Cortical Pathways Research Articles

Feature selectivity and invariance in marsupial primary visual cortex.

A fundamental question in sensory neuroscience revolves around how neurons represent complex visual stimuli. In mammalian primary visual cortex (V1), neurons decode intricate visual features to identify objects, with most being selective for edge orientation, but with half of those also developing invariance to edge position within their receptive fields. Position invariance allows cells to continue to code an edge even when it moves around. Combining feature selectivity and invariance is integral to successful object recognition. Considering the marsupial-eutherian divergence 160million years ago, we explored whether feature selectivity and invariance was similar in marsupials and eutherians. We recovered the spatial filters and non-linear processing characteristics of the receptive fields of neurons in wallaby V1 and compared them with previous results from cat cortex. We stimulated the neurons in V1 with white Gaussian noise and analysed responses using the non-linear input model. Wallabies exhibit the same high percentage of orientation selective neurons as cats. However, in wallabies we observed a notably higher prevalence of neurons with three or more filters compared to cats. We show that having three or more filters substantially increases phase invariance in the V1s of both species, but that wallaby V1 accentuates this feature, suggesting that the species condenses more processing into the earliest cortical stage. These findings suggest that evolution has led to more than one solution to the problem of creating complex visual processing strategies. KEY POINTS: Previous studies have shown that the primary visual cortex (V1) in mammals is essential for processing complex visual stimuli, with neurons displaying selectivity for edge orientation and position. This research explores whether the visual processing mechanisms in marsupials, such as wallabies, are similar to those in eutherian mammals (e.g. cats). The study found that wallabies have a higher prevalence of neurons with multiple spatial filters in V1, indicating more complex visual processing. Using a non-linear input model, we demonstrated that neurons with three or more filters increase phase invariance. These findings suggest that marsupials and eutherian mammals have evolved similar strategies for visual processing, but marsupials have condensed more capacity to build phase invariance into the first step in the cortical pathway.

Higher-order cortical and thalamic pathways shape visual processing streams in the mouse cortex.

Mammalian visual functions rely on distributed processing across interconnected cortical and subcortical regions. In higher-order visual areas (HVAs), visual features are processed in specialized streams that integrate feedforward and higher-order inputs from intracortical and thalamocortical pathways. However, the precise circuit organization responsible for HVA specialization remains unclear. We investigated the cellular architecture of primary visual cortex (V1) and higher-order visual pathways in the mouse, focusing on their roles in shaping visual representations. Using invivo functional imaging and neural circuit tracing, we found that HVAs preferentially receive inputs from both V1 and higher-order pathways tuned to similar spatiotemporal properties, with the strongest selectivity seen in layer 2/3 neurons. These neurons exhibit target-specific tuning and sublaminar specificity in their projections, reflecting cell-type-specific visual information flow. In contrast, HVA layer 5 pathways nonspecifically broadcast visual signals across cortical areas, suggesting a role in distributing HVA outputs. Additionally, thalamocortical pathways from the lateral posterior thalamic nucleus (LP) provide highly specific, nearly non-overlapping visual inputs to HVAs, complementing intracortical inputs and contributing to input functional diversity. Our findings suggest that the convergence of laminar and cell-type-specific pathways V1 and higher-order intracortical and thalamocortical pathways plays a key role in shaping the functional specialization and diversity of HVAs.

Insights from the Evolving Model of Two Cortical Visual Pathways.

The two cortical visual pathways framework has had a profound influence on theories and empirical studies of the visual system for over 40 years. By grounding physiological responses and behavior in neuroanatomy, the framework provided a critical guide for understanding vision. Although the framework has evolved over time, as our understanding of the physiology and neuroanatomy expanded, cortical visual processing is still often conceptualized as two separate pathways emerging from the primary visual cortex that support distinct behaviors ("what" vs. "where/how"). Here, we take a historical perspective and review the continuing evolution of the framework, discussing key and often overlooked insights. Rather than a functional and neuroanatomical bifurcation into two independent serial, hierarchical pathways, the current evidence points to two highly recurrent heterarchies with heterogeneous connections to cortical regions and subcortical structures that flexibly support a wide variety of behaviors. Although many of the simplifying assumptions of the framework are belied by the evidence gathered since its initial proposal, the core insight of grounding function and behavior in neuroanatomy remains fundamental. Given this perspective, we highlight critical open questions and the need for a better understanding of neuroanatomy, particularly in the human.

MDMA modulates human sensorimotor cortical pathways during gentle touch

Abstract The stimulant ± 3,4-methylenedioxymethamphetamine (MDMA) has been shown to enhance the perceived pleasantness of touch. However, the underlying neural processes contributing to touch-related effects of MDMA are not well understood. Using a double-blind, randomized, within-subject design, this study used fMRI to examine hemodynamic changes following MDMA (1.5 mg/kg) vs. lactose placebo administration during gentle touch stimulation in a healthy sample (N = 18). Participants were stroked on the forearm at a slower, more pleasant (3 cm/s), and a faster (30 cm/s), less pleasant speed. For the MDMA session, participants’ affective ratings of touch stimulation were higher than their placebo ratings. Increase in plasma oxytocin (OT) levels was also greater during the MDMA session. On the neural level, primary sensorimotor areas showed greater hemodynamic changes during the MDMA than during the placebo session for both touch speeds, indicating a relatively early influence within somatosensory pathways. Changes in OT levels showed an interaction with drug in an occipitotemporal region, area MT+, associated with motion perception. However, posterior insula did not show preferential activation for the slower stroking speed. These initial findings provide a basis for extending our knowledge of the neural processes underlying the effect of MDMA on affective touch.

EPS mid-career prize: An integrated framework for the learning, recognition and interpretation of words.

In this article, I review the evidence on the involvement of sleep and consolidation in word learning and processing during language comprehension, focusing on implications for theory. The theoretical basis for the review is a complementary systems account of word learning involving flexible (hippocampal) and stable (cortical) pathways to lexical knowledge. I argue that the accumulated data are consistent with a role for both pathways in both learning and recognition of lexical items, with sleep and consolidation supporting the transfer of recent experience between the pathways. The level of involvement of each pathway is dependent on key factors, such as consistency with prior knowledge in the case of learning, and reliance on context and/or automaticity in the case of recognition. As a consequence, the notion of a mental lexicon cannot really be restricted to just the listener's stable knowledge about words: flexible knowledge and recent experiences are also important. Furthermore, I argue that the flexible pathway plays a critical role even in the absence of new lexical items. The available evidence suggests that this pathway encodes (and potentially consolidates) recent linguistic experiences, providing potential benefits to interpretation of subsequent language and the long-term retention of knowledge. In conclusion, I propose that a dual-pathway account incorporating both flexibility and stability is necessary to explain the learning, recognition, and interpretation of words.

High-frequency episodic migraine: Time for its recognition as a migraine subtype?

High-frequency episodic migraine (HFEM) has gained attention in the field of headache research and clinical practice. In this narrative review, we analyzed the available literature to assess the evidence that could help decide whether HFEM may represent a distinct clinical and/or biological entity within the migraine spectrum. The output of the literature search included 61 papers that were allocated to one of the following topics: (i) socio-demographic features and burden; (ii) clinical and therapeutic aspects; (iii) pathophysiology; and (iv) classification. Multiple features differentiate subjects with HFEM from low-frequency episodic migraine and from chronic migraine: education, employment rates, quality of life, disability and psychiatric comorbidities load. Some evidence also suggests that HFEM bears a specific profile of activation of cortical and spinal pain-related pathways, possibly related to maladaptive plasticity. Subjects with HFEM bear a distinctive clinical and socio-demographic profile within the episodic migraine group, with a higher disease burden and an increased risk of transitioning to chronic migraine. Recognizing HFEM as a distinct entity is an opportunity for the better understanding of migraine and the spectrum of frequency with which it can manifest, as well as for stimulating further research and more adequate public health approaches.

Molecular programs guiding arealization of descending cortical pathways.

Layer 5 extratelencephalic (ET) neurons are present across neocortical areas and send axons to multiple subcortical targets1-6. Two cardinal subtypes exist7,8: (1) Slco2a1-expressing neurons (ETdist), which predominate in the motor cortex and project distally to the pons, medulla and spinal cord; and (2) Nprs1- or Hpgd-expressing neurons (ETprox), which predominate in the visual cortex and project more proximally to the pons and thalamus. An understanding of how area-specific ETdist and ETprox emerge during development is important because they are critical for fine motor skills and are susceptible to spinal cord injury and amyotrophic lateral sclerosis9-12. Here, using cross-areal mapping of axonal projections in the mouse neocortex, we identify the subtype-specific developmental dynamics of ET neurons. Whereas subsets of ETprox emerge by pruning of ETdist axons, others emerge de novo. We outline corresponding subtype-specific developmental transcriptional programs using single-nucleus sequencing. Leveraging these findings, we use postnatal in vivo knockdown of subtype-specific transcription factors to reprogram ET neuron connectivity towards more proximal targets. Together, these results show the functional transcriptional programs driving ET neuron diversity and uncover cell subtype-specific gene regulatory networks that can be manipulated to direct target specificity in motor corticofugal pathways.

Hereditary Patterns and Genetic Associations in Obsessive-Compulsive Disorder (OCD): Neuropsychiatric Insights, Genetic Influences, and Treatment Perspectives.

Obsessive-Compulsive Disorder (OCD), a prevalent neuropsychiatric condition, affects approximately 2%-3% of the global population. This paper provides an extensive overview of OCD, detailing its clinical manifestations, neurobiological underpinnings, and therapeutic approaches. It examines OCD's classification shift in the DSM-5, the role of the cortico-striatothalamo- cortical pathway in its development, and the various factors contributing to its etiology, such as genes, environmental factors, and genetic predispositions. The challenges in diagnosing OCD and the effectiveness of both psychological and pharmacotherapeutic treatments are discussed. The paper also highlights the significant overlap between OCD and other mental health disorders, emphasizing its impact on global disability. Moreover, the role of genetic factors in OCD, including twin studies and gene association studies, is elaborated, underscoring the complex interplay of hereditary and environmental influences in its manifestation. The review further delves into the polygenic nature of OCD, illustrating how multiple genes contribute to its development, and explores the implications of genetic studies in understanding the disorder's complexity. Additionally, this research study delves into the concept of polygenic inheritance in complex diseases, highlighting the role of multiple genes in increasing OCD risk. A Genome-wide Association Study (GWAS) is employed to assess Single Nucleotide Polymorphisms (SNPs) to unearth genetic associations with OCD. This comprehensive analysis provides valuable insights into OCD's genetic landscape, paving the way for enhanced diagnostic approaches and treatment modalities.

Structural Development of Speech Networks in Young Children at Risk for Speech Disorder.

Characterizing the structural development of the neural speech network in early childhood is important for understanding speech acquisition. To investigate speech in the developing brain, 94 children aged 4-7-years-old at risk for early speech disorder were scanned using diffusion weighted imaging (DWI) magnetic resonance imaging (MRI). Additionally, each child completed the Syllable Repetition Task (SRT), a validated measure of phoneme articulation. The DWI data were modeled using multi-compartment restriction spectrum imaging (RSI) to measure restricted and hindered diffusion properties in both grey and white matter. Consequently, we analyzed the diffusion data using both whole brain analysis, and automated fiber quantification (AFQ) analysis to establish tract profiles for each of six fiber pathways thought to be important for supporting speech development. In the whole brain analysis, we found that SRT performance was associated with restricted diffusion in bilateral inferior frontal gyrus ( pars opercularis ), right pre-supplementary/ supplementary motor area (pre-SMA/SMA), and bilateral cerebellar grey matter ( p < .005). Age moderated these associations in left pars opercularis and frontal aslant tract (FAT). However, in both cases only the cerebellar findings survived a cluster correction. We also found associations between SRT performance and restricted diffusion in cortical association fiber pathways, especially left FAT, and in the cerebellar peduncles. Analyses using automatic fiber quantification (AFQ) highlighted differences in high and low performing children along specific tract profiles, most notably in left but not right FAT. These findings suggest that individual differences in speech performance are reflected in structural gray and white matter differences as measured by restricted and hindered diffusion metrics, and offer important insights into developing brain networks supporting speech in very young children.

A spatial map: a propitious choice for constraining the binding problem.

Many studies have shown that the human visual system has two major functionally distinct cortical visual pathways: a ventral pathway, thought to be important for object recognition, and a dorsal pathway, thought to be important for spatial cognition. According to our and others previous studies, artificial neural networks with two segregated pathways can determine objects' identities and locations more accurately and efficiently than one-pathway artificial neural networks. In addition, we showed that these two segregated artificial cortical visual pathways can each process identity and spatial information of visual objects independently and differently. However, when using such networks to process multiple objects' identities and locations, a binding problem arises because the networks may not associate each object's identity with its location correctly. In a previous study, we constrained the binding problem by training the artificial identity pathway to retain relative location information of objects. This design uses a location map to constrain the binding problem. One limitation of that study was that we only considered two attributes of our objects (identity and location) and only one possible map (location) for binding. However, typically the brain needs to process and bind many attributes of an object, and any of these attributes could be used to constrain the binding problem. In our current study, using visual objects with multiple attributes (identity, luminance, orientation, and location) that need to be recognized, we tried to find the best map (among an identity map, a luminance map, an orientation map, or a location map) to constrain the binding problem. We found that in our experimental simulations, when visual attributes are independent of each other, a location map is always a better choice than the other kinds of maps examined for constraining the binding problem. Our findings agree with previous neurophysiological findings that show that the organization or map in many visual cortical areas is primarily retinotopic or spatial.

Frequency dependence of human thresholds: both perceptual and vestibuloocular reflex thresholds.

Although perceptual thresholds have been widely studied, vestibuloocular reflex (VOR) thresholds have received less attention, so the relationship between VOR and perceptual thresholds remains unclear. We compared the frequency dependence of human VOR thresholds to human perceptual thresholds for yaw head rotation in both upright ("yaw rotation") and supine ("yaw tilt") positions, using the same human subjects and motion device. VOR thresholds were generally a little smaller than perceptual thresholds. We also found that horizontal VOR thresholds for both yaw rotation about an Earth-vertical axis and yaw tilt (yaw rotation about an Earth-horizontal axis) were relatively constant across four frequencies (0.2, 0.5, 1, and 2 Hz), with little difference between yaw rotation and yaw tilt VOR thresholds. For yaw tilt stimuli, perceptual thresholds were slightly lower at the lowest frequency and nearly constant at all other (higher) frequencies. However, for yaw rotation, perceptual thresholds increased significantly at the lowest frequency (0.2 Hz). We conclude 1) that VOR thresholds were relatively constant across frequency for both yaw rotation and yaw tilt, 2) that the known contributions of velocity storage to the VOR likely yielded these VOR thresholds that were similar for yaw rotation and yaw tilt for all frequencies tested, and 3) that the integration of otolith and horizontal canal signals during yaw tilt when supine contributes to stable perceptual thresholds, especially relative to the low-frequency perceptual thresholds recorded during yaw rotation.NEW & NOTEWORTHY We describe for the first time that human VOR thresholds differ from human forced-choice perceptual thresholds, with the difference especially evident at frequencies below 0.5 Hz. We also report that VOR thresholds are relatively constant across frequency for both yaw rotation and yaw tilt. These findings are consistent with the idea that high-pass filtering in cortical pathways impacts cognitive decision-making.

Functional Neurologic Disorders: The Role of Limbic System

IntroductionFunctional Neurological Disorders (FND), also called hysteria or conversion disorder, have represented a challenge over the centuries in terms of comprehension of the mechanisms responsible for symptoms which mimic neurological diseases without organic damage. Charcot considered hysteria primarily a hereditary disorder, but also considered that environmental factors including physical and emotional stress served as provoking factors. The prevailing etiologic theories of FND are psychosocial and still strongly dominated by the Freudian concept of conversion – a psychologic symptom is converted into a somatic symptom as a way of dealing with the distress of the symptom. However, physiologic studies with fMRI are necessary to understand the neurological mechanisms involved in FND symptoms. Convergent neuroimaging findings have implicated abnormal limbic-motor interactions in response to emotional stimuli in FND patients, demonstrated a possible role of the limbic system (LS) in FND neurophysiology.ObjectivesUnderstand the role of LS in the neurophysiologic mechanisms involve in FND.MethodsSystematic review of the literature published in PubMed, using the terms “Functional Neurological Disorders”, “Limbic System”, “Emotions”.ResultsPhysiologic studies of functional weakness and sensory loss reveal normal functioning of primary motor and sensory cortex, but abnormalities of premotor cortex and association cortices. This suggests a top-down influence creating the dysfunction during the action control. Indeed, fMRI studies with FND motor patients show a hypoactivation of cortical and subcortical motor pathways, and a hyperactivity in limbic areas related with an abnormal limbic regulation with increased amygdala activity. In fact, studies have found a dysfunction in the medial prefrontal areas in FDN patients suggesting that they might have an abnormal affective representation (AR) of self-relevant information encoded in this region, which can later induce specific behavioral patterns of thought interaction with sensorimotor circuits. The abnormal AR could be influence by a dysfunction in LS regulation. Indeed, emotions are one of the major factors influencing movement choice. Moreover, limbic structures, such as the amygdala, can be influenced by genetic factors and/or early life stress. Thus, abnormal functioning of LS could lead to functional disorders by deranged top-down control.ConclusionsIn conclusion, FND patients may have an abnormal AR and/or emotion regulation mechanisms possibly due to prior experience or partly genetically determined which interact with lower-order functions leading to the production of the functional symptoms, where LS have an important role. However, much further empiric research is needed to better understand this fascinating and debilitating condition, as well as to derive new perspectives for more efficient therapeutic interventions in these patients.Disclosure of InterestNone Declared

Cortical lipid metabolic pathway alteration of early Alzheimer’s disease and candidate drugs screen

BackgroundLipid metabolism changes occur in early Alzheimer's disease (AD) patients. Yet little is known about metabolic gene changes in early AD cortex.MethodsThe lipid metabolic genes selected from two datasets (GSE39420 and GSE118553) were analyzed with enrichment analysis. Protein–protein interaction network construction and correlation analyses were used to screen core genes. Literature analysis and molecular docking were applied to explore potential therapeutic drugs.Results60 lipid metabolic genes differentially expressed in early AD patients’ cortex were screened. Bioinformatics analyses revealed that up-regulated genes were mainly focused on mitochondrial fatty acid oxidation and mediating the activation of long-chain fatty acids, phosphoproteins, and cholesterol metabolism. Down-regulated genes were mainly focused on lipid transport, carboxylic acid metabolic process, and neuron apoptotic process. Literature reviews and molecular docking results indicated that ACSL1, ACSBG2, ACAA2, FABP3, ALDH5A1, and FFAR4 were core targets for lipid metabolism disorder and had a high binding affinity with compounds including adenosine phosphate, oxidized Photinus luciferin, BMS-488043, and candidate therapeutic drugs especially bisphenol A, benzo(a)pyrene, ethinyl estradiol.ConclusionsAD cortical lipid metabolism disorder was associated with the dysregulation of the PPAR signaling pathway, glycerophospholipid metabolism, adipocytokine signaling pathway, fatty acid biosynthesis, fatty acid degradation, ferroptosis, biosynthesis of unsaturated fatty acids, and fatty acid elongation. Candidate drugs including bisphenol A, benzo(a)pyrene, ethinyl estradiol, and active compounds including adenosine phosphate, oxidized Photinus luciferin, and BMS-488043 have potential therapeutic effects on cortical lipid metabolism disorder of early AD.

Are we aware of neural activity in primary visual cortex? A neuropsychological case study.

According to a seminal hypothesis stated by Crick and Koch in 1995, one is not aware of neural activity in primary visual cortex (V1) because this region lacks reciprocal connections with prefrontal cortex (PFC). We provide here a neuropsychological illustration of this hypothesis in a patient with a very rare form of cortical blindness: ventral and dorsal cortical pathways were lesioned bilaterally while V1 areas were partially preserved. Visual stimuli escaped conscious perception but still activated V1 regions that were functionally disconnected from PFC. These results are consistent with the hypothesis of a causal role of PFC in visual awareness.

Obesity affects brain cortex gene expression in an APOE genotype and sex dependent manner.

Obesity is the top modifiable risk factor for Alzheimer's disease. We hypothesized that high fat diet (HFD)-induced obesity alters brain transcriptomics in APOE-genotype and sex dependent manners. Here, we investigated interactions between HFD, APOE, and sex, using a knock-in mouse model of the human APOE3 and APOE4 alleles. Six-month-old APOE3-TR and APOE4-TR mice were treated with either HFD or control chow. After 4 months, total RNA was extracted from the cerebral cortices and analyzed by poly-A enriched RNA sequencing on the Illumina platform. Female mice demonstrated profound HFD-induced transcriptomic changes while there was little to no effect in males. In females, APOE3 brains demonstrated about five times more HFD-induced transcriptomic changes (399 up-regulated and 107 down-regulated genes) compared to APOE4 brains (30 up-regulated and 60 down-regulated). Unsupervised clustering analysis revealed two gene sets that responded to HFD in APOE3 mice but not in APOE4 mice. Pathway analysis demonstrated that HFD in APOE3 mice affected cortical pathways related to feeding behavior, blood circulation, circadian rhythms, extracellular matrix, and cell adhesion. Female mice and APOE3 mice have the strongest cortical transcriptomic responses to HFD related to feeding behavior and extracellular matrix remodeling. The relative lack of response of the APOE4 brain to stress associated with obesity may leave it more susceptible to additional stresses that occur with aging and in AD.

A multimodal approach connecting cortical and behavioural responses to the visual continuity illusion.

In their recently published study, Gil, Valente and Shemesh combined behaviour, functional magnetic resonance imaging, electroencephalography and causal interventions to establish and validate a cortical processing substrate underlying the transition from static to dynamic visual states in the rat. Their research highlights the superior colliculus as the primary mediator of visual temporal discrimination by showing a direct correlation between behavioural and cortically derived flicker fusion frequency thresholds. This work provides the first empirical evidence addressing the previously established disparity between behavioural and cortically derived flicker fusion frequency thresholds. It demonstrates how important convergent multimodal approaches are to mapping and validating previously disputed cortical pathways. Here, we discuss and evaluate their work, suggesting possible future applications in the field of behavioural neuroscience.

Cortical field maps across human sensory cortex.

Cortical processing pathways for sensory information in the mammalian brain tend to be organized into topographical representations that encode various fundamental sensory dimensions. Numerous laboratories have now shown how these representations are organized into numerous cortical field maps (CMFs) across visual and auditory cortex, with each CFM supporting a specialized computation or set of computations that underlie the associated perceptual behaviors. An individual CFM is defined by two orthogonal topographical gradients that reflect two essential aspects of feature space for that sense. Multiple adjacent CFMs are then organized across visual and auditory cortex into macrostructural patterns termed cloverleaf clusters. CFMs within cloverleaf clusters are thought to share properties such as receptive field distribution, cortical magnification, and processing specialization. Recent measurements point to the likely existence of CFMs in the other senses, as well, with topographical representations of at least one sensory dimension demonstrated in somatosensory, gustatory, and possibly olfactory cortical pathways. Here we discuss the evidence for CFM and cloverleaf cluster organization across human sensory cortex as well as approaches used to identify such organizational patterns. Knowledge of how these topographical representations are organized across cortex provides us with insight into how our conscious perceptions are created from our basic sensory inputs. In addition, studying how these representations change during development, trauma, and disease serves as an important tool for developing improvements in clinical therapies and rehabilitation for sensory deficits.

Brief Myofascial Intervention Modulates Visual Event-Related Potential Response to Emotional Photographic Contents: A Pilot Study.

The use of touch for the treatment of psychiatric disorders is increasingly investigated, as it is shown that cognitive symptoms can be improved by various forms of massage. To investigate if the effect of massage is measurable using classical visual event-related potential components (P1, P2, late positive potential (LPP)), we performed a preliminary study on six participants using myofascial induction massage. Participants were shown emotionally valenced or neutral images before and after a 20 min myofascial massage. We found general increases in P2 amplitude following the intervention across all conditions (both neutral and affective), indicating increased attention or salience to visual stimuli. The magnitude of change was visibly larger for unpleasant stimuli, suggesting that visual perception and attention were modulated specifically in response to unpleasant visual images. The LPP showed reductions in amplitude after myofascial massage, suggesting increased emotional modulation following intervention, as a result of possible DMN alterations, consistent with region and function. We conclude that brief myofascial intervention supports other research in the field, finding that physical touch and massage techniques can alter cognition and perception. We posit further research to investigate its future use as an intervention for both physical and cognitive modulation. Importantly, we provide preliminary evidence that the neural processes that resonate with this type of massage involve complex feedforward and backward cortical pathways, of which a significant portion participate in modulating the visual perception of external stimuli.

Selective striatal fast-spiking interneuron inhibition induces cortical seizure.

Whether striatal fast-spiking interneurons are involved in cortical synchronization remains elusive. We performed acute microinjections of a selective FSI-AMPA receptor antagonist into the sensorimotor striatum of non-human primates to verify whether selective FSI inhibition within the sensorimotor striatum could potentially modify cortical excitability, thereby triggering focal seizures. Experiments were performed on three fascicularis monkeys. During each experimental session, low volumes of IEM-1460 (4-8 μL) were injected slowly at 1 μL/min. Spontaneous behavioral changes were classified according to the Racine scale modified for primates. These induced motor behaviors were correlated with electroencephalographic (EEG and EMG) measures. Power spectrum and time-frequency analysis were performed and compared between each period of interest. Pharmacological selective inhibition of striatal fast-spiking INs induced focal motor seizures. Back averaging confirmed that myoclonic activity was closely linked to cortical spikes-and-waves epileptic activity, with a significant increase in cortical EEG power in all studied frequency bands (p < .0001). Thus, striatal FSIs likely play a role in controlling cortical excitability through the cortico-striato-thalamo-cortical pathway. They may contribute to the pathophysiology of focal motor epilepsies by modulating the threshold at which focal motor seizures are triggered.

The impact of sex on the progression of AD atrophy‐based subtypes

AbstractBackgroundRecently, longitudinal subtypes in AD have been identified based on their different brain atrophy trajectories (Poulakis et al. 2022 Nat Commun), which follow either mediotemporal or cortical pathways. The mediotemporal pathway, which is the most prevalent, includes three longitudinal subtypes: the limbic predominant plus (LPA+), the limbic predominant (LPA), and the minimal atrophy (MA) subtypes. While the LPA+ is characterised by the fastest rate of atrophy starting in the entorhinal cortex and later spreading to the temporal lobe and the rest of the cortex, the LPA is restrained to atrophy in temporal regions. The MA subtype, on the other side, is characterised by minimal atrophy in mediotemporal areas. Although the discovery of brain atrophy trajectories in AD represents a significant contribution towards precision medicine, the impact of sex – a major risk factor for AD – on these trajectories has yet to be explored.MethodWe used longitudinal magnetic resonance imaging data as well as clinical data (up to 5 timepoints) from 3 international AD cohorts (ADNI, J‐ADNI and AIBL). AD individuals had previously been identified, as one of the following longitudinal subtypes: LPA+ (N = 23, 61% females), LPA (N = 93, 48% females), and MA subtype (N = 189, 48% females). We applied linear mixed effect models (LMMs) on 34 cortical and 7 subcortical regions to assess differences in sex within each AD longitudinal subtype. Results were adjusted for ageing effects, cohort, disease duration and intracranial volume.ResultLPA+ females showed greater atrophy over time compared to LPA+ males in frontal regions as well as in the lingual and the parahippocampal gyri. LPA females tended to show greater atrophy in the medial orbitofrontal cortex compared to LPA males. Finally, within the MA subtype, females showed greater atrophy than males in the hippocampus over time.ConclusionThis study demonstrates that sex‐specific regional vulnerabilities are crucial to consider in the study of AD heterogeneity, particularly within the mediotemporal pathway. Our results reveal that females exhibit distinct atrophy patterns over time compared to males in different AD subtypes, emphasizing the importance of investigating sex‐related differences to develop more targeted and effective interventions for AD.