Gyrus Network Research Articles

Phospholipase gamma2: A candidate genetic risk factor for Alzheimer’s disease that can alter synaptic function in DG‐perforant pathway of hippocampus

AbstractBackgroundPhospholipaseC γ2 (PLCG2) is known to have direct link with genetic risk factors for Alzheimer’s like dementia (AD). PLCG2 has been previously demonstrated to have association with Aß uptake through microglia. And mostly expressed in dentate gyrus (DG) network of hippocampus.MethodWT mouse were transfected with sh‐RNA of LV‐PLCG2 (U6 promotor, GFP as reporter; shRNA) or scrambled (used as control; shNT). Whole‐cell patch‐clamp recordings were performed on acute slices with glass pipette (<3‐4MΩ) at ‐70mv, which was accompanied with morphometry of perforant pathway (PP)‐DG circuitry. Two‐tailed Mann‐Whitney test was used for statistics unless otherwise mentioned, p<0.05 was considered to be significant.ResultWe found significant increase in APhalf width (p = 0.0274), rheobase (p = 0.0046) in shRNA on the other hand, input resistance (p = 0.0159), number of spike vs current injection (p = 0.0268) was significantly decreased. However, there were no significant change was observed in APonset (p = 0.6105), APamplitude (p = 0.7345), RMP (p = 0.7591) and firing threshold (p = 0.5247) in shRNA group when compared to shNT. mEPSC amplitude was found to be reduced (p = 0.0288) in shRNA condition, even the cumulative probability of mEPSC amplitude was also found to be significantly altered after silencing of PLCG2 gene in DG cells (p = 0.0014; Kolmogorof‐Smirnov test). mEPSC frequency of the miniature activity of transfected DG cells were did not show significant change (p = 0.7707). Sholl analysis of the DG cells expressing shRNA showed a decrease in the number of intersections vs distance from soma (P<0.05), accompanied by significant decrease in dendritic length (p = 0.0501), dendritic volume (p<0.0001) and dendritic surface area (p = 0.0273). When spine density was measured we have found a significant decrease in cumulative distribution of spine density (p<0.0001; Kolmogorof‐Smirnov test), which is tightly associated with decrease in spine length (p = 0.0209) and spine head diameter (P<0.0001). Furthermore, these dendritic and spine morphometric alteration is also accompanied with the decrease in the volume of mossy fiber gigantic bouton (mfB) with alteration in the number of filopodia per mfBs (p<0.05).ConclusionResults from the study, reflect critical insight of PLCG2 regulating neuronal and/or synaptic activity, which may underlie the cognitive dysfunction (viz. recognition memory) and synaptic alteration to the PP‐DG circuitry seen in AD.

Associations between the multitrajectory neuroplasticity of neuronavigated rTMS-mediated angular gyrus networks and brain gene expression in AD spectrum patients with sleep disorders.

The multifactorial influence of repetitive transcranial magnetic stimulation (rTMS) on neuroplasticity in neural networks is associated with improvements in cognitive dysfunction and sleep disorders. The mechanisms of rTMS and the transcriptional-neuronal correlation in Alzheimer's disease (AD) patients with sleep disorders have not been fully elucidated. Forty-six elderly participants with cognitive impairment (23 patients with low sleep quality and 23 patients with high sleep quality) underwent 4-week periods of neuronavigated rTMS of the angular gyrus and neuroimaging tests, and gene expression data for six post mortem brains were collected from another database. Transcription-neuroimaging association analysis was used to evaluate the effects on cognitive dysfunction and the underlying biological mechanisms involved. Distinct variable neuroplasticity in the anterior and posterior angular gyrus networks was detected in the low sleep quality group. These interactions were associated with multiple gene pathways, and the comprehensive effects were associated with improvements in episodic memory. Multitrajectory neuroplasticity is associated with complex biological mechanisms in AD-spectrum patients with sleep disorders. This was the first transcription-neuroimaging study to demonstrate that multitrajectory neuroplasticity in neural circuits was induced via neuronavigated rTMS, which was associated with complex gene expression in AD-spectrum patients with sleep disorders. The interactions between sleep quality and neuronavigated rTMS were coupled with multiple gene pathways and improvements in episodic memory. The present strategy for integrating neuroimaging, rTMS intervention, and genetic data provide a new approach to comprehending the biological mechanisms involved in AD.

Association between patent foramen ovale and migraine: evidence from a resting-state fMRI study

A relationship between migraine without aura (MO) and patent foramen ovale (PFO) has been observed, but the neural basis underlying this relationship remains elusive. Utilizing independent component analysis via functional magnetic resonance imaging, we examined functional connectivity (FC) within and across networks in 146 patients with MO (75 patients with and 71 patients without PFO) and 70 healthy controls (35 patients each with and without PFO) to elucidate the individual effects of MO and PFO, as well as their interaction, on brain functional networks. The main effect of PFO manifested exclusively in the FC among the visual, auditory, default mode, dorsal attention and salience networks. Furthermore, the interaction effect between MO and PFO was discerned in brain clusters of the left frontoparietal network and lingual gyrus network, as well as the internetwork FC between the left frontoparietal network and the default mode network (DMN), the occipital pole and medial visual networks, and the dorsal attention and salience networks. Our findings suggest that the presence of a PFO shunt in patients with MO is accompanied by various FC changes within and across networks. These changes elucidate the intricate mechanisms linked to PFO-associated migraines and provide a basis for identifying novel noninvasive biomarkers.

Impacted spike frequency adaptation associated with reduction of KCNQ2/3 exacerbates seizure activity in temporal lobe epilepsy.

Numerous epilepsy-related genes have been identified in recent decades by unbiased genome-wide screens. However, the available druggable targets for temporal lobe epilepsy (TLE) remain limited. Furthermore, a substantial pool of candidate genes potentially applicable to TLE therapy awaits further validation. In this study, we reveal the significant role of KCNQ2 and KCNQ3, two M-type potassium channel genes, in the onset of seizures in TLE. Our investigation began with a quantitative analysis of two publicly available TLE patient databases to establish a correlation between seizure onset and the downregulated expression of KCNQ2/3. We then replicated these pathological changes in a pilocarpine seizure mouse model and observed a decrease in spike frequency adaptation due to the affected M-currents in dentate gyrus granule neurons. In addition, we performed a small-scale simulation of the dentate gyrus network and confirmed that the impaired spike frequency adaptation of granule cells facilitated epileptiform activity throughout the network. This, in turn, resulted in prolonged seizure duration and reduced interictal intervals. Our findings shed light on an underlying mechanism contributing to ictogenesis in the TLE hippocampus and suggest a promising target for the development of antiepileptic drugs.

The Assimilation of Novel Information into Schemata and Its Efficient Consolidation.

Schemata enhance memory formation for related novel information. This is true even when this information is neutral with respect to schema-driven expectations. This assimilation of novel information into schemata has been attributed to more effective organizational processing that leads to more referential connections with the activated associative schema network. Animal data suggest that systems consolidation of novel assimilated information is also accelerated. In the current study, we used both multivariate and univariate fMRI analyses to provide further support for these proposals and to elucidate the neural underpinning of these processes. Twenty-eight participants (5 male) overlearned fictitious schemata for 7 weeks and then encoded novel related and control facts in the scanner. These facts were retrieved both immediately and 2 weeks later, also in the scanner. Our results conceptually replicate previous findings with respect to enhanced vmPFC-hippocampus coupling during encoding of novel related information and point to a prior knowledge effect that is distinct from situations where novel information is experienced as congruent or incongruent with a schema. Moreover, the combination of both multivariate and univariate results further specified the proposed contributions of the vmPFC, precuneus and angular gyrus network to the more efficient encoding of schema-related information. In addition, our data provide further evidence for more efficient systems consolidation of such novel schema-related and potentially assimilated information.SIGNIFICANCE STATEMENT Our prior knowledge in a certain domain, often termed schema, heavily influences whether and how we form memories for novel information that can be related to them. The results of the current study show how a ventromedial prefrontal-precuneal-angular network contributes to the more efficient encoding of novel related information. Furthermore, the observed increase in prefrontal-hippocampal coupling during this process points to a critical distinction from the previously described mechanisms supporting the encoding of information that is experienced as congruent with schema-driven expectations. In addition, we find further support for the proposal based on animal data that prior knowledge enhances also the consolidation of schema-related information.

Altered synaptic plasticity of the longitudinal dentate gyrus network in noise-induced anxiety

SummaryAnxiety is characteristic comorbidity of noise-induced hearing loss (NIHL), which causes physiological changes within the dentate gyrus (DG), a subfield of the hippocampus that modulates anxiety. However, which DG circuit underlies hearing loss-induced anxiety remains unknown. We utilize an NIHL mouse model to investigate short- and long-term synaptic plasticity in DG networks. The recently discovered longitudinal DG-DG network is a collateral of DG neurons synaptically connected with neighboring DG neurons and displays robust synaptic efficacy and plasticity. Furthermore, animals with NIHL demonstrate increased anxiety-like behaviors similar to a response to chronic restraint stress. These behaviors are concurrent with enhanced synaptic responsiveness and suppressed short- and long-term synaptic plasticity in the longitudinal DG-DG network but not in the transverse DG-CA3 connection. These findings suggest that DG-related anxiety is typified by synaptic alteration in the longitudinal DG-DG network.

Parvalbumin expressing interneurons control spike-phase coupling of hippocampal cells to theta oscillations

Encoding of information by hippocampal neurons is defined by the number and the timing of action potentials generated relative to ongoing network oscillations in the theta (5–14 Hz), gamma (30–80 Hz) and ripple frequency range (150–200 Hz). The exact mechanisms underlying the temporal coupling of action potentials of hippocampal cells to the phase of rhythmic network activity are not fully understood. One critical determinant of action potential timing is synaptic inhibition provided by a complex network of Gamma-amino-hydroxy-butyric acid releasing (GABAergic) interneurons. Among the various GABAergic cell types, particularly Parvalbumin-expressing cells are powerful regulators of neuronal activity. Here we silenced Parvalbumin-expressing interneurons in hippocampal areas CA1 and the dentate gyrus in freely moving mice using the optogenetic silencing tool eNpHR to determine their influence on spike timing in principal cells. During optogenetic inhibition of Parvalbumin-expressing cells, local field potential recordings revealed no change in power or frequency of CA1 or dentate gyrus network oscillations. However, CA1 pyramidal neurons exhibited significantly reduced spike-phase coupling to CA1 theta, but not gamma or ripple oscillations. These data suggest that hippocampal Parvalbumin-expressing interneurons are particularly important for an intact theta-based temporal coding scheme of hippocampal principal cell populations.

Morris Water Maze and Contextual Fear Conditioning Tasks to Evaluate Cognitive Functions Associated With Adult Hippocampal Neurogenesis.

New neurons are continuously generated and functionally integrated into the dentate gyrus (DG) network during the adult lifespan of most mammals. The hippocampus is a crucial structure for spatial learning and memory, and the addition of new neurons into the DG circuitry of rodents seems to be a key element for these processes to occur. The Morris water maze (MWM) and contextual fear conditioning (CFC) are among the most commonly used hippocampus-dependent behavioral tasks to study episodic-like learning and memory in rodents. While the functional contribution of adult hippocampal neurogenesis (AHN) through these paradigms has been widely addressed, results have generated controversial findings. In this review, we analyze and discuss possible factors in the experimental methods that could explain the inconsistent results among AHN studies; moreover, we provide specific suggestions for the design of more sensitive protocols to assess AHN-mediated learning and memory functions.

Research on Network Model of Dentate Gyrus Based on Bionics.

As an important part of the brain, the dentate gyrus has an irreplaceable effect in the process of memory generation. Therefore, the study of the dentate gyrus model has important significance in the study of brain function. This paper, combined with the real anatomical structure of the dentate gyrus, is based on the existing calculation model for studying the pathological state of the dentate gyrus, a network model of dentate gyrus based on bionics. Then, a simulation experiment on the normal dentate gyrus model is performed on the NEURON platform, the output of each neuron in the model is observed, and a conclusion that the improved model can respond to stimuli, generate action potentials, and transmit them along with the neural network is made. At the same time, the output results are compared with the existing pathological models, and the characteristics of the stimulus response between neurons in the dentate gyrus under normal physiological conditions are obtained. Finally, according to the semiquantitative classification definition and quantitative classification definition of the small-world network, the model is analyzed, and it is concluded that the improved dentate gyrus network model has small-world characteristics. Therefore, the neurons in the improved dentate gyrus model are tightly connected and can simulate the real dentate gyrus to a certain extent.

Functional MRI-based study on neuromechanism of trans-auricular vagus nerve stimulation for treatment-resistant depression

To explore the neuromechanism of trans-auricular vagus nerve stimulation (taVNS) for treatment-resistant depression(TRD) based on functional brain network. Twenty-eight patients with TRD were recruited from the psychiatric clinic or by the advertisement. The patients were treated by taVNS (5 Hz/20 Hz, 4-8 mA) at the auricular concha for 30 min, twice daily for 8 weeks. The symptom severity was assessed by 17-Item Hamilton Rating Scale for Depression (HAMD-17, ranging from 0 to 54 points, higher score indicates more severe conditions). Resting state fMRI data of the brain were collected to analyze changes of the regional homogeneity (ReHo), amplitude of low frequency fluctuation (ALFF) and resting state functional connectivity (rs-FC) before and after 8 weeks' taVNS by using DPARSF toolkit and the correlation between the rs-FC and clinical scale score was analyzed to assess the related brain mechanisms. Twenty-four patients finished the clinical study, and 23 patients finished the fMRI tests. After the treatment, the average score of HAMD-17 was significantly decreased (P<0.01), with the reduction rate being 66.95%; the ALFF and ReHo values of the right insula and putamen, the ReHo values of the right caudate nucleus and thalamus, as well as the rs-FC values of the right insula, left superior frontal gyrus and middle frontal gyrus were all significantly decreased (P<0.05). The reduced ReHo value in the right insular lobe was negatively correlated with the HAMD score reduction (P=0.001, r=-0.633). The rs-FC values of the right insula lobe and the left superior frontal gyrus were significantly negatively correlated with the reduced HAMD score(P=0.012, r=-0.512). TaVNS significantly relieves the symptoms of TRD patients, which may be related to its functions in regulating functional changes of the right insular and the left frontal gyrus network, and the limbic area and basal ganglia.

Effects of Methamphetamine on Within- and Between-Network Connectivity in Healthy Adults.

Methamphetamine (MA) abuse remains an urgent public health problem. Understanding how the drug affects brain function will help to identify how it leads to abuse and dependence. Previous studies indicate that MA and other stimulants have complex effects on resting state functional connectivity. Here, we used a hypothesis-free approach to examine the acute effects of MA (20 mg oral) versus placebo on neural connectivity in healthy adults. Using networks identified by an independent component analysis with placebo data, we examined the effects of MA on connectivity within and between resting state networks. The drug did not significantly alter connectivity within networks. MA did alter connectivity between some networks: it increased connectivity between both the thalamus and cerebellum to sensorimotor and middle temporal gyrus. However, MA decreased connectivity between sensorimotor and middle temporal gyrus networks. MA produced its expected subjective effects, but these were not significantly related to connectivity. The findings extend our knowledge of how MA affects connectivity, by reporting that it affects between-network connectivity but not within-network connectivity. Future studies with other behavioral measures may reveal relationships between the neural and behavioral actions of the drug.

Resilience to acute musculoskeletal pain: resting-state functional connectivity of regions associated with gray matter density differences following induction of low-back pain

Musculoskeletal pain is an aversive experience that exists within a variety of conditions and can result in significant impairment for individuals. Gaining greater understanding of the factors related to pain vulnerability and resilience to musculoskeletal pain may help target at-risk individuals for early intervention. This analysis builds on our previous work identifying regions where lower gray matter density (GMD) was associated with individuals who report pain following standardized, exercise induced musculoskeletal injury. Here we sought to examine the relationship between baseline resting state functional connectivity (rsFC) in a priori regions and networks, and delayed onset muscle soreness (DOMS) pain intensity following a single session of eccentric exercise. The present study is a secondary analysis from a portion of a larger, blinded, randomized experimental trial. All participants were healthy adults between the ages of 18 and 40 years recruited from the university and surrounding community. The primary outcome measure was functional connectivity assessed by using T2 rest image. Participants completed a baseline functional MRI scan and a high intensity trunk exercise protocol to induce DOMS in the erector spinae. Pain intensity ratings were collected 48-hours later. rsFC from four seed regions and three networks were separately regressed on pain intensity scores. Our results revealed that connectivity between left middle frontal gyrus, the left occipital gyrus and cerebellar network seeds and clusters associated with discriminative, emotional, and cognitive aspects of pain were associated with lower post-DOMS pain. Our results provide key support for the role of structural and functional coherence in regional and network connectivity in adaptive pain response and represent an important step in clarifying neural mechanisms of resilience to clinically relevant pain. Resilience to clinically relevant pain is associated with aspects of regional and network neural coherence. Investigations of pain modulatory capacity that integrate multimodal neuroimaging metrics are called for. R01AT006334, PI Dr. Mark Bishop.

Effects of Maternal Fish Oil and/or 5-Methyl-Tetrahydrofolate Supplementation during Pregnancy on Offspring Brain Resting-State at 10 Years Old: A Follow-Up Study from the NUHEAL Randomized Controlled Trial.

Recent studies have shown that maternal supplementation with folate and long-chain polyunsaturated fatty acids (LC-PUFAs) during pregnancy may affect children’s brain development. We aimed at examining the potential long-term effect of maternal supplementation with fish oil (FO) and/or 5-methyl-tetrahydrofolate (5-MTHF) on the brain functionality of offspring at the age of 9.5–10 years. The current study was conducted as a follow-up of the Spanish participants belonging to the Nutraceuticals for a Healthier Life (NUHEAL) project; 57 children were divided into groups according to mother’s supplementation and assessed through functional magnetic resonance imaging (fMRI) scanning and neurodevelopment testing. Independent component analysis and double regression methods were implemented to investigate plausible associations. Children born to mothers supplemented with FO (FO and FO + 5-MTHF groups, n = 33) showed weaker functional connectivity in the default mode (DM) (angular gyrus), the sensorimotor (SM) (motor and somatosensory cortices) and the fronto-parietal (FP) (angular gyrus) networks compared to the No-FO group (placebo and 5-MTHF groups, n = 24) (PFWE < 0.05). Furthermore, no differences were found regarding the neuropsychological tests, except for a trend of better results in an object recall (memory) test. Considering the No-FO group, the aforementioned networks were associated negatively with attention and speed-processing functions. Mother’s FO supplementation during pregnancy seems to be able to shape resting-state network functioning in their children at school age and appears to produce long-term effects on children´s cognitive processing.

Association Between Resting-State Functional Connectivity and Reading in Two Writing Systems in Japanese Children With and Without Developmental Dyslexia.

Introduction: Japanese is unique, as it features two distinct writing systems that share the same sound and meaning: syllabic Hiragana and logographic Kanji scripts. Acquired reading difficulties in Hiragana and Kanji have been examined in older patients with brain lesions. However, the precise mechanisms underlying deficits in developmental dyslexia (DD) remain unclear.Materials and Methods: The neural signatures of Japanese children with DD were examined by using resting-state functional magnetic resonance imaging. We examined 22 dyslexic and 46 typically developing (TD) children, aged 7–14 years.Results: Reading performance in each writing system was correlated with neural connectivity in TD children. In contrast, in children with DD, weak associations between neural connectivity and reading performance were observed. In TD children, Hiragana-reading fluency was positively correlated with the left fusiform gyrus network. No significant correlations between Hiragana fluency and neural connectivity were observed in children with DD. Correspondingly, there were fewer correlations between Kanji accuracy and strength of reading-related connectivity in children with DD, whereas positive correlations with the bilateral fronto-parietal network and negative correlations with the left fusiform network were found in TD children.Discussion: These data suggest that positive and negative coupling with neural connectivity is associated with developing Japanese reading skills. Further, different neural connectivity correlations between Hiragana fluency and Kanji accuracy were detected in TD children but less in children with DD.Conclusion: The two writing systems may exert differential effects and deficits on reading in healthy children and in children with DD, respectively.Impact statementThis is the first study of the precise neurobiological characteristics of dyslexia in Japanese children. Because the Japanese language uniquely features two writing systems and there is a low prevalence of dyslexia among Japanese children, our results from an examination of this population provided unique insights into the neural bases of dyslexia. Using resting-state functional magnetic resonance imaging, we determined possible networks that may be implicated in the reading deficits present in these and other children who suffer from dyslexia.

Age-related differences in structural and functional prefrontal networks during a logical reasoning task.

In logical reasoning, difficulties in inhibition of currently-held beliefs may lead to unwarranted conclusions, known as belief bias. Aging is associated with difficulties in inhibitory control, which may lead to deficits in inhibition of currently-held beliefs. No study to date, however, has investigated the underlying neural substrates of age-related differences in logical reasoning and the impact of belief load. The aim of the present study was to delineate age differences in brain activity during a syllogistic logical reasoning task while the believability load of logical inferences was manipulated. Twenty-nine, healthy, younger and thirty, healthy, older adults (males and females) completed a functional magnetic resonance imaging experiment in which they were asked to determine the logical validity of conclusions. Unlike younger adults, older adults engaged a large-scale network including anterior cingulate cortex and inferior frontal gyrus during conclusion stage. Our functional connectivity results suggest that while older adults engaged the anterior cingulate network to overcome their intuitive responses for believable inferences, the inferior frontal gyrus network contributed to higher control over responses during both believable and unbelievable conditions. Our functional results were further supported by structure-function-behavior analyses indicating the importance of cingulum bundle and uncinate fasciculus integrity in rejection of believable statements. These novel findings lend evidence for age-related differences in belief bias, with potentially important implications for decision making where currently-held beliefs and given assumptions are in conflict.

GABA bouton subpopulations in the human dentate gyrus are differentially altered in mesial temporal lobe epilepsy.

Medically intractable temporal lobe epilepsy is a devastating disease, for which surgical removal of the seizure onset zone is the only known cure. Multiple studies have found evidence of abnormal dentate gyrus network circuitry in human mesial temporal lobe epilepsy (MTLE). Principal neurons within the dentate gyrus gate entorhinal input into the hippocampus, providing a critical step in information processing. Crucial to that role are GABA-expressing neurons, particularly parvalbumin (PV)-expressing basket cells (PVBCs) and chandelier cells (PVChCs), which provide strong, temporally coordinated inhibitory signals. Alterations in PVBC and PVChC boutons have been described in epilepsy, but the value of these studies has been limited due to methodological hurdles associated with studying human tissue. We developed a multilabel immunofluorescence confocal microscopy and a custom segmentation algorithm to quantitatively assess PVBC and PVChC bouton densities and to infer relative synaptic protein content in the human dentate gyrus. Using en bloc specimens from MTLE subjects with and without hippocampal sclerosis, paired with nonepileptic controls, we demonstrate the utility of this approach for detecting cell-type specific synaptic alterations. Specifically, we found increased density of PVBC boutons, while PVChC boutons decreased significantly in the dentate granule cell layer of subjects with hippocampal sclerosis compared with matched controls. In contrast, bouton densities for either PV-positive cell type did not differ between epileptic subjects without sclerosis and matched controls. These results may explain conflicting findings from previous studies that have reported both preserved and decreased PV bouton densities and establish a new standard for quantitative assessment of interneuron boutons in epilepsy.NEW & NOTEWORTHY A state-of-the-art, multilabel immunofluorescence confocal microscopy and custom segmentation algorithm technique, developed previously for studying synapses in the human prefrontal cortex, was modified to study the hippocampal dentate gyrus in specimens surgically removed from patients with temporal lobe epilepsy. The authors discovered that chandelier and basket cell boutons in the human dentate gyrus are differentially altered in mesial temporal lobe epilepsy.

Semantic deficits in ALS related to right lingual/fusiform gyrus network involvement.

BackgroundThe clinicopathological continuity between amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) is well known. Although ALS demonstrates language symptoms similar to FTLD, including semantic dementia, word reading impairments in ALS have not been well studied. “Jukujikun” are Kanji-written words with irregular pronunciation comparable to “exception words” and useful for detecting semantic deficits in Japan. We conducted a cross-sectional study to investigate Jukujikun reading impairments and related network changes in ALS.MethodsWe enrolled 71 ALS patients and 69 healthy controls (HCs). Age-, sex-, and education matched HCs were recruited from another cohort study concurrently with patient registration. We examined neuropsychological factors including low frequency Jukujikun reading. We performed resting-state functional magnetic resonance imaging with voxel-based graph analysis on a subset of participants who agreed.FindingsLow frequency Jukujikun score was decreased in ALS (15·0[11·0–19·0](median[25–75 percentile])) compared with HCs (19·0[17·3–20·0]) (p < 0·001, effect size = 0·43). Fifty-two percent of ALS (N = 37) with low frequency Jukujikun score ≤ 5th percentile of HCs was classified as ALS with positive Jukujikun deficit (ALS-JD+). Compared with HCs, ALS-JD+ showed decreased degree centrality in the right lingual/fusiform gyrus, where connectivities with regions associated with word perception, semantic processing, or speech production were decreased. They also showed increased degree centrality in the left inferior/middle temporal gyrus, associated with increased connectivities involving semantic processing.InterpretationDysfunction of the “hub” in the right lingual/fusiform gyrus can affect semantic deficit in ALS. Considering neuropsychological symptoms as network impairments is vital for understanding various diseases.FundMHLW and MEXT, Japan.

Semantic Deficits in ALS Related to Right Lingual/Fusiform Gyrus Network Involvement: A Case-Control Study

Background: The clinicopathological continuity between amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) is well known. Although patients with ALS demonstrate similar language symptoms to patients with FTLD, including semantic dementia, word reading impairments in ALS have not been well studied. are kanji-written with irregular pronunciation that applies to exception words and are useful for detecting semantic deficits in Japan. We investigated Jukujikun reading impairments and related changes in resting-state networks in patients with ALS. Methods: We enrolled 140 participants, including 71 ALS patients and 69 healthy controls. We examined demographic and comprehensive neuropsychological factors, including Jukujikun. We also performed resting-state functional magnetic resonance imaging with voxel-based graph analysis on a subset of participants who agreed to participate in the imaging study to investigate the regions and related networks associated with Jukujikun impairments in ALS. Findings: Fifty-two percent of ALS patients (N=37) exhibited a significantly reduced score in Jukujikun reading compared with controls. We classified those patients as ALS with positive Jukujikun deficit (ALS-JD+) and the other patients as ALS with negative deficit (ALS-JD-). Resting-state network analysis showed significantly decreased degree centrality in the right fusiform/lingual gyrus and increased degree centrality in the left inferior/middle temporal gyrus in ALS-JD+ compared with ALS-JD- and controls. Seed-based analysis also revealed that the dysfunction in the right fusiform/lingual gyrus depended on decreased connectivity with regions associated with visual word perception, semantic processing, and speech. On the other hand, the observed increased degree centrality in the left inferior/middle temporal gyrus was derived from regions related to semantic processing. Interpretation Dysfunction of the hub in the right fusiform/lingual gyrus can affect semantic deficit in ALS. Considering neuropsychological symptoms as network impairments is vital for understanding various diseases. Funding MHLW and MEXT, Japan. Funding Statement: MHLW and MEXT, Japan. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The study conformed to the Ethical Guidelines for Medical and Health Research Involving Human Subjects endorsed by the Japanese government. The study protocol was approved by the Ethics Review Committee of the Nagoya University Graduate School of Medicine, and written informed consent was obtained from all participants.

Lack of β-amyloid cleaving enzyme-1 (BACE1) impairs long-term synaptic plasticity but enhances granule cell excitability and oscillatory activity in the dentate gyrus in vivo.

BACE1 is a β-secretase involved in the cleavage of amyloid precursor protein and the pathogenesis of Alzheimer's disease (AD). The entorhinal cortex and the dentate gyrus are important for learning and memory, which are affected in the early stages of AD. Since BACE1 is a potential target for AD therapy, it is crucial to understand its physiological role in these brain regions. Here, we examined the function of BACE1 in the dentate gyrus. We show that loss of BACE1 in the dentate gyrus leads to increased granule cell excitability, indicated by enhanced efficiency of synaptic potentials to generate granule cell spikes. The increase in granule cell excitability was accompanied by prolonged paired-pulse inhibition, altered network gamma oscillations, and impaired synaptic plasticity at entorhinal-dentate synapses of the perforant path. In summary, this is the first detailed electrophysiological study of BACE1 deletion at the network level in vivo. The results suggest that BACE1 is important for normal dentate gyrus network function. This has implications for the use of BACE1 inhibitors as therapeutics for AD therapy, since BACE1 inhibition could similarly disrupt synaptic plasticity and excitability in the entorhinal-dentate circuitry.

Frequency specific resting state functional abnormalities in psychosis.

Resting state functional magnetic resonance imaging studies of psychosis have focused primarily on the amplitude of low-frequency fluctuations in the blood oxygen level dependent (BOLD) signal ranging from .01 to 0.1 Hz. Few studies, however, have investigated the amplitude of frequency fluctuations within discrete frequency bands and higher than 0.1 Hz in patients with psychosis at different illness stages. We investigated BOLD signal within three frequency ranges including slow-4 (.027-.073 Hz), slow-3 (.074-0.198 Hz) and slow-2 (0.199-0.25 Hz) in 89 patients with either first-episode or chronic psychosis and 119 healthy volunteers. We investigated the amplitude of frequency fluctuations within three frequency bands using 47 regions-of-interest placed within 14 known resting state networks derived using group independent component analysis. There were significant group x frequency interactions for the visual and motor cortex networks, with the largest significant group differences (patients < healthy volunteers) evident in slow-4 and slow-3, respectively. Also, healthy volunteers had an overall higher amplitude of frequency fluctuations compared to patients across the three frequency ranges in the visual cortex, dorsal attention and motor cortex networks with the opposite effect (patients > healthy volunteers) evident within the salience and frontal gyrus networks. Subsequent analyses indicated that these effects were evident in both first-episode and chronic patients. Our study provides new data regarding the importance of BOLD signal fluctuations within different frequency bands in the neurobiology of psychosis.