Search Results (515)

Background: Clinical and experimental evidence suggests comorbidity between diabetes mellitus (DM) and epilepsy, including a higher incidence of status epilepticus (SE). However, the association between Type 2 Diabetes Mellitus (T2DM) and epilepsy is not fully understood. Therefore, this study aimed to analyze the severity of SE and the consequent brain injury in male Wistar rats with T2DM. Methods: To induce T2DM, postnatal day (P) 3 rats were injected with streptozocin (STZ, 100 mg/kg, s.c.; n = 18); control rats received an equal volume of citrate buffer (pH 4.5) used as vehicle (n = 16). Glycemia was monitored at P30, P40, P60, and P90 in both experimental groups. Subsequently, rats were injected intraperitoneally with lithium chloride (LiCl, 3 mEq/kg, i.p.), and 18 h later, at P90, SE was induced by pilocarpine hydrochloride (30 mg/kg, s.c.). Matched control rats were injected with LiCl and physiological saline solution. The severity of SE, the neurodegeneration, cell and tissue loss, and microglia and glial responses were evaluated in the hippocampus, amygdala, thalamus, the piriform cortex. Results: Hyperglycemia was evident at P90 in STZ rats compared with vehicle (p < 0.05). T2DM rats had a higher frequency of stage V seizures and increased latency to the first stage V seizure and to SE compared with control rats (p < 0.05). T2DM rats showed an increased number of Fluoro-Jade B-positive cells, a reduction in cell density, and tissue loss, associated with an increased microglia density but a reduced glial cell count after SE (p < 0.05). Conclusions: Our findings suggest that T2DM is associated with greater seizure severity and increased brain injury following SE. Full article

Visual impairment impacts nearly half a billion people globally. Corrective glasses, artificial lens replacement, and medical management have markedly improved the management of diseases inherent to the eye, such as refractive errors, cataracts, and glaucoma. However, therapeutic strategies for retinopathies, optic nerve damage, and distal optic pathways remain limited. The complex optic apparatus comprises multiple neural structures that transmit information from the retina to the diencephalon to the cortex. Over the last few decades, innovations have emerged to address the loss of function at each step of this pathway. Given the retina’s lack of regenerative potential, novel treatment options have focused on replacing lost retinal cell types through cellular replacement with stem cells, restoring lost gene function with genetic engineering, and imparting new light sensation capabilities with optogenetics. Additionally, retinal neuroprosthetics have shown efficacy in restoring functional vision, and neuroprosthetic devices targeting the optic nerve, thalamus, and cortex are in early stages of development. Non-invasive neuromodulation has also shown some promise in modulating the visual cortex. Recently, the first in-human whole-eye transplant was performed. While functional vision was not restored, the feasibility of such a transplant with viable tissue graft at one year was demonstrated. Subsequent studies are now focused on guidance cues for axonal regeneration past the graft site to reach the lateral geniculate nucleus. Although the methods discussed above have shown promise individually, improvements in vision have been modest at best. Achieving the goal of restoration of functional vision will clearly require further development of cellular therapies, genetic engineering, transplantation, and neuromodulation. A concerted multidisciplinary effort involving scientists, engineers, ophthalmologists, neurosurgeons, and reconstructive surgeons will be necessary to restore vision for patients with vision loss from these challenging pathologies. In this expert review article, we describe the current literature in visual neurorestoration with respect to cellular therapeutics, genetic therapies, optogenetics, neuroprosthetics, non-invasive neuromodulation, and whole-eye transplant. Full article

Background/Objectives: The vestibulothalamic tract (VTT) serves as a crucial pathway transmitting vestibular information from the brainstem nuclei to the thalamus, where integration with other sensory modalities occurs. This study aimed to investigate the structural connectivity between three vestibular nuclei and three thalamic nuclei in the human brain using diffusion tensor imaging (DTI) tractography. Methods: Twelve healthy adults underwent DTI to visualize vestibulothalamic connections using probabilistic tractography. Results: Results revealed distinct patterns of connectivity: the lateral vestibular nucleus (LVN) exhibited the highest reconstruction rates to both the ventral posterolateral (95.8%) and ventral posteromedial (83.3%), while the medial vestibular nucleus (MVN) showed the strongest connection to the ventral intermediate (75.0%). All vestibulothalamic tracts predominantly passed through the tegmentum of the midbrain, with limited or absent contributions from the tectum. Conclusions: These findings indicate differential roles of vestibular nuclei in relaying information to thalamic targets, with the LVN showing preferential projections to sensory relay nuclei and the MVN contributing to motor-related thalamic regions. Such insights may have important implications for the diagnosis and treatment of vestibular disorders, as well as for advancing anatomical research. These findings provide anatomical insights that may help explain symptoms of vestibular and thalamic lesions and guide rehabilitation strategies for balance and gaze control disorders. Full article

Schizophrenia (SZ) is a severe mental disorder associated with an array of symptoms characterized as positive, negative and cognitive dysfunctions. While SZ is a multifaceted disorder affecting several regions of the brain, altered thalamocortical systems have emerged as a leading contributor to SZ. Specifically, it has been shown that: (1) the thalamus is functionally disconnected from the prefrontal cortex (PFC) in SZ; (2) neural activity and blood flow to the PFC are greatly diminished in SZ (hypofrontality); and (3) delta oscillations are abnormally present in the PFC during the waking state in SZ. We suggest that the abnormal delta oscillations drive the other PFC signs of SZ. Specifically, decreases in energy required to maintain delta, would initiate the reduced PFC perfusion of SZ (hypofrontality), and contribute to the ‘mismatched’ thalamic and PFC activity of SZ. As SZ involves glutamate (NMDAR) hypofunction and dopamine hyperfunction, both NMDAR antagonists and dopamine agonists produce marked increases in delta oscillations in nucleus reuniens (RE) of the thalamus and its target structures, including the PFC. This would suggest that RE is a primary source for the elicitation of PFC delta activity, and the presence of delta during waking (together with associated signs) would indicate that the prefrontal cortex is disabled (or non-functional) in schizophrenia. Full article

Background: Urinary continence relies on a complex interplay between urine storage and voiding involving both spinal reflex circuits and supraspinal brain areas to coordinate volun-tary control over emptying. Despite a vast number of studies on the pathophysiology of neurogenic bladder and urge incontinence, less is known about the central correlates of bladder filling. Methods: An ALE (activation likelihood estimation) meta-analysis including a total count of 14 studies investigating 243 participants under different conditions of bladder filling during functional neuroimaging was performed to demonstrate the neuroanatomical correlates of bladder filling. The literature search and reporting were conducted according to the PRISMA-P 2020 guideline. Data analysis was performed using the GingerAle software version 3.0.2 and was displayed with the Mango software 4.1 on an anatomical MNI template. Results: Synthesizing studies on the functional neuroanatomy of urine storage, bihemispheric clusters of activation in the thalamus, the insula and the cingulate were observed. Conclusion: The present ALE meta-analysis indicates that the supraspinal representation of urine storage involves areas of autonomous–homeostatic processing which allow for the perception of the usually unconscious inner state of bladder filling and enable postponing and voluntary voiding. Full article

Major depressive disorder is a mental health condition characterized by ongoing feelings of sadness, trouble focusing or making decisions, and a frequent sense of fatigue or hopelessness that lasts for a prolonged period. If left undiagnosed, it can have serious consequences, including suicide. This study proposes a 3D convolutional neural network model to detect major depressive disorder using 3D grey matter images from magnetic resonance imaging. The proposed 3D convolutional architecture comprises multiple hierarchical convolutional and pooling layers, designed to automatically learn spatial patterns from magnetic resonance imaging data. The model was optimized via Bayesian hyperparameter tuning, achieving an accuracy of 72.26%, an area under the receiver operating characteristic curve of 0.80, and an area under the precision–recall curve of 0.81 on a large multisite dataset comprising 1276 patients and 1104 healthy controls. Gradient-weighted class activation mapping is utilized to find brain regions associated with major depressive disorder. From this study, six regions were identified, namely, the frontal lobe, parietal lobe, temporal lobe, thalamus, insular cortex and corpus callosum which may be affected by major depressive disorder. Full article

Fibromyalgia syndrome (FMS) is a chronic disorder marked by widespread musculoskeletal pain, fatigue, mood disturbances, and cognitive impairments. Current treatments primarily focus on symptom management. Ashwagandha (Withania somnifera), a traditional Ayurvedic herb, is known for its adaptogenic and neuroprotective properties. This study evaluated the protective effects of the methanolic root extract of Ashwagandha (ARE) in a reserpine-induced fibromyalgia model in male Swiss albino mice. Mice received oral ARE (100 mg/kg) for 17 days and reserpine (0.5 mg/kg, subcutaneously) for three consecutive days to induce fibromyalgia-like symptoms. Behavioral assessments included Von Frey, tail suspension, rotarod, and Y-maze tests. Histological analysis was conducted on the hippocampus and thalamus; however, neurochemical analysis focused on markers such as serotonin, norepinephrine, IL-1β, TNFα, MDA, and NO. Results indicated that ARE significantly reduced pain and depressive-like behavior and improved motor function (p < 0.0001); however, no significant changes were observed in open-field locomotion. Histological examination revealed protection of Ashwagandha against neurodegeneration and improved hippocampal integrity, accompanied by increased serotonin and norepinephrine levels and decreased pro-inflammatory cytokines. These findings suggest that Ashwagandha root extract may offer therapeutic benefits for managing fibromyalgia symptoms. Full article

In this paper, we aimed to evaluate the efficacy and usefulness of three brief, easy-to-administer, and repeatable tests, namely SDMT, Digit Span Forward (DSF), and Digit Span Backward (DSB) in MS patients (MSp), and compared the results with those of healthy volunteers (CONs). We were hoping to identify the most sensitive test that could be used regularly in clinical practice. In addition, we tried to identify the metabolic background of the cognitive setting using the advanced radiological method, Mescher–Garwood (MEGA)-edited 1H Magnetic Resonance Spectroscopy (1H-MRS). A total of 22 relapsing MSp and 22 CONs were enrolled. The SDMT, DSF, and DSB tests were used on all participants. The patients also underwent a 1H-MRS brain examination. In addition to N-Acetyl-Aspartate (tNAA), Myoinositol (mIns), Choline (tCho), and Creatine (tCr) were also evaluated GABA and Glutamate–Glutamine (Glx) ratios. CONs were superior to MSp in the results of all neurocognitive tests. The DSB was found to be the most sensitive test for identifying MSp. The SDMT in MSp correlated with inflammatory and degenerative metabolites in the thalamus, hippocampus, and corpus callosum. A correlation between increased Glx- and GABA-ratios and SDMT was found. Unlike the SDMT, the DSF and DSB showed correlations with inflammatory metabolites in the caudate nucleus and hypothalamus. DSF correlated with GABA ratios in the hippocampus. Our study confirms the efficacy of DSF and DSB tests in evaluating working memory cognitive impairment in MSp, showing an association of the tests with specific brain metabolites. Full article

Background/Objectives: Fibromyalgia causes chronic long-term pain, with symptoms lasting for months to years. Given the lack of evidence-based methods for diagnosing and assessing fibromyalgia, it ranks among the most difficult chronic pain conditions to treat. Programmed cell death ligand 1 (PD-L1) can inhibit acute and chronic pain transmission by inhibiting neuronal ion channels. Methods: Here, we aimed to explore the analgesic efficacy and mechanism of PD-L1/PD1 in an intermittent cold stress-induced fibromyalgia pain mouse model. Results: Von Frey and Hargreaves tests were performed, showing that the mouse model exhibited mechanical (day 4: 2.08 ± 0.13 g, n = 9) and thermal hyperalgesia (day 4: 3.93 ± 0.45 s, n = 9). Electroacupuncture (EA) or intraventricular PD-L1 injection effectively alleviated the nociceptive response and led to low PD-1 levels in the mouse dorsal root ganglia, spinal cord, thalamus, somatosensory cortex, and cerebellum, as measured through Western blots. In contrast, the pain-related kinase levels increased after fibromyalgia induction; these effects were reversed by EA and PD-L1 via the inhibition of microglia/astrocytes and Toll-like receptor 4. Conclusions: Our results show that EA can treat fibromyalgia pain in mice through effects on the PD-L1/PD1 pathway, indicating its potential as a therapeutic target in fibromyalgia. Full article

Background: Adeno-associated viral (AAV) vectors are the leading platform for gene therapy, but common delivery routes show limited spread to distal cortical structures, hence the utility of direct, intrathalamic infusions for broader transgene distribution. In this preliminary study, we recapitulate previous studies targeting the thalamus as a conduit to achieve cortical transgene spread and showcase novel data evaluating biodistribution of a green fluorescent protein (GFP) using cryo-fluorescence tomography (CFT). For the first time in nonhuman primates (NHPs) and coupled with magnetic resonance imaging (MRI)-guidance, we demonstrated the application of CFT as a powerful tool to map out vector distribution in the NHP brain. Methods: Briefly, a single thalamic infusion was performed in African green monkeys using ClearPoint’s navigational platform to deliver an AAV serotype 2 vector containing a GFP payload. Transgene biodistribution was assessed in the left and right hemispheres using CFT and histological analysis, respectively. Results: Infusions were successfully performed with sub-millimetric target accuracy and with minimal error, achieving ~86% thalamic coverage with the largest infusion volume. Histology confirmed the presence of the GFP transgene, with the strongest signal in the cerebral gray/white matter and internal capsule, while CFT allowed for the three-dimensional detection of the transgene starting at the site of infusion and spreading to multiple cortical regions. Conclusions: These findings suggest that by combining MRI-guided technology with CFT imaging, it is feasible to map whole-brain gene biodistribution in NHPs. This proof-of-concept study bridges the gap between cellular microscopy and MRI-guidance to provide a complete picture of disease and treatment with clinical applicability. Full article

The study assesses the relationship between thalamic proton-MR spectroscopy (¹H-MRS) metabolites and thalamic ¹¹C-ER176 translocator-protein positron emission tomography (TSPO-PET) standardized uptake value ratios (SUVR) to advance our understanding of thalamic involvement in multiple sclerosis (MS)-associated neurodegeneration and disability. In this prospective cross-sectional study, patients with MS (pwMS) and controls underwent 3T-MRI, ¹H-MRS, and ¹¹C-ER176-PET targeting the thalamus. MRI-derived thalamic volume was normalized by intracranial volume. ¹H-MRS metabolites—N-acetylaspartate (NAA), glutamate (Glu), glutamine (Gln), total choline (tCho), and myo-inositol (mIns)—were normalized to total creatine (tCr). Clinical disability was evaluated using MS-specific tests of Expanded Disability Status Scale-EDSS and MS-functional composite-MSFC (including Paced Auditory Serial Addition Test-PASAT). Compared to controls (n = 30), pwMS (n = 21) exhibited smaller thalamic volume, higher thalamic ¹H-MRS mIns/tCr (putative gliosis marker), and higher thalamic ¹¹C-ER176-PET SUVR (glial density marker). In pwMS, higher thalamic mIns/tCr (r = −0.67) and tCho/tCr (r = −0.52) correlated with smaller thalamic volume. In pwMS, higher thalamic mIns/tCr correlated with higher thalamic ¹¹C-ER176-PET SUVR (r = 0.48) and decreased cognitive function (PASAT, rho = −0.48). In controls, decreased thalamic NAA/tCr correlated with increased thalamic ¹¹C-ER176-PET SUVR (r = −0.41). Thalamus, a core central nervous system relay, is affected early in MS disease course. Glial-mediated innate immune activation in the thalamus, evaluated by increased ¹H-MRS mIns/tCr and ¹¹C-ER176-PET SUVR, is associated with loss of thalamic volume and increased disability in pwMS. The multimodal imaging approach with ¹H-MRS mIns/tCr and ¹¹C-ER176-PET SUVR emerges as potential glial biomarkers, to better understand disease mechanisms and evaluate therapeutic interventions targeting glial activity in MS. Full article

The diagnosis and monitoring of progressive multiple sclerosis (PMS) require further development of fast and effective clinical tools. Relations between MRI-based brain atrophy measures and cognitive impairment in people with primary progressive and secondary progressive MS (PwPPMS, n = 20 and PwSPMS, n = 19, respectively) were investigated in a prospective study with follow-up after a mean 14.97 ± 4.67 months. MRI analysis showed that at baseline and follow-up in PwSPMS, the left thalamic fraction and corpus callosum fraction were significantly lower than in PwPPMS (baseline: 0.39 ± 0.04 vs. 0.44 ± 0.06, p = 0.0203 and 0.26 ± 0.05 vs. 0.30 ± 0.05, p = 0.0097; respectively and follow-up: 0.40 ± 0.04 vs. 0.44 ± 0.07, p = 0.0443 and 0.25 ± 0.06 vs. 0.30 ± 0.05, p = 0.0103, respectively). In contrast, only at baseline, PwPPMS had a significantly lower cerebellar white matter fraction (CWMF) than PwSPMS (1.83 ± 0.20 vs. 2.01 ± 0.24, p = 0.0132). No other significant differences were observed in the MRI fractions at either study time point or in the changes of the MRI fractions between the PwPPMS and PwSPMS. However, a significant decline in the right putaminal fraction was found during observation in PwSPMS (0.332% ± 0.05% vs. 0.328% ± 0.05%, p = 0.0479). Cognitive test scores and their changes did not differ significantly between the subgroups. Declines in the Brief Visuospatial Memory Test Revised in the whole PMS group (18.74 ± 7.43 vs. 17.03 ± 7.61, p = 0.0209) and in PwPPMS (19.50 ± 8.29 vs. 17.20 ± 7.72, p = 0.0338), as well as in the Brief International Cognitive Assessment for Multiple Sclerosis in PwPPMS (1.05 ± 0.89 vs. 1.25 ± 1.02, p = 0.0421), were observed. In both PwPMS and PwPPMS, a worsening on the Symbol Digit Modalities Test (SDMT) was associated with the reduction of fractions of white matter, cerebellum and right thalamus. SDMT performance also correlated with both gray matter fraction (GMF) and CWMF in the whole group, and with cerebellar gray matter fraction (CGMF) in PwPPMS. In PwSPMS, only Stroop Color and Word Test scores correlated with GMF and CGMF. In conclusion, subtle differences between PwPPMS and PwSPMS were detected both in MRI and neuropsychological parameters. Thus, our results indicate the need for a multicomponent attempt in characterizing progression in different clinical courses of MS. Full article

Ferroptosis is a new mode of cell death, which is characterized by inducing the accumulation of lipid peroxides dependent on iron ions and reactive oxygen species. It has been found that ferroptosis can lead to follicle atresia by promoting granulosa cell death and increasing its reactive oxygen species content, but the specific mechanism has not been elucidated. Through transcriptome sequencing, we found that ferroptosis markers and related genes were upregulated in porcine atretic follicles. PTGS2 was found to be differentially expressed between atretic and healthy follicles. By inhibiting NF-κB nuclear translocation, inhibition of the PTGS2 gene expression reduced the degree of ferroptosis in granulosa cells and rescued granulosa cell death and oxidative stress caused by ferroptosis. Therefore, we propose that the NF-κB/PTGS2 axis plays a key role in ferroptosis-induced granulosa cell death, leading to follicular atresia. Melatonin, a neurohormone secreted by the pineal gland of the upper thalamus, is involved in the regulation of various metabolic, immune, reproductive, and other processes. In the ferroptosis treatment group, melatonin treatment alleviated the degree of ferroptosis (downregulation of ferroptosis marker genes and markers) and decreased the expression of PTGS2. In summary, we have demonstrated that melatonin inhibits ferroptosis via the NF-κB/PTGS2 axis in granulosa cells. Full article

Background: Mindfulness and mind wandering are cognitive traits central to attentional control and psychological well-being, yet their neural underpinnings are yet to be elucidated. This study aimed to identify structural brain networks comprising gray matter (GM) and white matter (WM) that predict individual differences in mindfulness and distinct mind wandering tendencies (deliberate and spontaneous). Methods: Using structural MRI data and self-report measures from 76 participants, we applied an unsupervised data-fusion machine learning technique (parallel independent component analysis) to identify GM and WM networks associated with mindfulness and mind wandering traits. Results: Our analysis revealed several distinct brain networks linked to these cognitive constructs. Specifically, one GM network involving subcortical regions, including the caudate and thalamus, positively predicted mindfulness and deliberate mind wandering, while negatively influencing spontaneous mind wandering through the mediating role of the mindfulness facet “acting with awareness.” In addition, two separate WM networks, predominantly involving frontoparietal and temporal regions, were directly associated with reduced spontaneous mind wandering. Conclusions: These findings advance our current knowledge by demonstrating that specific GM and WM structures are involved in mindfulness and different forms of mind wandering. Our results also show that the “acting with awareness” facet has a mediating effect on spontaneous mind wandering, which provides supporting evidence for attentional and executive control models. These new insights into the neuroanatomical correlates of mindfulness and mind wandering have implications for ongoing research in the growing topic of mindfulness and mind wandering, mindfulness-based interventions, and other clinical applications. Full article

Although diagnostic criteria and research are constantly advancing, distinguishing between progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) remains a significant challenge. This difficulty stems from their similar clinical symptoms and the lack of reliable biomarkers. In this work, we present a detailed review of fluorodeoxyglucose (FDG)–positron emission tomography (PET), exploring its potential role in differentiating PSP and CBS, drawing on their established utility in other neurodegenerative diseases. We searched the PubMed database from its inception for original research articles assessing the utility of FDG-PET for the diagnosis or differential diagnosis of PSP and CBS from other neurodegenerative conditions. A total of 91 studies were eligible. These 91 studies were categorized as follows: (a) 20 studies included only patients with PSP, (b) 15 studies included only patients with CBS, (c) 39 studies involved patients with Parkinson’s disease and atypical Parkinsonian disorders, including subgroups of PSP and/or CBS, and (d) 17 studies compared patients with PSP and/or CBS to individuals with Alzheimer’s disease, frontotemporal dementia, or other dementias. Most FDG-PET studies involving PSP and CBS were not specifically designed for these disorders. An additional obstacle lies in the methodological variability across studies. Despite several studies achieving high diagnostic accuracy for PSP and/or CBS with specificity exceeding 90% using FDG-PET, sensitivity remains considerably lower. CBS appears to have a distinct hypometabolic pattern compared to PSP, marked by asymmetry and predominant cortical involvement. CBS more often affects posterior cortical regions (parietal and posterior parts of the frontal cortex, and sometimes temporal and occipital parts) and the thalamus, whereas PSP appears to affect the striatum, frontal cortex, anterior cingulate, and subtentorial structures, typically in a more symmetrical manner. Large, multicenter studies are needed, utilizing standardized imaging and protocols. Full article