Modulating Gamma Oscillations Promotes Brain Connectivity to Improve Cognitive Impairment.

Dementia causes a substantial global economic burden, but effective treatment is lacking. Recently, studies have revealed that gamma-band waves of electrical brain activity, particularly 40 Hz oscillations, are closely associated with high-order cognitive functions and can activate microglia to clear amyloid-ß deposition. Here, we found that compared with sham stimulation, applying 40-Hz high-frequency repetitive transcranial magnetic stimulation (rTMS) over the bilateral angular gyrus in patients with probable Alzheimer's disease (AD; n = 37) resulted in up to 8 weeks of significantly improved cognitive function. Power spectral density analysis of the resting-state electroencephalography (EEG) demonstrated that 40-Hz rTMS modulated gamma-band oscillations in the left posterior temporoparietal region. Further testing with magnetic resonance imaging and TMS-EEG revealed the following: 40-Hz rTMS 1) prevented gray matter volume loss, 2) enhanced local functional integration within bilateral angular gyrus, as well as global functional integration in bilateral angular gyrus and the left middle frontal gyrus, 3) strengthened information flow from the left posterior temporoparietal region to the frontal areas and strengthened the dynamic connectivity between anterior and posterior brain regions. These findings demonstrate that modulating gamma-band oscillations effectively improves cognitive function in patients with probable AD by promoting local, long-range, and dynamic connectivity within the brain.

Transcutaneous Spinal Cord Direct-Current Stimulation Modulates Functional Activity and Integration in Idiopathic Restless Legs Syndrome.

Idiopathic restless legs syndrome (RLS) is a sensorimotor disorder and is suggested to be caused by central nervous system abnormalities. Non-invasive transcutaneous spinal direct-current stimulation (tsDCS) was recently used for RLS therapy. However, the neurophysiological basis of tsDCS treatment is still unknown. In this study, we explored the neural basis of tsDCS in 15 RLS patients and 20 gender- and age-matched healthy controls using resting-state functional magnetic resonance imaging. We calculated the whole-brain voxel-wise fractional amplitude of low-frequency fluctuations (fALFF), regional homogeneity (ReHo), and weighted degree centrality (DC) to characterize the intrinsic functional activities and the local and global functional integration. We found that tsDCS can effectively improve the sleep and RLS symptoms in RLS patients. Moreover, after tsDCS therapy, the RLS patients showed decreased fALFF in the right anterior insula/temporal pole, decreased ReHo in the supplementary motor area, increased weighted DC in the left primary visual cortex, and decreased weighted DC in the right posterior cerebellum. The changed patterns were consistent with that found between RLS patients and healthy controls. The weighted DC in the left primary visual cortex after treatment and the fALFF in the right anterior insula/temporal pole before treatment were significantly and marginally correlated with sleep and RLS symptom scores, respectively. These results revealed that tsDCS can normalize the functional patterns of RLS patients and is an effective way for RLS therapy. Our findings provide the neurophysiological basis for tsDCS treatment and may facilitate understanding the neuropathology of RLS and directing other neuromodulation treatments.

Increased Gray Matter Density and Functional Connectivity of the Pons in Restless Legs Syndrome.

BACKGROUND: Neurophysiological and radiological studies provide accumulating evidence for the involvement of the brainstem in the pathogenesis of restless legs syndrome (RLS). The analysis of the various subregions of the brainstem may help us better understand the pathophysiological mechanisms underlying the disorder. In this study, we investigated the structural and functional changes in the various subregions of the brainstem in RLS patients. METHODS: The subregional changes in gray matter density and functional connectivity in the brainstem were analyzed in 20 drug-naive idiopathic RLS patients, as well as 18 normal control (NC) subjects for comparison. Correlation analyses and multivariate pattern analyses using linear support vector machine (SVM) were conducted. RESULTS: We found significantly increased gray matter density in two clusters in the pons (designated pons_1 and pons_2) and in one cluster in the midbrain in RLS patients compared with NC subjects. Further functional connectivity analyses revealed significantly decreased functional connectivity between the midbrain and the right middle occipital gyrus, between pons_1 and the right orbital part of the superior frontal gyrus, and between pons_2 and the right parahippocampus in RLS compared with NC. Moreover, the functional connectivity between pons_2 and the right supplementary motor area (SMA) was significantly increased in RLS compared with NC. This change in RLS was marginally correlated with RS_RLS scores in the RLS patients. SVM-based classification showed an AUC of 0.955 using gray matter density of pons_2, and functional connectivity between pons_2 and SMA as features. CONCLUSION: Collectively, our findings suggest that changes in gray matter density and functional connectivity in the pons may play a pathologic role in RLS. Furthermore, these abnormal changes in the pons might help to discriminate RLS from healthy subjects.

Effect of Transcranial Alternating Current Stimulation for the Treatment of Chronic Insomnia: A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Clinical Trial.

BACKGROUND: Not all adults with chronic insomnia respond to the recommended therapeutic options of cognitive behavioral therapy and approved hypnotic drugs. Transcranial alternating current stimulation (tACS) may offer a novel potential treatment modality for insomnia. OBJECTIVES: This study aimed to examine the efficacy and safety of tACS for treating adult patients with chronic insomnia. METHODS: Sixty-two participants with chronic primary insomnia received 20 daily 40-min, 77.5-Hz, 15-mA sessions of active or sham tACS targeting the forehead and both mastoid areas in the laboratory on weekdays for 4 consecutive weeks, followed by a 4-week follow-up period. The primary outcome was response rate measured by the Pittsburgh Sleep Quality Index (PSQI) at week 8. Secondary outcomes were remission rate, insomnia severity, sleep onset latency (SOL), total sleep time (TST), sleep efficiency, sleep quality, daily disturbances, and adverse events at the end of the 4-week intervention and at the 4-week follow-up. RESULTS: Of 62 randomized patients, 60 completed the trial. During the 4-week intervention, 1 subject per group withdrew due to loss of interest and time restriction, respectively. Based on PSQI, at 4-week follow-up, the active group had a higher response rate compared to the sham group (53.4% [16/30] vs. 16.7% [5/30], p = 0.009), but remission rates were not different between groups. At the end of the 4-week intervention, the active group had higher response and remission rates than the sham group (p < 0.001 and p = 0.026, respectively). During the trial, compared with the sham group, the active group showed a statistically significant decrease in PSQI total score, a shortened SOL, an increased TST, improved sleep efficiency, and improved sleep quality (p < 0.05 or p < 0.001). Post hoc analysis revealed that, in comparison with the sham group, the active group had improved symptoms, except for daily disturbances, at the end of the 4-week intervention, and significant improvements in all symptoms at the 4-week follow-up. No adverse events or serious adverse responses occurred during the study. CONCLUSION: The findings show that the tACS applied in the present study has potential as an effective and safe intervention for chronic insomnia within 8 weeks.

Ictal High-Frequency Oscillation for Lateralizing Patients With Suspected Bitemporal Epilepsy Using Wavelet Transform and Granger Causality Analysis.

Identifying lateralization of bilateral temporal lobe epilepsy (TLE) is a challenging issue; scalp electroencephalography (EEG) and routine band electrocorticography (ECoG) fail to reveal the epileptogenic focus for further temporal lobectomy treatment. High-frequency oscillations (HFOs) can be utilized as a biomarker for lateralizing the onset zone in suspected bitemporal epilepsy. Except subjective vision detect the HFOs, objective verification should be performed to raise the accuracy. In the present research, we prospectively studied 10 patients with refractory temporal seizures and who underwent ECoG with wide-band frequency amplifiers (2,048 Hz); all patients had a class I outcome after temporal resection. Pre- and ictal HFOs will be analyzed by wavelet transform (WT) and Granger causality (GC) to objectively verify lateralization of the seizure onset zone (SOZ). WT analysis showed ictal HFOs in 10 patients mainly covered from 80 to 115 Hz (average, 92.59 ± 10.23 Hz), and there was distinct bandpass boundary between pre-ictal HFOs and ictal HFOs. GC analysis showed five patients (2, 4, 5, 6, and 7), no matter the pre-ictal or ictal state, had the highest GC degree in SOZ itself. The remaining patients (1, 3, 8, 9, and 10) had the highest GC degree in SOZ with its adjacent regions in the pre-ictal and ictal stages. GC analysis further confirmed the result of the WT and suggested HFOs are initiated and propagated in the local brain region mainly, afterward, transmitting to adjacent brain regions. These results indicated that the combination of WT and GC analyses significantly contributes to accurate lateralization in patients with suspected bitemporal epilepsy.

Simultaneously applying cathodal tDCS with low frequency rTMS at the motor cortex boosts inhibitory aftereffects.

BACKGROUND: Transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) can modulate cortical excitability. However, the combining effect of tDCS and rTMS at the same motor cortex is unknown. NEW METHODS: We have recently developed a new stimulation protocol that simultaneously combines two well-documented methods. Eleven right-handed healthy subjects undertook four sessions at the left cortical representation area of right first dorsal interosseous muscle in randomized order, the order was counter balanced. Session one was the sham control without tDCS or rTMS. Session two involved cathodal tDCS with sham rTMS. Session three involved rTMS with sham tDCS. Session four was the combination of cathodal tDCS and rTMS(tDCS-rTMS). Cathodal tDCS was applied at 1 mA, and 1200 rTMS pulses were applied at 1 Hz with 90% resting motor threshold (RMT). All stimulation durations lasted for 20 min. RMT was monitored pre- and post-stimulation immediately after finishing the stimulation. Single pulse TMS induced MEP amplitudes were monitored before and after stimulation for 30 min afterwards. RESULTS: Neither stimulus modality changed the value of RMT. As compared to sham stimulation, MEP amplitudes decreased in other three conditions. MEP amplitudes in tDCS-rTMS were much more inhibited than either tDCS or rTMS alone. COMPARISON WITH EXISTING METHODS: We could reproduce inhibitory effect of 1 mA cathodal tDCS and 1 Hz rTMS in concordance with previous literature. The novel simultaneous tDCS-rTMS stimulation protocol can induce enhanced excitability change than either tDCS or rTMS. CONCLUSIONS: Simultaneous application of cathodal tDCS with low frequency rTMS produces a stronger inhibitory effect.

Altered Brain Function in Drug-Naïve Major Depressive Disorder Patients With Early-Life Maltreatment: A Resting-State fMRI Study.

Childhood Maltreatment (CM) is an important risk factor for major depressive disorder (MDD). Previous studies using emotional task-state functional magnetic resonance (task-state fMRI) found that altered brain function in prefrontal-limbic regions was the key neuropathological mechanism in adult MDD patients with experience of early-life maltreatment. However, to the best of our knowledge, there is no published study investigating brain function in MDD patients with CM experience using resting-state fMRI (rs-fMRI). In present study, we aimed to detect altered resting-state brain activity in MDD patients with CM experience, and identify significantly activated brain regions, which may provide new insights into the neural mechanism underlying the relationship between MDD and CM experience. The results showed MDD patients with CM experience were associated with increased amplitude of low-frequency fluctuation (ALFF) and altered function connection (FC) in the prefrontal cortex, when compared to MDD patients without CM. Of note, left frontal middle gyrus (LFEG) was found as a specific brain region which differentiates MDD patients with CM from patients without CM. These results suggest that rs-fMRI is a useful method in studying the correlation between MDD and CM experience and altered function of LFEG in resting-state may explain the correlation between MDD and CM experience.

Altered Resting-State Brain Activities in Drug-Naïve Major Depressive Disorder Assessed by fMRI: Associations With Somatic Symptoms Defined by Yin-Yang Theory of the Traditional Chinese Medicine.

Identification of biological markers for defining subtypes of major depressive disorder (MDD) is critical for better understanding MDD pathophysiology and finding effective treatment intervention. The "Yin and Yang" theory is a fundamental concept of traditional Chinese Medicine (TCM). The theory differentiates MDD patients into two subtypes, Yin and Yang, based on their somatic symptoms, which had empirically been used for the delivery of effective treatment in East Asia. Nonetheless, neural processes underlying Yin and Yang types in MDD are poorly understood. In this study, we aim to provide physiological evidence using functional magnetic resonance imaging (fMRI) to identify altered resting-state brain activity associated with Yin and Yang types in drug-naïve MDD patients. The Yin type and Yang type MDD patients showed increased amplitude of low-frequency fluctuation (ALFF) in different cortical brain areas in the parietal, temporal, and frontal lobe, compared to matched healthy controls. Differential ALFF is also observed in several cortical areas in frontal lobe and insula between Yin and Yang type group. Of note, although ALFF is increased in the inferior parietal lobe in both Yin and Yang type group, inferior parietal lobe-centered functional connectivity (FC) is increased in Yang type, but is decreased in Ying type, compared with matched healthy controls. These results suggest that differential resting-state brain activity and functional connectivity in Yin and Yang types may contribute to biological measures for better stratification of heterogeneous MDD patients.

Alterations of Sub-cortical Gray Matter Volume and Their Associations With Disease Duration in Patients With Restless Legs Syndrome.

Object: The purpose of this study was to uncover the pathology of restless legs syndrome (RLS) by exploring brain structural alterations and their corresponding functional abnormality. Method: Surface-based morphometry (SBM) and voxel-based morphometry (VBM) were performed to explore the alterations in cortical and sub-cortical gray matter volume (GMV) in a cohort of 20 RLS and 18 normal controls (NC). Furthermore, resting-state functional connectivity (RSFC) was also performed to identify the functional alterations in patients with RLS. Results: We found significant alterations of sub-cortical GMV, especially the bilateral putamen (PUT), rather than alterations of cortical GMV in patients with RLS compared to NC using both SBM and VBM. Further sub-regional analysis revealed that GMV alterations of PUT was mostly located in the left dorsal caudal PUT in patients with RLS. In addition, altered RSFC patterns of PUT were identified in patients with RLS compared to NC. Moreover, correlation analyses showed that the GMV of the left caudate and the left ventral rostral PUT were positively correlated with disease duration in patients with RLS. Conclusions: The alterations of subcortical GMV might imply that the primarily affected areas are located in sub-cortical areas especially in the sub-region of PUT by the pathologic process of RLS, which might be used as potential biomarkers for the early diagnosis of RLS.

Effect of yizhitongxuan decoction on learning and memory ability, Gaq/11 expression and Na(+)-K(+)-ATP enzyme activity in rat models of Alzheimer's disease.

OBJECTIVE: To study the effects of Yizhitongxuan decoction on learning and memory abilities, Gaq/11 expression and Na(+)-K(+)-ATP enzyme activity in rat models of Alzheimer's disease (AD) caused by injecting Abeta25-35 into the hippocampus. METHODS: Ninety male Wistar rats (age > or = 10 months) were selected and injected with Abeta25-35 into their hippocampi to establish model animals, which were randomly divided into six groups including a sham-operated group (blank group), a model group, a donepezil HCL group (Western Medicine group), and a high/general/dilute concentrations of Yizhitongxuan decoction groups (TCM I II III group). The Morris water maze was used to examine the learning and memory abilities of rats in each group by place navigation and spatial probe tests. Then, the rats were sacrificed to collect the hippocampi for biochemical tests, using western blotting to detect the expression of Gaq/11 and an ultramicro Na(+)-K(+)-ATP enzyme kit to measure Na(+)-K(+)-ATP enzyme activity. RESULTS: Yizhitongxuan decoction improved model rats' learning and memory abilities, and increased the expression of Gaq/11 in the hippocampus and the level of Na(+)-K(+)-ATP enzyme activity in brain tissue. CONCLUSION: Yizhitongxuan decoction could improve model rats' learning and memory abilities, and had a regulating effect on the expression of Gaq/11 and Na(+)-K(+)-ATP enzyme activity.