Delta-mediated cross-frequency coupling organizes oscillatory activity across the rat cortico-basal ganglia network

The brain's ability to integrate different behavioral and cognitive processes relies on its capacity to generate neural oscillations in a cooperative and coordinated manner. Cross-frequency coupling (CFC) has recently been proposed as one of the mechanisms involved in organizing brain activity. Here we investigated the phase-to-amplitude CFC (PA-CFC) patterns of the oscillatory activity in the cortico-basal ganglia network of healthy, freely moving rats. Within-structure analysis detected consistent PA-CFC patterns in the four regions analyzed, with the phase of delta waves modulating the amplitude of activity in the gamma (low-gamma ~50 Hz; high-gamma ~80 Hz) and high frequency ranges (high frequency oscillations HFO, ~150 Hz). Between-structure analysis revealed that the phase of delta waves parses the occurrence of transient episodes of coherence in the gamma and high frequency bands across the entire network, providing temporal windows of coherence between different structures. Significantly, this specific spatio-temporal organization was affected by the action of dopaminergic drugs. Taken together, our findings suggest that delta-mediated PA-CFC plays a key role in the organization of local and distant activities in the rat cortico-basal ganglia network by fine-tuning the timing of synchronization events across different structures. KEYWORDS: cortico-basal ganglia network; cross-frequency coupling; dopaminergic system; local field potentials; nested interactions; nested oscillations; oscillatory activit

Ketamine-induced oscillations in the motor circuit of the rat basal ganglia

Oscillatory activity can be widely recorded in the cortex and basal ganglia. This activity may play a role not only in the physiology of movement, perception and cognition, but also in the pathophysiology of psychiatric and neurological diseases like schizophrenia or Parkinson's disease. Ketamine administration has been shown to cause an increase in gamma activity in cortical and subcortical structures, and an increase in 150 Hz oscillations in the nucleus accumbens in healthy rats, together with hyperlocomotion.We recorded local field potentials from motor cortex, caudate-putamen (CPU), substantia nigra pars reticulata (SNr) and subthalamic nucleus (STN) in 20 awake rats before and after the administration of ketamine at three different subanesthetic doses (10, 25 and 50 mg/Kg), and saline as control condition. Motor behavior was semiautomatically quantified by custom-made software specifically developed for this setting.Ketamine induced coherent oscillations in low gamma (~ 50 Hz), high gamma (~ 80 Hz) and high frequency (HFO, ~ 150 Hz) bands, with different behavior in the four structures studied. While oscillatory activity at these three peaks was widespread across all structures, interactions showed a different pattern for each frequency band. Imaginary coherence at 150 Hz was maximum between motor cortex and the different basal ganglia nuclei, while low gamma coherence connected motor cortex with CPU and high gamma coherence was more constrained to the basal ganglia nuclei. Power at three bands correlated with the motor activity of the animal, but only coherence values in the HFO and high gamma range correlated with movement. Interactions in the low gamma band did not show a direct relationship to movement.These results suggest that the motor effects of ketamine administration may be primarily mediated by the induction of coherent widespread high-frequency activity in the motor circuit of the basal ganglia, together with a frequency-specific pattern of connectivity among the structures analyzed

Epilepsy and neuropsychiatric comorbidities in mice carrying a recurrent Dravet syndrome SCN1A missense mutation

Dravet Syndrome (DS) is an encephalopathy with epilepsy associated with multiple neuropsychiatric comorbidities. In up to 90% of cases, it is caused by functional happloinsufficiency of the SCN1A gene, which encodes the alpha subunit of a voltage-dependent sodium channel (Nav1.1). Preclinical development of new targeted therapies requires accessible animal models which recapitulate the disease at the genetic and clinical levels. Here we describe that a C57BL/6 J knock-in mouse strain carrying a heterozygous, clinically relevant SCN1A mutation (A1783V) presents a full spectrum of DS manifestations. This includes 70% mortality rate during the first 8 weeks of age, reduced threshold for heat-induced seizures (4.7 °C lower compared with control littermates), cognitive impairment, motor disturbances, anxiety, hyperactive behavior and defects in the interaction with the environment. In contrast, sociability was relatively preserved. Electrophysiological studies showed spontaneous interictal epileptiform discharges, which increased in a temperature-dependent manner. Seizures were multifocal, with different origins within and across individuals. They showed intra/inter-hemispheric propagation and often resulted in generalized tonic-clonic seizures. 18F-labelled flourodeoxyglucose positron emission tomography (FDG-PET) revealed a global increase in glucose uptake in the brain of Scn1aWT/A1783V mice. We conclude that the Scn1aWT/A1783V model is a robust research platform for the evaluation of new therapies against DS

Oscilaciones cerebrales: papel fisiopatológico y terapéutico en algunas enfermedades neurológicas y psiquiátricas

Se usa el término «oscilación o actividad oscilatoria» para referirse a las fluctuaciones rítmicas de los potenciales postsinápticos de un grupo neuronal (potenciales de campo local) o de una región cortical (EEG, electrocorticografía) y también al patrón de descarga rítmico de los potenciales de acción de una neurona o un grupo neuronal. La actividad oscilatoria posibilita la sincronización entre grupos neuronales de la misma área cortical o de áreas distantes entre sí que intervienen en una acción motora, tarea cognitiva o perceptiva. Con frecuencia es motivo de confusión asociar la presencia de actividad oscilatoria con fenómenos de sincronización, ya que ambos fenómenos aunque relacionados no son equivalentes. En patologías neurológicas o psiquiátricas tan distintas como la enfermedad de Parkinson u otros movimientos anormales, la epilepsia o la esquizofrenia se han descrito anomalías de la actividad oscilatoria de distintas estructuras cerebrales o de su sincronización que podrían jugar un papel relevante en su fisiopatología. En esta revisión se discuten estos aspectos haciendo hincapié en su importancia por ser un mecanismo básico del funcionamiento cerebral y un nuevo mecanismo fisiopatólogico de la sintomatología de algunas enfermedades cerebrales.The terms «oscillations» or «oscillatory activity» are frequently used not only to define the rhythmic fluctuations of the postsynaptic potentials of a neuronal group (local field potentials) or a cortical region (EEG, MEG), but also to indicate the rhythmic discharge pattern of action potentials from a neuron or a small group of neurons. Oscillatory activity makes possible the synchronization of different neuronal groups from nearby or distant cortical regions that participate in the same motor, sensory or cognitive task. The presence of oscillatory activity is usually associated to the existence of synchronization, but both phenomena are not necessarily always equivalent. Abnormalities of oscillatory activities or synchronization within or between different brain structures have been described in several neurological and psychiatric diseases; these abnormalities might play a relevant pathophysiological role in Parkinson’s disease (and other movement disorders), schizophrenia or epilepsy. This review discusses all these aspects, with emphasis on their potential role both as a basic mechanism in brain function and as a pathophysiological substrate for some of the symptoms and signs observed in several diseases

Transfer of SCN1A to the brain of adolescent mouse model of Dravet syndrome improves epileptic, motor, and behavioral manifestations

Dravet syndrome is a genetic encephalopathy characterized by severe epilepsy combined with motor, cognitive, and behavioral abnormalities. Current antiepileptic drugs achieve only partial control of seizures and provide little benefit on the patient’s neurological development. In >80% of cases, the disease is caused by haploinsufficiency of the SCN1A gene, which encodes the alpha subunit of the Nav1.1 voltage-gated sodium channel. Novel therapies aim to restore SCN1A expression in order to address all disease manifestations. We provide evidence that a high-capacity adenoviral vector harboring the 6-kb SCN1A cDNA is feasible and able to express functional Nav1.1 in neurons. In vivo, the best biodistribution was observed after intracerebral injection in basal ganglia, cerebellum, and prefrontal cortex. SCN1A A1783V knockin mice received the vector at 5 weeks of age, when most neurological alterations were present. Animals were protected from sudden death, and the epileptic phenotype was attenuated. Improvement of motor performance and interaction with the environment was observed. In contrast, hyperactivity persisted, and the impact on cognitive tests was variable (success in novel object recognition and failure in Morris water maze tests). These results provide proof of concept for gene supplementation in Dravet syndrome and indicate new directions for improvement

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Theta-phase closed-loop stimulation induces motor paradoxical responses in the rat model of Parkinson disease

Background: High-frequency deep brain stimulation (DBS) has become a widespread therapy used in the treatment of Parkinson's Disease (PD) and other diseases. Although it has proved beneficial, much recent attention has been centered around the potential of new closed-loop DBS implementations. Objective: Here we present a new closed-loop DBS scheme based on the phase of the theta activity recorded from the motor cortex. By testing the implementation on freely moving 6-OHDA lesioned and control rats, we assessed the behavioral and neurophysiologic effects of this implementation and compared it against the classical high-frequency DBS. Results: Results show that both stimulation modalities produce significant and opposite changes on the movement and neurophysiological activity. Close-loop stimulation, far from improving the animals' behavior, exert contrary effects to those of high-frequency DBS which reverts the parkinsonian symptoms. Motor improvement during open-loop, high-frequency DBS was accompanied by a reduction in the amount of cortical beta oscillations while akinetic and disturbed behavior during close-loop stimulation coincided with an increase in the amplitude of beta activity. Conclusion: Cortical-phase-dependent close-loop stimulation of the STN exerts significant behavioral and oscillatory changes in the rat model of PD. Open-loop and close-loop stimulation outcomes differed dramatically, thus suggesting that the scheme of stimulation determines the output of the modulation even if the target structure is maintained. The current framework could be extended in future studies to identify the correct parameters that would provide a suitable control signal to the system. It may well be that with other stimulation parameters, this sort of DBS could be beneficial

Delta-mediated cross-frequency coupling organizes oscillatory activity across the rat cortico-basal ganglia network

The brain's ability to integrate different behavioral and cognitive processes relies on its capacity to generate neural oscillations in a cooperative and coordinated manner. Cross-frequency coupling (CFC) has recently been proposed as one of the mechanisms involved in organizing brain activity. Here we investigated the phase-to-amplitude CFC (PA-CFC) patterns of the oscillatory activity in the cortico-basal ganglia network of healthy, freely moving rats. Within-structure analysis detected consistent PA-CFC patterns in the four regions analyzed, with the phase of delta waves modulating the amplitude of activity in the gamma (low-gamma ~50 Hz; high-gamma ~80 Hz) and high frequency ranges (high frequency oscillations HFO, ~150 Hz). Between-structure analysis revealed that the phase of delta waves parses the occurrence of transient episodes of coherence in the gamma and high frequency bands across the entire network, providing temporal windows of coherence between different structures. Significantly, this specific spatio-temporal organization was affected by the action of dopaminergic drugs. Taken together, our findings suggest that delta-mediated PA-CFC plays a key role in the organization of local and distant activities in the rat cortico-basal ganglia network by fine-tuning the timing of synchronization events across different structures. KEYWORDS: cortico-basal ganglia network; cross-frequency coupling; dopaminergic system; local field potentials; nested interactions; nested oscillations; oscillatory activit

An interactive framework for the detection of ictal and interictal activities: cross-species and stand-alone implementation

Background and objective: Despite advances on signal analysis and artificial intelligence, visual inspec- tion is the gold standard in event detection on electroencephalographic recordings. This process requires much time of clinical experts on both annotating and training new experts for this same task. In sce- narios where epilepsy is considered, the need for automatic tools is more prominent, as both seizures and interictal events can occur on hours- or days-long recordings. Although other solutions have al- ready been proposed, most of them are not integrated on clinical and basic science environments due to their complexity and required specialization. Here we present a pipeline that arises from coordinated efforts between life-science researchers, clinicians and data scientists to develop an interactive and it- erative workflow to train machine-learning tools for the automatic detection of electroencephalographic events in a variety of scenarios. Methods: The approach consists on a series of subsequent steps covering data loading and configuration, event annotation, model training/re-training and event detection. With slight modifications, the combi- nation of these blocks can cope with a variety of scenarios. To illustrate the flexibility and robustness of the approach, three datasets from clinical (patients of Dravet Syndrome) and basic research environments (mice model of the same disease) were evaluated. From them, and in response to researchers’ daily needs, four real world examples of interictal event detection and seizure classification tasks were selected and processed. Results: Results show that the current approach was of great aid for event annotation and model de- velopment. It was capable of creating custom machine-learning solutions for each scenario with slight adjustments on the analysis protocol, easily accessible to users without programming skills. Final anno- tator similarity metrics reached values above 80% on all cases of use, reaching 92.3% on interictal event detection on human recordings. Conclusions: The presented framework is easily adaptable to multiple real world scenarios and the inter- active and ease-to-use approach makes it manageable to clinical and basic researches without program- ming skills. Nevertheless, it is conceived so data scientists can optimize it for specific scenarios, improving the knowledge transfer between these fields