Effects of transcranial ultrasound stimulation pulsed at 40 Hz on Aβ plaques and brain rhythms in 5×FAD mice

Background Alzheimer’s disease (AD) is the most common cause of dementia, and is characterized by amyloid-β (Aβ) plaques and tauopathy. Reducing Aβ has been considered a major AD treatment strategy in pharmacological and non-pharmacological approaches. Impairment of gamma oscillations, which play an important role in perception and cognitive function, has been shown in mouse AD models and human patients. Recently, the therapeutic effect of gamma entrainment in AD mouse models has been reported. Given that ultrasound is an emerging neuromodulation modality, we investigated the effect of ultrasound stimulation pulsed at gamma frequency (40 Hz) in an AD mouse model. Methods We implanted electroencephalogram (EEG) electrodes and a piezo-ceramic disc ultrasound transducer on the skull surface of 6-month-old 5×FAD and wild-type control mice (n = 12 and 6, respectively). Six 5×FAD mice were treated with two-hour ultrasound stimulation at 40 Hz daily for two weeks, and the other six mice received sham treatment. Soluble and insoluble Aβ levels in the brain were measured by enzyme-linked immunosorbent assay. Spontaneous EEG gamma power was computed by wavelet analysis, and the brain connectivity was examined with phase-locking value and cross-frequency phase-amplitude coupling. Results We found that the total Aβ42 levels, especially insoluble Aβ42, in the treatment group decreased in pre- and infra-limbic cortex (PIL) compared to that of the sham treatment group. A reduction in the number of Aβ plaques was also observed in the hippocampus. There was no increase in microbleeding in the transcranial ultrasound stimulation (tUS) group. In addition, the length and number of microglial processes decreased in PIL and hippocampus. Encelphalographic spontaneous gamma power was increased, and cross-frequency coupling was normalized, implying functional improvement after tUS stimulation. Conclusion These results suggest that the transcranial ultrasound-based gamma-band entrainment technique can be an effective therapy for AD by reducing the Aβ load and improving brain connectivity.

The Influence of Stomach Back-Shu and Front-Mu Points on Insular Functional Connectivity in Functional Dyspepsia Rat Models

Functional Dyspepsia (FD) is a common functional gastrointestinal disease, which can reduce the quality of life in patients. Prior research has indicated that insula is closely related to FD and that acupuncture can regulate the functional connectivity (FC) of FD. Therefore, we hypothesized that acupuncture on FD was effected through the insular pathway. To test our hypothesis, we performed electroacupuncture (EA) on FD rat models and then examined the FC between insula and other brain regions through resting-state functional magnetic resonance imaging (rs-fMRI). Seven-day-old male infant Sprague-Dawley (SD) rats were randomly divided into control group, FD model group, and FD acupuncture group, with twelve rats per group (n = 36). Upon establishing successful models, the FD acupuncture group was subjected to EA intervention using Stomach back-shu (BL-21) and front-mu (RN-12) points for ten consecutive days for durations of 20 minutes each day. After intervention, each group was subject to rs-fMRI. The digital image data obtained were analyzed using FC analysis methods. Subsequently, gastric ligation was performed to measure gastric emptying rates. Before EA intervention, the FD model group exhibited decreased functional connections between the insula and a number of brain regions. After EA intervention, FD acupuncture group exhibited increasing FC between insula and regions when compared to the FD model group, such as the primary somatosensory cortex (S1), hippocampal CA3 (CA3), polymorphic layer of dentate gyrus (PoDG), caudate putamen (CPu), and oral pontine reticular nuclei (PnO) P < 0.05 ; decreasing FC was also exhibited between insula and regions such as the bilateral primary and secondary motor cortexes (M1/2), paraventricular hypothalamic nucleus (PVA), and limbic cortex (LC). These findings indicate that the effective treatment of FD using EA may be through regulating the abnormal FC between insula and several brain regions, in particular CA3, PoDG, and PVA.

Contextual Fear Memory Maintenance Changes Expression of pMAPK, BDNF and IBA-1 in the Pre-limbic Cortex in a Layer-Specific Manner

Post-traumatic stress disorder (PTSD) is a debilitating and chronic fear-based disorder. Pavlovian fear conditioning protocols have long been utilised to manipulate and study these fear-based disorders. Contextual fear conditioning (CFC) is a particular Pavlovian conditioning procedure that pairs fear with a particular context. Studies on the neural mechanisms underlying the development of contextual fear memories have identified the medial prefrontal cortex (mPFC), or more specifically, the pre-limbic cortex (PL) of the mPFC as essential for the expression of contextual fear. Despite this, little research has explored the role of the PL in contextual fear memory maintenance or examined the role of neuronal mitogen-activated protein kinase (pMAPK; ERK 1/2), brain-derived neurotrophic factor (BDNF), and IBA-1 in microglia in the PL as a function of Pavlovian fear conditioning. The current study was designed to evaluate how the maintenance of two different long-term contextual fear memories leads to changes in the number of immune-positive cells for two well-known markers of neural activity (phosphorylation of MAPK and BDNF) and microglia (IBA-1). Therefore, the current experiment is designed to assess the number of immune-positive pMAPK and BDNF cells, microglial number, and morphology in the PL following CFC. Specifically, 2 weeks following conditioning, pMAPK, BDNF, and microglia number and morphology were evaluated using well-validated antibodies and immunohistochemistry (n = 12 rats per group). A standard CFC protocol applied to rats led to increases in pMAPK, BDNF expression and microglia number as compared to control conditions. Rats in the unpaired fear conditioning (UFC) procedure, despite having equivalent levels of fear to context, did not have any change in pMAPK, BDNF expression and microglia number in the PL compared to the control conditions. These data suggest that alterations in the expression of pMAPK, BDNF, and microglia in the PL can occur for up to 2 weeks following CFC. Together the data suggest that MAPK, BDNF, and microglia within the PL of the mPFC may play a role in contextual fear memory maintenance.

Subregions of DLPFC display graded yet distinct structural and functional connectivity

The human dorsolateral prefrontal cortex (DLPFC, approximately corresponding to Brodmann areas 9 and 46) has demonstrable roles in diverse executive functions such as working memory, cognitive flexibility, planning, inhibition, and abstract reasoning. However, it remains unclear whether this is the result of one functionally homogeneous region or whether there are functional subdivisions within the DLPFC. Here, we divided the DLPFC into seven areas along with rostral-caudal and dorsal-ventral axes anatomically and explored their respective patterns of structural and functional connectivity. In vivo probabilistic tractography and resting-state functional magnetic resonance imaging were employed to map out the patterns of connectivity from each DLPFC subregions. Structural connectivity demonstrated graded intra-regional connectivity within the DLPFC. The patterns of structural connectivity between the DLPFC subregions and other cortical areas revealed that he dorsal-rostral subregions was restricted to connect to other frontal and limbic areas, whereas the ventral-caudal region was widely connected to frontal, temporal, parietal, and limbic cortex. Functional connectivity analysis demonstrated that subregions of DLPFC were strongly interconnected to each other. The dorsal subregions were associated with the default mode network (DMN), while middle dorsal-rostral subregions were linked with the multiple demand network (MDN), respectively. Similar to the results of structural connectivity, the ventral-caudal subregion showed increased functional coupling with both DMN and MDN. Our results suggest that DLPFC may be subdivided by the diagonal axis of the dorsal-ventral axis and rostral-caudal axis, which support the patterns of connectivity the parts of the DLPFC reflects its integrative executive function.

Posture Instability Is Associated with Dopamine Drop of Nigrostriatal System and Hypometabolism of Cerebral Cortex in Parkinson Disease

Background: Posture instability (PI) is known to be a severe complication in Parkinson’s disease (PD), and its mechanism remains poorly understood. Our study aims to explore the changes of brain network in PI of PD, and further investigate the role of peripheral inflammation on activities of different brain regions in PD with PI. Methods: 167 individuals were recruited, including 36 PD cases with PI and 131 ones without PI. We carefully assessed the status of motor and cognitive function, measured serum inflammatory factors, and detected the dopaminergic pathways and the metabolism of different brain regions by positron emission tomography (PET). Data analysis was conducted by variance, univariate analysis, chi-square analysis, logistic regression, and partial correlation. Result: No difference was found for age or onset age between the two groups (P>0.05). Female patients were susceptible to posture impairment and had a 2.14-fold risk for PI compared with male patients in PD (P<0.05). Patients with PI had more severe impairment of motor and cognitive function for a longer duration than those without PI (P<0.05). The mean uptake ratios of presynaptic vesicular monoamine transporter (VMAT2), which were detected in the caudate nucleus and putamen, were lower in PI group than those without PI (P<0.05). There were lower activities of the midbrain, caudate nucleus, and anterior medial temporal cortex in PI group than those in the non-PI group (P<0.05). Although serum concentrations of immunoglobulins (IgG, IgM, and IgA) and complements (C3, C4) were higher in PI group than those in the non-PI group, only serum IgM concentration had a significant difference between the two groups (P<0.05). We further explored significant inverse correlations of IgG, IgM, IgA, and C4 with activities of some cerebral cortex in PI of PD (P<0.05). Conclusion: Female patients were susceptible to posture instability and had a 2.14-fold risk for PI of PD. Patients with PI had more severe impairments of motor and cognitive function for a longer duration than those without PI. PI was associated with dopamine drop of the nigrostriatal system and lower activities of the limbic cortex in PD. Peripheral inflammation may be involved in degeneration of the cerebral cortex in PD combined with PI.

Exposure to 2.45 GHz Radiation Triggers Changes in HSP-70, Glucocorticoid Receptors and GFAP Biomarkers in Rat Brain

Brain tissue may be especially sensitive to electromagnetic phenomena provoking signs of neural stress in cerebral activity. Fifty-four adult female Sprague-Dawley rats underwent ELISA and immunohistochemistry testing of four relevant anatomical areas of the cerebrum to measure biomarkers indicating induction of heat shock protein 70 (HSP-70), glucocorticoid receptors (GCR) or glial fibrillary acidic protein (GFAP) after single or repeated exposure to 2.45 GHz radiation in the experimental set-up. Neither radiation regime caused tissue heating, so thermal effects can be ruled out. A progressive decrease in GCR and HSP-70 was observed after acute or repeated irradiation in the somatosensory cortex, hypothalamus and hippocampus. In the limbic cortex; however, values for both biomarkers were significantly higher after repeated exposure to irradiation when compared to control animals. GFAP values in brain tissue after irradiation were not significantly different or were even lower than those of nonirradiated animals in all brain regions studied. Our results suggest that repeated exposure to 2.45 GHz elicited GCR/HSP-70 dysregulation in the brain, triggering a state of stress that could decrease tissue anti-inflammatory action without favoring glial proliferation and make the nervous system more vulnerable.

Transcriptional and cellular signatures of cortical morphometric similarity remodelling in chronic pain

Chronic pain is a highly debilitating and poorly understood condition. Here, we attempt to advance our understanding of the brain mechanisms driving chronic pain by investigating alterations in morphometric similarity (MS) and corresponding transcriptomic and cellular signatures, in three cohorts of patients with distinct chronic pain syndromes (knee osteoarthritis, low back pain and fibromyalgia). We uncover a novel pattern of cortical MS remodelling involving mostly MS increases in the insula and limbic cortex, which cuts across the boundaries of specific pain syndromes. We show that cortical MS remodelling in chronic pain spatially correlates with the brain-wide expression of genes involved in the glial immune response and neuronal plasticity. Cortical remodelling in chronic pain might involve a disruption of multiple elements of the cellular architecture of the brain. Therefore, multi-target therapeutic approaches tackling both glial activation and neuronal hyperexcitability might better encompass the full neurobiology of chronic pain.

Targeting the centromedian thalamic nucleus for deep brain stimulation

ObjectivesDeep brain stimulation (DBS) of the centromedian thalamic nucleus (CM) is an emerging treatment for multiple brain diseases, including the drug-resistant epilepsy Lennox-Gastaut syndrome (LGS). We aimed to improve neurosurgical targeting of the CM by: (1) developing a structural MRI approach for CM visualisation, (2) identifying the CM’s neurophysiological characteristics using microelectrode recordings (MERs) and (3) mapping connectivity from CM-DBS sites using functional MRI (fMRI).Methods19 patients with LGS (mean age=28 years) underwent presurgical 3T MRI using magnetisation-prepared 2 rapid acquisition gradient-echoes (MP2RAGE) and fMRI sequences; 16 patients proceeded to bilateral CM-DBS implantation and intraoperative thalamic MERs. CM visualisation was achieved by highlighting intrathalamic borders on MP2RAGE using Sobel edge detection. Mixed-effects analysis compared two MER features (spike firing rate and background noise) between ventrolateral, CM and parafasicular nuclei. Resting-state fMRI connectivity was assessed using implanted CM-DBS electrode positions as regions of interest.ResultsThe CM appeared as a hyperintense region bordering the comparatively hypointense pulvinar, mediodorsal and parafasicular nuclei. At the group level, reduced spike firing and background noise distinguished CM from the ventrolateral nucleus; however, these trends were not found in 20%–25% of individual MER trajectories. Areas of fMRI connectivity included basal ganglia, brainstem, cerebellum, sensorimotor/premotor and limbic cortex.ConclusionsIn the largest clinical trial of DBS undertaken in patients with LGS to date, we show that accurate targeting of the CM is achievable using 3T MP2RAGE MRI. Intraoperative MERs may provide additional localising features in some cases; however, their utility is limited by interpatient variability. Therapeutic effects of CM-DBS may be mediated via connectivity with brain networks that support diverse arousal, cognitive and sensorimotor processes.