromes as well. Standing in the twilight zone between MDs and epilepsy, the pathogenesis of PKD is unclear. Gamma oscillations arise from the inhibitory interneurons which are crucial in the thalamocortical circuits. The role of synchronized gamma oscillations in sensory gating is an important mechanism of automatic cortical inhibition. The patterns of gamma oscillations have been used to characterize neurophysiological features of many neurological diseases, including epilepsy and MDs. This study was aimed to investigate the features of gamma synchronizations in PKD. In the paired-pulse electrical-stimulation task, we recorded the magnetoencephalographic data with distributed source modeling and time-frequency analysis in 19 patients of newly-diagnosed PKD without receiving pharmacotherapy and 18 healthy controls. In combination with the magnetic resonance imaging, the source of gamma oscillations was localized in the primary somatosensory cortex. Somatosensory evoked fields of PKD patients had a reduced peak frequency (p < 0.001 for the first and the second response) and a prolonged peak latency (the first response p = 0.02, the second response p = 0.002), indicating the synchronization of gamma oscillation is significantly attenuated. The power ratio between two responses was much higher in the PKD group (p = 0.013), indicating the incompetence of activity suppression. Aberrant gamma synchronizations revealed the defective sensory gating of the somatosensory area contributes the pathogenesis of PKD. Our findings documented disinhibited cortical function is a pathomechanism common to PKD and epilepsy, thus rationalized the clinical overlaps of these two diseases and the therapeutic effect of antiepileptic agents for PKD. There is a greater reduction of the peak gamma frequency in PRRT2-related PKD than the non-PRRT PKD group (p = 0.028 for the first response, p = 0.004 for the second response). Loss-of-function PRRT2 mutations could lead to synaptic dysfunction. The disinhibiton change on neurophysiology reflected the impacts of PRRT2 mutations on human neurophysiology.

Background: Spinocerebellar ataxia type 3 (SCA) is a cerebellum-dominant degenerative disorder that is characterized primarily by infratentorial damage, although less severe supratentorial involvement may contribute to the clinical manifestation. These impairments may result from the efferent loss of the cerebellar cortex and degeneration of the cerebral cortex. Method: We used the three-dimensional fractal dimension (3D-FD) method to quantify the morphological changes in the supratentorial regions and assessed atrophy in the relatively focal regions in patients with SCA3. A total of 48 patients with SCA3 and 50 sex- and age-matched healthy individuals, as the control group, participated in this study. The 3D-FD method was proposed to distinguish 97 automatic anatomical label regions of gray matter (left cerebrum: 45, right cerebrum: 45, cerebellum: 7) between healthy individuals and patients with SCA3. Results: Patients with SCA3 exhibited reduced brain complexity within both the traditional olivopontocerebellar atrophy (OPCA) pattern and specific supratentorial regions. The study results confirmed the extensive involvement of extracerebellar regions in SCA3. The atrophied regions of SCA3 in infratentorial and supratentorial cortex showed a wide range of overlapped areas as in two functional cortexes, namely cerebellum-related cortex and basal ganglia-related cortex. Conclusions: Our results found that the atrophy of the SCA3 are not only limited in the infratentorial regions. Both cerebellar related cortex and basal ganglia related cortex were affected in the disease process of SCA3. Our findings might correlate to the common symptoms of SCA3, such as ataxia, Parkinsonism, dysarthria, and dysmetria. SCA3 should no longer be considered a disease limited to the cerebellum and its connections; rather, it should be considered a pathology affecting the whole brain.

This study investigated the effectiveness of Ai Chi compared to conventional water-based exercise on balance performance in individuals with chronic stroke. A total of 20 individuals with chronic stroke were randomly allocated to receive either Ai Chi or conventional water-based exercise for 60 min/time, 3 times/week, and a total of 6 weeks. Balance performance assessed by limit of stability (LOS) test and Berg balance scale (BBS). Fugl-Meyer assessment (FMA) and gait performance were documented for lower extremity movement control and walking ability, respectively. Excursion and movement velocity in LOS test was significantly increased in anteroposterior axis after receiving Ai Chi (p = 0.005 for excursion, p = 0.013 for velocity) but not conventional water-based exercise. In particular, the improvement of endpoint excursion in the Ai Chi group has significant inter-group difference (p = 0.001). Both groups showed significant improvement in BBS and FMA yet the Ai Chi group demonstrated significantly better results than control group (p = 0.025). Ai Chi is feasible for balance training in stroke, and is able to improve weight shifting in anteroposterior axis, functional balance, and lower extremity control as compared to conventional water-based exercise.

In daily life, mobility requires walking while performing a cognitive or upper-extremity motor task. Although previous studies have evaluated the effects of dual tasks on gait performance, few studies have evaluated cortical activation and its association with gait disturbance during dual tasks. In this study, we simultaneously assessed gait performance and cerebral oxygenation in the bilateral prefrontal cortices (PFC), premotor cortices (PMC), and supplemental motor areas (SMA), using functional near-infrared spectroscopy, in 17 young adults performing dual tasks. Each participant was evaluated while performing normal-pace walking (NW), walking while performing a cognitive task (WCT), and walking while performing a motor task (WMT). Our results indicated that the left PFC exhibited the strongest and most sustained activation during WCT, and that NW and WMT were associated with minor increases in oxygenation levels during their initial phases. We observed increased activation in channels in the SMA and PMC during WCT and WMT. Gait data indicated that WCT and WMT both caused reductions in walking speed, but these reductions resulted from differing alterations in gait properties. WCT was associated with significant changes in cadence, stride time, and stride length, whereas WMT was associated with reductions in stride length only. During dual-task activities, increased activation of the PMC and SMA correlated with declines in gait performance, indicating a control mechanism for maintaining gait performance during dual tasks. Thus, the regulatory effects of cortical activation on gait behavior enable a second task to be performed while walking.

Patients with spinocerebellar ataxia type 3 (SCA3) have exhibited cerebral cortical involvement and various mental deficits in previous studies. Clinically, conventional measurements, such as the Mini-Mental State Examination (MMSE) and electroencephalography (EEG), are insensitive to cerebral cortical involvement and mental deficits associated with SCA3, particularly at the early stage of the disease. We applied a three-dimensional fractal dimension (3D-FD) method, which can be used to quantify the shape complexity of cortical folding, in assessing cortical degeneration. We evaluated 48 genetically confirmed SCA3 patients by employing clinical scales and magnetic resonance imaging and using 50 healthy participants as a control group. According to the Scale for the Assessment and Rating of Ataxia (SARA), the SCA3 patients were diagnosed with cortical dysfunction in the cerebellar cortex; however, no significant difference in the cerebral cortex was observed according to the patients' MMSE ratings. Using the 3D-FD method, we determined that cortical involvement was more extensive than involvement of traditional olivopontocerebellar regions and the corticocerebellar system. Moreover, the significant correlation between decreased 3D-FD values and disease duration may indicate atrophy of the cerebellar cortex and cerebral cortex in SCA3 patients. The change of the cerebral complexity in the SCA3 patients can be detected throughout the disease duration, especially it becomes substantial at the late stage of the disease. Furthermore, we determined that atrophy of the cerebral cortex may occur earlier than changes in MMSE scores and EEG signals.

Two different training strategies to improve turning performance in individuals with Parkinson's disease (PD) were designed and investigated in this study. Subjects were randomly assigned to a specific exercise group, turning-based training group, or control group to receive training that emphasized balance and strengthening, turning-based treadmill training, and general exercise training, respectively. A total of 12 30-min training sessions followed by 10 min of turning training on a level surface were administered over 4 to 6 weeks. The results (n = 12 for each group) showed that both the specific exercise and turning-based training group experienced improved turning performance, the primary outcome, compared with the control group (specific exercise, 33% change, p = 0.016; turning-based training, 35% change, p = 0.021). For the secondary outcomes, the specific exercise group performed better than the control group on the Tinetti balance scale, limit of stability test and lower extremity extensor and abductor strength. The turning-based training groups performed better than the control group in sensory organization and ankle plantar flexor strength. In summary, specific exercise training and turning-based treadmill training were both effective in improving turning performance in participants with PD. However, the improvements in turning performance of these two groups resulted from improving different aspects of impairment in individuals with PD.

Functional connectome analysis in panic disorder (PDO) is a relatively new field for research. We tried to investigate the functional connectome alterations in PDO to re-examine the precision and role of fear network model for the pathophysiology of PDO.We enrolled 53 PDO patients and 54 controls with imaging data in this study. After preprocessing, we calculated the connectivity matrix of functional connectivity in whole brain for each subject. Then network-based statistics (The University of Melbourne and Melbourne Health, Australia) of connectome was used to perform group comparisons between patients and controls. The correlation between network measures of significant subnetwork and illness duration or severity of PDO was also performed.Within the 6 network models, only 1 network survived after multiple corrections. We found decreased functional connectivity in the edges between the following nodes: the left parahippocampal gyrus, bilateral precentral gyri, bilateral middle cingulate gyri, bilateral supramarginal gyri, bilateral calcarine fissures, and right lingual gyrus. The central hubs were the left parahippocampal gyrus and left precentral gyrus. The importance of limbic areas and connection with sensory and motor regions might shed light on the revision of fear network model for the pathophysiology of PDO.

Memory impairment is a frequent complication of brain ischemia. Neurogenesis is implicated in learning and memory and is regulated by the transcription factor c-Fos. Preconditioning intermittent hypoxia (IH) attenuates ischemia-related memory impairments, but it is not known whether post-ischemia IH intervention has a similar effect. We investigated the effects of post-ischemia IH on hippocampal neurogenesis and c-Fos expression as well as spatial learning and memory in rats.