Subcortical Areas Research Articles

Choroid plexus volume is enlarged in long COVID and associated with cognitive and brain changes.

Patients with post-COVID condition (PCC) present with diverse symptoms which persist at long-term after SARS-CoV-2 infection. Among these symptoms, cognitive impairment is one of the most prevalent and has been related to brain structural and functional changes. The underlying mechanisms of these cognitive and brain alterations remain elusive but neuroinflammation and immune mechanisms have been majorly considered. In this sense, the choroid plexus (ChP) volume has been proposed as a marker of neuroinflammation in immune-mediated conditions and the ChP epithelium has been found particularly susceptible to the effects of SARS-CoV-2. The objective was to investigate the ChP in PCC and evaluate its relationships with cognition, brain, and immunological alterations. One-hundred and twenty-nine patients with PCC after a mean of 14.79 ± 7.17 months of evolution since the infection and 36 healthy controls were recruited. Participants underwent a neuropsychological, and neuroimaging assessment and immunological markers evaluation. Results revealed ChP volume enlargement in PCC compared to healthy controls. The ChP enlargement was associated with cognitive dysfunction, grey matter volume reduction in frontal and subcortical areas, white matter integrity and diffusivity changes and functional connectivity changes. These ChP changes were also related to intermediate monocytes levels. Findings suggest that the ChP integrity may play a relevant role in the pathophysiology of cognitive deficits and the observed brain changes in PCC. The previously documented function of the ChP in maintaining brain homeostasis and regulating the entry of immune cells into the brain supports the presence of neuroinflammatory mechanisms in this disorder.

Association of Early fMRI Connectivity Alterations With Different Cognitive Phenotypes in Patients With Newly Diagnosed Parkinson Disease.

According to the dual syndrome hypothesis, patients with Parkinson disease (PD) with visuospatial deficits are more likely to progress to dementia, compared with patients with a prevalent dysexecutive syndrome. In this study, we aimed to investigate whether early connectivity changes in the dorsolateral prefrontal cortex (DLPFC) and the precuneus (PCun)-which are critical to fronto-executive and visuospatial functions, respectively-can identify distinct cognitive phenotypes in cognitively intact newly diagnosed patients with PD. Newly diagnosed, drug-naïve patients with PD (≤2 years from clinical onset) with normal Montreal Cognitive Assessment (MoCA), were consecutively enrolled from our Movement Disorders Clinics in Italy. Sex-matched and age-matched healthy controls (HCs) were enrolled among nonconsanguineous patients' relatives. Participants underwent 3T-fMRI to investigate resting-state functional connectivity (rs-FC) of DLPFC and PCun with a seed-based approach at baseline (T0). K-means cluster analysis was performed on z scores of rs-FC values of patients with PD to identify clusters of patients sharing common patterns of connectivity. Differences in neurophysiologic, motor, and nonmotor scales among PD clusters were assessed at T0 and after a 3.5-year follow-up (T1). The study included 68 patients with PD (27% women; mean age: 60 ± 9 years; Hoehn & Yahr score: 1.4 ± 0.5; MoCA score: 27.9 ± 1.6) and 31 HCs (39% women; mean age 64.2 ± 9.3 years) at T0. Forty-two patients completed T1 evaluation. Patients displayed reduced rs-FC of both DLPFC and PCun with several cortical and subcortical areas compared with HCs. Cluster 1 was defined by lower values of rs-FC in all investigated regions of interest while clusters 2 and 3, respectively, by higher and intermediate values. Despite none meeting criteria for mild cognitive impairment (MCI) at T0, cluster 1 was older and lower performing in global cognition, fronto-executive, and memory domains, compared with clusters 2 and 3 (all p < 0.031). At T1, a more evident worsening in global cognition, fronto-executive, and visuospatial domains and nonmotor and motor symptoms was observed in clusters 1 and 3 vs cluster 2 (all p < 0.04), with MCI being more frequent in clusters 1 and 3. Early connectivity changes of the DLPFC and the PCun occur in newly diagnosed patients with PD without MCI and can distinguish cognitive phenotypes, as confirmed after a longitudinal clinical observation.

Sex-specific associations of serum testosterone with gray matter volume and cerebral blood flow in midlife individuals at risk for Alzheimer's disease.

Testosterone, an essential sex steroid hormone, influences brain health by impacting neurophysiology and neuropathology throughout the lifespan in both genders. However, human research in this area is limited, particularly in women. This study examines the associations between testosterone levels, gray matter volume (GMV) and cerebral blood flow (CBF) in midlife individuals at risk for Alzheimer's disease (AD), according to sex and menopausal status. A cohort of 294 cognitively normal midlife participants, 83% female, ages 35-65 years, with an AD family history and/or Apolipoprotein E epsilon 4 (APOE-4) genotype, underwent volumetric Magnetic Resonance Imaging (MRI) to measure GMV and MR-Arterial Spin Labeling (ASL) for measurement of CBF. We used voxel-based analysis and volumes of interest to test for associations between testosterone (both total and free testosterone) and brain imaging outcomes, stratified by sex and menopausal status. Higher total and free testosterone levels were associated with larger GMV in men, with peak effects in frontal and temporal regions. Conversely, in women, higher testosterone levels correlated with higher CBF, with peak effects in frontal and limbic regions, subcortical areas and hypothalamus. Among women, associations between testosterone and GMV were observed at the premenopausal and perimenopausal stages, but not postmenopause, whereas associations of testosterone with CBF were significant starting at the perimenopausal stage and were more pronounced among hormone therapy non-users. Results were independent of age, APOE-4 status, midlife health indicators, and sex hormone-binding globulin levels. These findings indicate sex-specific neurophysiological effects of testosterone in AD-vulnerable regions in midlife individuals at risk for AD, with variations observed across sex and menopausal status. This underscores the need for further research focusing on the neuroprotective potential of testosterone in both sexes.

Reactivation and consolidation of memory traces during post-encoding rest across the adult lifespan.

Episodic memory is a critical cognitive function that enables the encoding, storage, and retrieval of new information. Memory consolidation, a key stage of episodic memory, stabilizes this newly encoded information into long-lasting brain "storage." Studies using fMRI to investigate post-encoding awake rest holds promise to shed light on early, immediate consolidation mechanisms. Here, we review fMRI studies during episodic memory to document common methods to investigate post-encoding consolidation, such as multivoxel pattern analysis (MVPA) and functional connectivity, and the current state of the science in both healthy younger and older adults. In young adults, post-encoding reactivation of stimuli-specific neural patterns in the hippocampus and its connectivity with cortical and subcortical areas (e.g., visual-temporal cortex, medial prefrontal, and medial parietal cortex) correlate with subsequent memory performance. Conversely, studies in older adults highlight the importance of large-scale brain networks during post-encoding rest, particularly the default mode network (DMN). Alterations in connectivity between the DMN and task-positive networks may help older adults maintain episodic memory. Furthermore, non-invasive brain stimulation techniques can enhance these post-encoding consolidation processes and improve memory performance in both younger and older adults. Notably, a lack of studies has investigated post-encoding memory consolidation in neurodegenerative disorders. This review underscores the importance of understanding how post-encoding neural reactivation and connectivity evolve with age to partially explain age-related declines in episodic memory performance and how such declines can be restored.

Memory enhancement by transcranial radiofrequency wave treatment occurs without appreciably increasing brain temperature.

We have previously shown in small studies that full brain Transcranial Radiofrequency Wave Treatment (TRFT) to subjects with Alzheimer's Disease could stop and reverse their cognitive decline. An 8-emitter head device, the "MemorEM", was used in these studies to provide TRFT at 915MHz frequency and power level of 1.6W/kg Specific Absorption Rate (SAR) during daily 1-hour treatments. Although no deleterious side effects during up to 2.5 years of treatment were reported, it is important to rule out the possibility that brain heating will occur during TRFT in humans at a higher power level of 4.0W/kg SAR, which is anticipated for future clinical testing in order to increase treatment intensity/efficacy to deep sub-cortical areas. To examine if brain heating occurs during a single 1-hour treatment at 4W/kg SAR, a hollow human head phantom filled with brain-analogous gel and with an attached MemorEM head device was utilized. Brain temperatures were taken at 64 specific coordinates within the brain gel before and immediately following one-hour of TRFT. Results revealed none of the 64 sites having a temperature increase after TRFT of 1°C or more. Indeed, 45 of the 64 sites exhibited a temperature rise of less than 0.5°C, with just three sites exhibiting an increase between 0.75 and 0.9°C. These results demonstrate that TRFT in a human head phantom that mimics the electromagnetic properties of the human head, does not appreciably increase brain temperature (i.e., is non-thermal) at 915MHz frequency and 4W/kg SAR power level. Thus, TRFT would appear to be safe at 4W/kg for long-term daily treatments.

Altered topology in cortical morphometric similarity network in recurrent major depressive disorder

BackgroundRecurrent major depressive disorder (RDD) is increasingly understood to be associated with a 'disconnection' within the brain areas. But, the true understanding of cortical connectivities remains challenging. Morphometric similarity network (MSN) with multi-modal magnetic resonance imaging (MRI) could provide more information about cortical micro-architecture changes in individuals with RDD. MethodsHere, we integrated multi-modal features from T1-weighted imaging, diffusion tensor imaging (DTI), and inhomogeneous magnetization transfer imaging (ihMT) to construct MSN. We used graph theory to calculate topological changes in MSN and explore their relationship with the severity and recurrence. The topological properties of 42 RDD patients were compared with 56 age, sex, and education-matched healthy controls. ResultsRDD subjects showed significantly decreased global efficiency, increased characteristic path length, reduced nodal efficiencies in the parietal lobe, subcortical area, and temporal lobe, increased betweenness centrality in the left supplementary motor area (SMA), decreased intra-modular connections in the parietal module and decreased inter-modular connections between the parietal and prefrontal modules. Notably, the global efficiency, characteristic path length, local efficiency of the right superior parietal gyrus, and inter-modular connections between the parietal and prefrontal modules were significantly associated with the number of depressive episodes. The betweenness centrality in SMA and the intra-modular connections in the parietal module showed a positive relationship with 17-item Hamilton Rating Scale for Depression (HAMD) scores. ConclusionsThe altered topology of MSN may serve as potential underlying pathological mechanisms of RDD. The impaired information integration of the network, particularly the disconnection within the fronto-parietal network, may be associated with the recurrence of depression. The SMA and the fronto-parietal network may be related to the severity of depression.

DISINTEGRATION OF THE SELF SYSTEM IN A PATIENT WITH SEMANTIC VARIANT PPA (SVPPA) DIAGNOSED FOLLOWING SARS-COV-2 INFECTION AND COVID-19

The aim of this study is to present a patient with semantic variant PPA (svPPA) diagnosed following SARS-CoV-2 infection and COVID-19 contraction, who experienced a dramatic disintegration of the Self system.The patient, a 45-year-old bilingual physician with no chronic diseases, contracted SARS-CoV-2 in November 2020, confirmed by RT-PCR. During acute COVID-19, he developed high fever (40C) and neurological symptoms such as severe headache, dizziness, confusion, and loss of smell. About 16 weeks later, he had difficulties understanding common words in Polish and English (he was bilingual). One year post-COVID-19, his language impairment has intensified affecting word comprehension and naming. His syntax and phonology in Polish remained relatively intact, but he appeared confused. Despite losing word meaning, he could still use various objects. Psychiatric examination showed no mental illness, while neurological and neuropsychological assessments revealed long COVID with predominant aphasia symptoms. He had problems with lexical classification and higher-level differentiation. A MRI one year after COVID-19 showed significant asymmetric cortical atrophy in the temporal regions, predominantly on the left side, and in subcortical areas. In the Polish Boston Naming Test (BNT), he had difficulty recalling well-known items and used general descriptions instead (the patient occasionally mixed Polish and English). In the Pyramids and Palm Trees Test (PPTT) we found impairment of semantic memory. Surface dyslexia and dysgraphia were also found. Working memory impairment increased as the disease progressed. Information flow was profoundly disturbed, and ERPs to all stimuli significantly reduced. Two years after contracting COVID-19, the patient exhibited significant loss of object knowledge and constructional apraxia. He developed blank speech, making incoherent statements. As the disease progressed the patient lost his sense of identity, unable to recognize objects or faces, including his reflection. In June 2023, just over two and a half years after contracting COVID-19, the patient developed pneumonia. He was hospitalized and died a few days later. Post-mortem examinations revealed asymmetric cortical atrophy of the temporal lobes, more severe in the left hemisphere, which is associated with language functions. TDP-43 proteinopathy was also diagnosed. We will discuss the multifaceted symptoms and significance of this case study for modern medicine.This reliably documented case serves as a significant contribution to modern neuroscience, offering valuable insights into the intersection of COVID-19 and neurodegenerative diseases, and paving the way for future research and improved patient care.

Boundary Complexity of (Sub-) Cortical Areas Predict Deep Brain Stimulation Outcomes in Parkinson's Disease.

While deep brain stimulation (DBS) remains an effective therapy for Parkinson's disease (PD), sources of variance in patient outcomes are still not fully understood, underscoring a need for better prognostic criteria. Here we leveraged routinely collected T1-weighted (T1-w) magnetic resonance imaging (MRI) data to derive patient-specific measures of brain structure and evaluate their usefulness in predicting changes in PD medications in response to DBS. Preoperative T1-w MRI data from 231 patients with PD were used to extract regional measures of fractal dimension (FD), sensitive to the structural complexities of cortical and subcortical areas. FD was validated as a biomarker of Parkinson's disease (PD) progression through comparison of patients with PD and healthy controls (HCs). This analysis revealed significant group differences in FD across nine brain regions which supports its utility as a marker of PD. We evaluated the impact of adding imaging features (FD) to a clinical model that included demographics and clinical parameters-age, sex, total number and location of DBS electrodes, and preoperative motor response to levodopa. This model aimed to explain variance and predict changes in medication following DBS. Regression analysis revealed that inclusion of the FD of distributed brain areas correlated with post-DBS reductions in medication burden, explaining an additional 13.6% of outcome variance (R 2 =0.388) compared to clinical features alone (R 2 =0.252). Hypergraph-based classification learning tasks achieved an area under the receiver operating characteristic curve of 0.64 when predicting with clinical features alone, versus 0.76 when combining clinical and imaging features. These findings demonstrate that PD effects on brain morphology linked to disease progression influence DBS outcomes. The work also highlights FD as a potentially useful imaging biomarker to enhance DBS candidate selection criteria for optimized treatment planning.

Advanced technologies for the study of neuronal cross-organ regulation: a narrative review

The nervous system plays an integral role in the homeostasis of living organisms through the regulation of multiple organ systems. Research has highlighted the extensive role of the nervous system in regulating organ function, including key aspects such as metabolic processes, respiratory, cardiovascular, and immune responses. These findings are inseparable from the development of new technologies such as viral tracing, optogenetics, whole-tissue imaging, and neural activity recording. As technology continues to advance, our understanding of the regulatory role of the nervous system in other organs has expanded to more complex cognitive and emotional control systems, such as the cerebral cortex and subcortical areas. Recent studies have also shown the bidirectional cross-organ regulatory mechanisms between the gut microbiota and the brain. In addition, the body–brain axis also monitors inflammatory responses to ensure a balance between proinflammatory and anti-inflammatory responses. This review delves into the intricate regulatory functions of the nervous system as they pertain to cross-organ communication, emphasizing the broader implications that extend beyond mere metabolic regulation. It employs cutting-edge technologies such as viral tracing, whole-tissue clearing, optogenetics, and in vivo neuronal activity recording to dissect the influence of the nervous system on various organs, including but not limited to the heart, liver, and spleen. These advanced methodologies have substantially broadened our comprehension of the fundamental operations of the nervous system within diverse physiological systems, revealing the complex neural networks that orchestrate organ-specific functions. Our review highlights the significant potential of advanced technologies in neuronal cross-organ regulation to pave the way for therapeutic strategies aimed at addressing a wide array of conditions that impact organ health.

Cortico-thalamic tremor circuits and their associations with deep brain stimulation effects in essential tremor.

Essential tremor (ET) is one of the most common movement disorders in adults. Deep brain stimulation (DBS) of the ventralis intermediate nucleus (VIM) of the thalamus and/or the posterior subthalamic area (PSA) has been shown to provide significant tremor suppression in patients with ET, but with significant inter-patient variability and habituation to the stimulation. Several non-invasive neuromodulation techniques targeting other parts of the central nervous system, including cerebellar, motor cortex, or peripheral nerves, have also been developed for treating ET, but the clinical outcomes remain inconsistent. Existing studies suggest that pathology in ET may emerge from multiple cortical and subcortical areas, but its exact mechanisms remain unclear. By simultaneously capturing neural activities from motor cortices and thalami, and hand tremor signals recorded via accelerometers in fifteen human subjects who have undergone lead implantations for DBS, we systematically characterized the efferent and afferent cortico-thalamic tremor networks. Through the comparisons of these network characteristics and tremor amplitude between DBS OFF and ON conditions, we further investigated the associations between different tremor network characteristics and the magnitude of DBS effect. Our findings implicate the thalamus, specifically the contralateral hemisphere, as the primary generator of tremor in ET, with a significant contribution of the ipsilateral hemisphere as well. Although there is no direct correlation between the cortico-tremor connectivity and tremor power or reduced tremor by DBS, the strength of connectivity from the motor cortex to the thalamus and vice versa at tremor frequency predicts baseline tremor power and effect of DBS. Interestingly, there is no correlation between these two connectivity pathways themselves, suggesting that, independent of the subcortical pathway, the motor cortex appears to play a relatively distinct role, possibly mediated through an afferent/feedback loop in the propagation of tremor. DBS has a greater clinical effect in those with stronger cortico-thalamo-tremor connectivity involving the contralateral thalamus, which is also associated with bigger and more stable tremor measured with an accelerometer. Interestingly, stronger cross-hemisphere coupling between left and right thalami is associated with more unstable tremor. Together this study provides important insights into a better understanding of the cortico-thalamic tremor generating network and its implication for the development of patient-specific therapeutic approaches for ET.

Effect of cerebral sinus venous thrombosis and its location on cerebral blood flow: a [15O]water PET study in acute stroke patients compared to healthy volunteers

BackgroundSymptoms in acute cerebral sinus venous thrombosis (CSVT) are highly variable, ranging from headaches to fatal stroke, and the basis for this high inter-individual variability is poorly understood. The present study aimed to assess whether acute CSVT significantly alters regional cerebral blood flow (CBF), if findings differ from CBF patterns know from large-artery occlusion in stroke, and whether the pattern of CBF alterations depends on clot location. Therefore, we retrospectively analyzed 12 patients with acute CSVT 10.6 ± 4.6 days after symptom onset and ten healthy volunteers who underwent [15O]water PET (two scans each, 300 ± 14 MBq [15O]water). Static image datasets (15–75 s after injection; normalized to cerebellum) reflecting relative CBF (rCBF) were analyzed using voxel- and region-of-interest-based analysis (AAL3-atlas). We mirrored datasets of patients with left-sided CSVT to harmonize the affected hemisphere.ResultsSeven and five patients showed right- and left-sided CSVT, respectively. The superior sagittal sinus (SSS) was involved in 8/12 patients. CSVT patients had extensive rCBF deficits in the voxel-based analysis with accentuation in the right (ipsilateral) frontal cortex and caudate nucleus compared to controls, which were most pronounced in cortical areas in those with involvement of the SSS (8/12), and in subcortical areas in those without involvement of the SSS (4/12; p < 0.05, false discovery rate corrected). ROI-analysis demonstrated significant frontal (p = 0.01) and caudate nucleus (p = 0.008) rCBF deficits driven by patients with and without SSS occlusion, respectively.Conclusions[15O]water PET was able to visualize characteristic patterns of impaired rCBF, which were different from intracranial large-artery occlusion in acute ischemic stroke, and exhibited substantial rCBF alterations depending on the involvement of the SSS. Our findings provide novel insights into the effects of disturbed venous drainage on CBF in acute CSVT, which may aid in understanding the pathophysiology, and guide future therapy of acute CSVT.

Patterns of tau, amyloid and synuclein pathology in ageing, Alzheimer's disease and synucleinopathies.

Alzheimer's disease (AD) is neuropathologically defined by deposits of misfolded hyperphosphorylated tau (HP-tau) and β-amyloid. Lewy body (LB) dementia, which includes dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), is characterised pathologically by α-synuclein aggregates. HP-tau and β-amyloid can also occur as copathologies in LB dementia, and a diagnosis mixedAD/DLB can be made if present in sufficient quantities. We hypothesised the spread of these abnormal proteins selectively affects vulnerable areas, resulting in pathologic regional covariance that differentially associates with pre-mortem clinical characteristics. Our aims were to map regional quantitative pathology (HP-tau, β-amyloid, α-synuclein) and investigate the spatial distributions from tissue microarray (TMA) post-mortem samples across healthy aging, AD and LB dementia. The study involved 159 clinico-pathologically diagnosed human post-mortem brains (48 controls, 47 AD, 25 DLB, 20 mixedAD/DLB, 19 PDD). The burden of HP-tau, β-amyloid and α-synuclein was quantitatively assessed in cortical and subcortical areas. Principal components (PC) analysis was applied across all cases to determine the pattern nature of HP-tau, β-amyloid and α-synuclein. Further analyses explored the relationships of these pathological patterns with cognitive and symptom variables. Cortical (tauPC1) and temporolimbic (tauPC2) patterns were observed for HP-tau. For β-amyloid, a cortical-subcortical pattern (amylPC1) was identified. For α-synuclein, four patterns emerged: 'posterior temporal - occipital (synPC1)', 'anterior temporal-frontal (synPC2)', 'parieto-cingulate-insula (synPC3)', and 'frontostriatal-amygdala (synPC4)'. Distinct synPC scores were apparent among DLB, mixedAD/DLB and PDD, and may relate to different spreading patterns of α-synuclein pathology. In dementia, cognitive measures correlated with tauPC1, tauPC2 and amylPC1 pattern scores (P≤0.02), whereas such variables did not relate to α-synuclein parameters in these or combined LB dementia cases. Mediation analysis then revealed that in the presence of amylPC1, tauPC1 had a direct effect on global cognition in dementia (n=65, P=0.04), while tauPC1 mediated the relationship between amylPC1 and cognition through the indirect pathway (amylPC1→ tauPC1 → global cognition) (P<0.05). Lastly, in synucleinopathies, synPC1 and synPC4 pattern scores were associated with visual hallucinations and motor impairment, respectively (P=0.02). In conclusion, distinct patterns of α-synuclein pathology were apparent in LB dementia, which could explain some of the disease heterogeneity and differing spreading patterns among these conditions. Visual hallucinations and motor severity were associated with specific α-synuclein topographies in LB dementia that may be important to the clinical phenotype, and could, after necessary testing/validation, be integrated into semi-quantitative routine pathological assessment.

Identification of pathological pathways centered on circRNA dysregulation in association with irreversible progression of Alzheimer’s disease

BackgroundCircular RNAs (circRNAs) are highly stable regulators, often accumulated in mammalian brains and thought to serve as “memory molecules” that govern the long process of aging. Mounting evidence demonstrated circRNA dysregulation in the brains of Alzheimer’s disease (AD) patients. However, whether and how circRNA dysregulation underlies AD progression remains unexplored.MethodsWe combined Poly(A)-tailing/RNase R digestion experimental approach with CARP, our published computational framework using pseudo-reference alignment for more sensitive and accurate circRNA detection to identify genome-wide circRNA dysregulation and their downstream pathways in the 5xFAD mouse cerebral cortex between 5 and 7 months of age, a critical window marks the transition from reversible to irreversible pathogenic progression. Dysregulated circRNAs and pathways associated with disease progression in 5xFAD cortex were systematically compared with circRNAs affected in postmortem subcortical areas of a large human AD cohort. A top-ranked circRNA conserved and commonly affected in AD patients and 5xFAD mice was depleted in cultured cells to examine AD-relevant molecular and cellular changes.ResultsWe discovered genome-wide circRNA alterations specifically in 5xFAD cortex associated with AD progression, many of which are commonly dysregulated in the subcortical areas of AD patients. Among these circRNAs, circGigyf2 is highly conserved and showed the highest net reduction specifically in the 7-month 5xFAD cortex. CircGIGYF2 level in AD patients’ cortices negatively correlated with dementia severity. Mechanistically, we found multiple AD-affected splicing factors that are essential for circGigyf2 biogenesis. Functionally, we identified and experimentally validated the conserved roles of circGigyf2 in sponging AD-relevant miRNAs and AD-associated RNA binding proteins (RBPs), including the cleavage and polyadenylation factor 6 (CPSF6). Moreover, circGigyf2 downregulation in AD promoted silencing activities of its sponged miRNAs and enhanced polyadenylation site processing efficiency of CPSF6 targets. Furthermore, circGigyf2 depletion in a mouse neuronal cell line dysregulated circGigyf2-miRNA and circGigyf2-CPSF6 axes and potentiated apoptotic responses upon insults, which strongly support the causative roles of circGigyf2 deficiency in AD neurodegeneration.ConclusionsTogether, our results unveiled brain circRNAs associated with irreversible disease progression in an AD mouse model that is also affected in AD patients and identified novel molecular mechanisms underlying the dysregulation of conserved circRNA pathways contributing to AD pathogenesis.

Unique Cortical and Subcortical Activation Patterns for Different Conspecific Calls in Marmosets.

The common marmoset (Callithrix jacchus) is known for its highly vocal nature, displaying a diverse range of calls. Functional imaging in marmosets has shown that the processing of conspecific calls activates a brain network that includes fronto-temporal areas. It is currently unknown whether different call types activate the same or different networks. In this study, nine adult marmosets (four females) were exposed to four common vocalizations (phee, chatter, trill, and twitter), and their brain responses were recorded using event-related functional magnetic resonance imaging at 9.4 T. We found robust activations in the auditory cortices, encompassing core, belt, and parabelt regions, and in subcortical areas like the inferior colliculus, medial geniculate nucleus, and amygdala in response to these calls. Although a common network was engaged, distinct activity patterns were evident for different vocalizations that could be distinguished by a 3D convolutional neural network, indicating unique neural processing for each vocalization. Our findings also indicate the involvement of the cerebellum and medial prefrontal cortex in distinguishing particular vocalizations from others.

VTA dopamine neurons are hyperexcitable in 3xTg-AD mice due to casein kinase 2-dependent SK channel dysfunction

Alzheimer’s disease (AD) patients exhibit neuropsychiatric symptoms that extend beyond classical cognitive deficits, suggesting involvement of subcortical areas. Here, we investigated the role of midbrain dopamine (DA) neurons in AD using the amyloid + tau-driven 3xTg-AD mouse model. We found deficits in reward-based operant learning in AD mice, suggesting possible VTA DA neuron dysregulation. Physiological assessment revealed hyperexcitability and disrupted firing in DA neurons caused by reduced activity of small-conductance calcium-activated potassium (SK) channels. RNA sequencing from contents of single patch-clamped DA neurons (Patch-seq) identified up-regulation of the SK channel modulator casein kinase 2 (CK2), which we corroborated by immunohistochemical protein analysis. Pharmacological inhibition of CK2 restored SK channel activity and normal firing patterns in 3xTg-AD mice. These findings identify a mechanism of ion channel dysregulation in VTA DA neurons that could contribute to behavioral abnormalities in AD, paving the way for novel treatment strategies.

Direct visualization of microwires in hybrid depth electrodes using high-resolution photon-counting CT.

Hybrid depth electrodes are increasingly being used for epilepsy monitoring and human neurophysiology research. Microwires extending from the tip of the Behnke-Fried (BF) electrode into (sub)cortical areas allow to isolate single neurons and perform microstimulation. Conventional CT or MRI visualize the entire microwire bundle as an artifact extending from the BF electrode tip with low resolution, without proper identification of individual microwires. We illustrate the first direct visualization method of individual microwires using high-resolution photon-counting CT (PCCT). Coregistration of the PCCT scan with a preoperative MRI can visualize individual wires directly in cortex, which is an advantage as it provides feedback on the accuracy of the implantation method and can guide future implantations. This PCCT technique allows for accurately depicting individual microwires which could be relevant for neuroscientific research through improved visualization and implantation of specific cortical and subcortical brain areas. PLAIN LANGUAGE SUMMARY: Researchers are using hybrid depth electrodes to study epilepsy and brain activity. These electrodes, called Behnke-Fried (BF) electrodes, have microwires at the tip that can record single neurons and stimulate brain areas. Regular CT or MRI scans do not show the individual microwires clearly. The authors use a new high-resolution photon-counting CT (PCCT) technique, which can show each individual microwire in the brain. By combining PCCT with MRI, the authors can precisely see where the microwires are located. This could improve future implantation surgeries and brain research.

Functional and connectivity correlates associated with Parkinson's disease psychosis: a systematic review.

Neural underpinnings of Parkinson's disease psychosis remain unclear to this day with relatively few studies and reviews available. Using a systematic review approach, here, we aimed to qualitatively synthesize evidence from studies investigating Parkinson's psychosis-specific alterations in brain structure, function or chemistry using different neuroimaging modalities. PubMed, Web of Science and Embase databases were searched for functional MRI (task-based and resting state), diffusion tensor imaging, PET and single-photon emission computed tomography studies comparing Parkinson's disease psychosis patients with Parkinson's patients without psychosis. We report findings from 29 studies (514 Parkinson's psychosis patients, mean age ± SD = 67.92 ± 4.37 years; 51.36% males; 853 Parkinson's patients, mean age ± SD = 66.75 ± 4.19 years; 55.81% males). Qualitative synthesis revealed widespread patterns of altered brain function across task-based and resting-state functional MRI studies in Parkinson's psychosis patients compared with Parkinson's patients without psychosis. Similarly, white matter abnormalities were reported in parietal, temporal and occipital regions. Hypo-metabolism and reduced dopamine transporter binding were also reported whole brain and in sub-cortical areas. This suggests extensive alterations affecting regions involved in high-order visual processing and attentional networks.

M/EEG source localization for both subcortical and cortical sources using a convolutional neural network with a realistic head conductivity model.

While electroencephalography (EEG) and magnetoencephalography (MEG) are well-established noninvasive methods in neuroscience and clinical medicine, they suffer from low spatial resolution. Electrophysiological source imaging (ESI) addresses this by noninvasively exploring the neuronal origins of M/EEG signals. Although subcortical structures are crucial to many brain functions and neuronal diseases, accurately localizing subcortical sources of M/EEG remains particularly challenging, and the feasibility is still a subject of debate. Traditional ESIs, which depend on explicitly defined regularization priors, have struggled to set optimal priors and accurately localize brain sources. To overcome this, we introduced a data-driven, deep learning-based ESI approach without the need for these priors. We proposed a four-layered convolutional neural network (4LCNN) designed to locate both subcortical and cortical sources underlying M/EEG signals. We also employed a sophisticated realistic head conductivity model using the state-of-the-art segmentation method of ten different head tissues from individual MRI data to generate realistic training data. This is the first attempt at deep learning-based ESI targeting subcortical regions. Our method showed excellent accuracy in source localization, particularly in subcortical areas compared to other methods. This was validated through M/EEG simulations, evoked responses, and invasive recordings. The potential for accurate source localization of the 4LCNNs demonstrated in this study suggests future contributions to various research endeavors such as the clinical diagnosis, understanding of the pathophysiology of various neuronal diseases, and basic brain functions.

Morphological Evaluation of Corpus Callosum Atrophy Over Time in Relapsing Remitting Multiple Sclerosis

Objective: Multiple sclerosis (MS) is a chronic central nervous system (CNS) disease that generally affects young adults and is marked by inflammation, demyelination, and neurodegeneration. Magnetic resonance imaging (MRI) is widely used diagnosis tool for relapsing remitting MS (RRMS). Corpus callosum (CC), the largest commissural tract in brain which is associated with both cognitive and physical impairment by atrophy in MS. Our study aimed to evaluate CC in RRMS patients using MR images and compare it to measurements from healthy controls within the same age. Methods: We manually measured changes in CC thickness in T1 brain MR images of RRMS patients in 2017, 2019, and 2022. Results: Our results showed that control group had greater thickness, length, and index values in all CC sections compared to patient group. Additionally, a significant difference was observed in thickness of genu and splenium sections and CC index between patient and control groups. However, no significant difference was detected in truncus part of CC or overall CC length. CC measurements in patient group decreased over time, with 1st MRI showing greater values than 2nd and 3rd MRI scans. Furthermore, there was a statistically significant difference in thickness of truncus part of CC and volume values of subcortical areas between 2nd-3rd and 1st-3rd MRI measurements. Conclusion: As a result of these findings, our study provides important information about changes in CC measurements for MS patients.

A novel scoring system proposal to guide surgical treatment indications for high grade gliomas in elderly patients: DAK-75.

High-grade gliomas are the most prevalent neurooncological desease in adults, their incidence increases with age, peaking in the seventh decade. This paper aims to address how to select patients for surgical resection by identifying pre-surgical predictors of 12-month mortality in newly diagnosed HGG patients aged ≥ 75years. A prognostic score will be proposed to guide surgical decisions based on expected survival. Retrospective observational single-center cohort study was carried out at the "Città della Salute e della Scienza-Molinette" University Hospital in Turin, Italy. All consecutive patients aged ≥ 75years newly diagnosed with HGG were included, regardless of whether they underwent surgical resection. Clinical, radiological, histological and molecular data were collected.Variables potentially available at the time of diagnosis were considered to develop a multivariable logistic regression predictive model, with 12-months overall survival as the dependent variable. 102 patients aged 75years or older received a new diagnosis of high-grade glioma, of whom 68 underwent surgical resection. Patients undergoing surgery were slightly younger (76.9 vs 79.0years, p = 0.007) and had better performance status (median KPS 80 vs 70). Most tumors undergoing surgery were localized in cortical or subcortical non-motor areas (p < 0.001) and less frequently deep-seated (p = 0.023) or multifocal (p < 0.001). A predictive model, the DAK-75 score, was developed: the AUROC of the final model was 0.822 (95% CI 0.741-0.902). The score includes clinical presentation, tumor location, and KPS, ranging from 0 to 20, categorizing risk scores into low-risk and high-risk groups (< or > 8). Higher scores corresponded to fewer surgical patients and higher one-year mortality rates (92.2% vs 47.1%, p < 0.001). DAK-75 score may represent a valuable tool in the decision-making process for neurosurgical intervention in elderly patients diagnosed with HGG. Further studies are needed to externally and prospectively validate the scoring system.