The Relationship between Childhood Trauma Experiences and Psychotic Vulnerability in Obsessive Compulsive Disorder: An Italian Cross-Sectional Study.

People with obsessive compulsive disorder (OCD) are at increased risk of developing psychotic disorders; yet little is known about specific clinical features which might hint at this vulnerability. The present study was aimed at elucidating the pathophysiological mechanism linking OCD to psychosis through the investigation of childhood trauma experiences in adolescents and adults with OCD. One hundred outpatients, aged between 12 and 65 years old, were administered the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and its Child version (CY-BOCS), as well as the Childhood Trauma Questionnaire (CTQ); Cognitive-Perceptual basic symptoms (COPER) and high-risk criterion Cognitive Disturbances (COGDIS) were assessed in the study sample. Greater childhood trauma experiences were found to predict psychotic vulnerability (p = 0.018), as well as more severe OCD symptoms (p = 0.010) and an earlier age of OCD onset (p = 0.050). Participants with psychotic vulnerability reported higher scores on childhood trauma experiences (p = 0.02), specifically in the emotional neglect domain (p = 0.01). In turn, emotional neglect and psychotic vulnerability were found higher in the pediatric group than in the adult group (p = 0.01). Our findings suggest that childhood trauma in people with OCD may represent an indicator of psychotic vulnerability, especially in those with an earlier OCD onset. Research on the pathogenic pathways linking trauma, OCD, and psychosis is needed.

The association between childhood trauma and motor structure in obsessive-compulsive rituals: An ethological and evolutionary approach.

OBJECTIVE: Ethological models have highlighted a specific motor structure of compulsions in obsessive-compulsive disorder (OCD), based on the rigid repetitions of acts, and with the adaptive significance of facing unpredictable conditions. Such an evolutionary mechanism might explain the robust association between childhood traumatic experiences (CTEs) and OCD. However, a relationship between CTEs and the motor structure of compulsions has not been investigated yet. The first objective of the study was to confirm a specific motor structure of OCD compulsions with respect to control behaviors; the second objective was to assess a possible association between the motor structure of compulsions and CTEs severity. METHOD: Thirty-two OCD outpatients (13 female, Mage = 44.50 years, SE = 19.71) and 27 healthy controls (10 female, Mage = 37.62 years, SE = 16.20), matched for sex and age, provided a videotape of their compulsions and corresponding ordinary acts, respectively. Behavior was scored with the software "Observer." Participants were administered the Yale-Brown Obsessive Compulsive Scale and the Childhood Trauma Questionnaire. A dependent t test was used to compare the motor structure of behavior between the groups; Pearson's correlations to investigate associations between motor parameters and CTEs. RESULTS: Compulsions showed a specific motor structure due to the repetition of functional and nonfunctional acts. CTEs severity was especially associated with the repetition of functional acts, independently from OCD severity. CONCLUSION: Our findings, in confirming a peculiar motor structure for OCD compulsions, hint for the first time at a link between CTEs and compulsive repetition of functional acts, which would represent a plastic developmental response to CTEs unpredictability. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Ligand-gated mechanisms leading to ictogenesis in focal epileptic disorders.

We review here the neuronal mechanisms that cause seizures in focal epileptic disorders and, specifically, those involving limbic structures that are known to be implicated in human mesial temporal lobe epilepsy. In both epileptic patients and animal models, the initiation of focal seizures - which are most often characterized by a low-voltage fast onset EEG pattern - is presumably dependent on the synchronous firing of GABA-releasing interneurons that, by activating post-synaptic GABAA receptors, cause large increases in extracellular [K+] through the activation of the co-transporter KCC2. A similar mechanism may contribute to seizure maintenance; accordingly, inhibiting KCC2 activity transforms seizure activity into a continuous pattern of short-lasting epileptiform discharges. It has also been found that interactions between different areas of the limbic system modulate seizure occurrence by controlling extracellular [K+] homeostasis. In line with this view, low-frequency electrical or optogenetic activation of limbic networks restrain seizure generation, an effect that may also involve the activation of GABAB receptors and activity-dependent changes in epileptiform synchronization. Overall, these findings highlight the paradoxical role of GABAA signaling in both focal seizure generation and maintenance, emphasize the efficacy of low-frequency activation in abating seizures, and provide experimental evidence explaining the poor efficacy of antiepileptic drugs designed to augment GABAergic function in controlling seizures in focal epileptic disorders.

Limbic and olfactory cortical circuits in focal seizures.

Epilepsies affecting the limbic regions are common and generate seizures often resistant to pharmacological treatment. Clinical evidence demonstrates that diverse regions of the mesial portion of the temporal lobe participate in limbic seizures; these include the hippocampus, the entorhinal, perirhinal and parahippocampal regions and the piriform cortex. The network mechanisms involved in the generation of olfactory-limbic epileptiform patterns will be here examined, with particular emphasis on acute interictal and ictal epileptiform discharges obtained by treatment with pro-convulsive drugs and by high-frequency stimulations on in vitro preparations, such as brain slices and the isolated guinea pig brain. The interactions within olfactory-limbic circuits can be summarized as follows: independent, region-specific seizure-like events (SLE) are generated in the olfactory and in the limbic cortex; SLEs generated in the hippocampal-parahippocampal regions tend to remain within these areas; the perirhinal region controls the neocortical propagation and the generalization of limbic seizures; interictal spiking in the olfactory regions prevents the invasion by SLEs generated in limbic regions. The potential relevance of these observations for human focal epilepsy is discussed.

A clinical investigation of psychotic vulnerability in early-onset Obsessive-Compulsive Disorder through Cognitive-Perceptive basic symptoms.

Childhood-onset Obsessive-Compulsive Disorder (OCD) shows distinct comorbidity patterns and developmental pathways, as well as an increased risk of psychosis with respect to adult-onset forms. Nevertheless, little is known about the prodromal symptoms of psychosis in children and adolescents with a primary diagnosis of OCD. The present study was aimed at evaluating the occurrence of Cognitive-Perceptual basic symptoms (COPER) and high- risk criterion Cognitive Disturbances (COGDIS) in pediatric and adults OCD patients, verifying if they might vary according to the age of onset of OCD. The study included 90 outpatients with a primary diagnosis of obsessive-compulsive disorder. The study sample was collapsed into three groups according to the age at onset: 1) very early onset group (< 10 years); 2) early onset group (11-18 years); 3) adult-onset group (> 18 years). All patients were administered the Yale-Brown Obsessive- Compulsive Scale (Y-BOCS) and its Child version (CY-BOCS), the Schizophrenia Proneness Instrument-Adult (SPIA) and its Child and Adolescent version (SPI-CY) and the Social and Occupational Functioning Assessment Scale (SOFAS). COPER and COGDIS symptoms were positively associated with OCD severity and detectable, respectively, in 28.9 and 26.7% of our study sample. The very early onset group significantly had higher COPER and COGDIS symptoms than the adult-onset group. Our data suggest that COPER and COGDIS symptoms are frequent in obsessive patients, in particular in those with earlier onset; therefore, their detection in childhood-onset OCD may represent an early and specific indicator of psychotic vulnerability.

GABAA signaling, focal epileptiform synchronization and epileptogenesis.

Under physiological conditions, neuronal network synchronization leads to different oscillatory EEG patterns that are associated with specific behavioral and cognitive functions. Excessive synchronization can, however, lead to focal or generalized epileptiform activities. It is indeed well established that in both epileptic patients and animal models, focal epileptiform EEG patterns are characterized by interictal and ictal (seizure) discharges. Over the last three decades, employing in vitro and in vivo recording techniques, several experimental studies have firmly identified a paradoxical role of GABAA signaling in generating interictal discharges, and in initiating-and perhaps sustaining-focal seizures. Here, we will review these experiments and we will extend our appraisal to evidence suggesting that GABAA signaling may also contribute to epileptogenesis, i.e., the development of plastic changes in brain excitability that leads to the chronic epileptic condition. Overall, we anticipate that this information should provide the rationale for developing new specific pharmacological treatments for patients presenting with focal epileptic disorders such as mesial temporal lobe epilepsy (MTLE).

Ultrasounds induce blood-brain barrier opening across a sonolucent polyolefin plate in an in vitro isolated brain preparation.

The blood-brain barrier (BBB) represents a major obstacle to the delivery of drugs to the central nervous system. The combined use of low-intensity pulsed ultrasound waves and intravascular microbubbles (MB) represents a promising solution to this issue, allowing reversible disruption of the barrier. In this study, we evaluate the feasibility of BBB opening through a biocompatible, polyolefin-based plate in an in vitro whole brain model. Twelve in vitro guinea pig brains were employed; brains were insonated using a planar transducer with or without interposing the polyolefin plate during arterial infusion of MB. Circulating MBs were visualized with an ultrasonographic device with a linear probe. BBB permeabilization was assessed by quantifying at confocal microscopy the extravasation of FITC-albumin perfused after each treatment. US-treated brains displayed BBB permeabilization exclusively in the volume under the US beam; no significant differences were observed between brains insonated with or without the polyolefin plate. Control brains not perfused with MB did not show signs of FITC-albumin extravasation. Our preclinical study suggests that polyolefin cranial plate could be implanted as a skull replacement to maintain craniotomic windows and perform post-surgical repeated BBB opening with ultrasound guidance to deliver therapeutic agents to the central nervous system.

Mapping region-specific seizure-like patterns in the in vitro isolated guinea pig brain.

Specific neurophysiological seizure patterns in patients with focal epilepsy depend on cerebral location and the underlying neuropathology. Location-specific patterns have been also reported in experimental models. Two focal seizure patterns, named p-type and l-type, typical of neocortical and mesial temporal regions were identified in both patients explored with intracerebral EEG and in animal models. These two patterns were recorded in the olfactory regions and in the entorhinal cortex after either 4AP or BMI administration. Here we mapped epileptiform activities in other cortices to verify the existence of specific epileptiform patterns. Field potentials were simultaneously recorded at multiple locations in olfactory, limbic and neocortical regions of the isolated guinea pig brain after arterial administration of either 4AP or BMI. Most neocortical areas did not generate new distinctive focal seizure-like event (SLE), beside the p-type and l-type patterns. Spiking activity was typically recorded after BMI in all new analyzed regions, whereas SLEs were commonly observed during 4AP perfusion. We confirmed the presence of reproducible region-specific epileptiform patterns in all explored cortical areas and demonstrated that strongly inter-connected areas generate similar SLEs. Our study suggests that p- and l-type SLE represent the most common focal seizure patterns during acute manipulations with pro-epileptic compounds.

A hypothesis for the role of axon demyelination in seizure generation.

Loss of myelin and altered oligodendrocyte distribution in the cerebral cortex are commonly observed both in postsurgical tissue derived from different focal epilepsies (such as focal cortical dysplasias and tuberous sclerosis) and in animal models of focal epilepsy. Moreover, seizures are a frequent symptom in demyelinating diseases, such as multiple sclerosis, and in animal models of demyelination and oligodendrocyte dysfunction. Finally, the excessive activity reported in demyelinated axons may promote hyperexcitability. We hypothesize that the extracellular potassium rise generated during epileptiform activity may be amplified by the presence of axons without appropriate myelin coating and by alterations in oligodendrocyte function. This process could facilitate the triggering of recurrent spontaneous seizures in areas of altered myelination and could result in further demyelination, thus promoting epileptogenesis.

Activity- and pH-dependent adenosine shifts at the end of a focal seizure in the entorhinal cortex.

Adenosine (ADO) is an endogenous modulator of neuronal excitability, with anticonvulsant and neuroprotective effects. It has been proposed that the activity-dependent release of ADO promoted by the extracellular acidification occurring during seizures contributes to seizure termination. To verify this hypothesis, we recorded field potentials, pH and ADO changes measured with enzymatic biosensors during acute focal seizures in the medial entorhinal cortex (mEC) of the isolated guinea-pig brain maintained in vitro. The effect of ADO on seizure-like events (SLEs) induced by GABAa receptor antagonism with bicuculline methiodide (BMI; 50 µM) was assessed by arterial applications of 1 mM ADO. ADO either reduced or prevented epileptiform activity. The A1 receptor antagonist DPCPX (100-500 µM) prolonged BMI-induced seizures and was able to precipitate SLEs in the absence of proconvulsant. Simultaneous recordings of brain activity, extracellular ADO and pH shifts demonstrated that ADO decreases at the onset and progressively rises toward the end of SLEs induced by either BMI or 4-aminopyridine (4AP; 50 µM), reaching maximal values 1-5 min after SLE termination. ADO changes were preceded by a SLE-dependent extracellular acid shift. Both pH acidification and ADO changes were abolished by 22 mM HEPES in the arterial perfusate. In these conditions, SLE duration was prolonged. Our data confirm that ADO plays a role in regulating brain excitability. Its increase depends on seizure-induced acid pH shift and it is maximal after the end of the SLE. These findings strongly suggest that ADO contributes to termination of focal seizures and to the establishment of the postictal depression.

Piriform cortex ictogenicity in vitro.

The piriform cortex is recognized to play critical roles in focal ictogenesis, both in animal models and in humans. We review here the contribution of in vitro studies performed on rodent brain tissue that were aimed at understanding the ictogenic properties of the piriform cortex and the contiguous olfactory areas. During in vitro experiments, epileptiform events can be easily generated in the piriform area by diverse pro-convulsive drugs (4-aminopyridine, bicuculline, picrotoxin) or by electrical stimulation. Simultaneous intracellular and field potential recordings performed on in vitro preparations, which include brain slices of rats and mice and the isolated brains of guinea pigs, demonstrated that both the piriform cortex proper and the endopiriform nucleus (also considered part of the piriform area) generate interictal spikes, high-frequency oscillations and seizure-like activities that mimic focal discharges. These findings were confirmed both by optical recordings of intrinsic signals coupled with brain activity and by fast imaging of optical signals generated by voltage-sensitive dyes. Overall, these studies demonstrated that epileptiform discharges effectively propagate from the piriform structures to the limbic regions, supporting the conditions for secondarily generalized ictogenesis.

GABAA receptor-mediated networks during focal seizure onset and progression in vitro.

Focal seizures are triggered by the pathological synchronization of a functionally altered group of neurons. In vivo and in vitro results in rodents and single unit studies in humans suggest that seizure can be initiated by increased activity in interneuronal networks. We review here the data derived from in vitro perparations to describe the function of GABAergic network in different phases of focal seizures. The data demonstrate that GABA-mediated synchronization of interneuronal activity has an active role in shaping focal seizure dynamics.

Recording Electrical Brain Activity with Novel Stretchable Electrodes Based on Supersonic Cluster Beam Implantation Nanotechnology on Conformable Polymers.

BACKGROUND: Multielectrodes are implanted in central and peripheral nervous systems for rehabilitation and diagnostic purposes. The physical resistance of intracranial devices to mechanical stress is critical and fractures or electrode displacement may occur. We describe here a new recording device with stretchable properties based on Supersonic Cluster Beam Implantation (SCBI) technology with high mechanical adaptability to displacement and movement. RESULTS: The capability of SCBI-based multichannel electrodes to record brain electrical activity was compared to glass/silicon microelectrodes in acute in vitro experiments on the isolated guinea pig brain preparation. Field potentials and power frequency analysis demonstrated equal recording features for SCBI and standard electrodes. Chronic in vivo epidural implantation of the SCBI electrodes confirmed excellent long-term recording properties in comparison to standard EEG metal electrodes. Tissue biocompatibility was demonstrated by neuropathological evaluation of the brain tissue 2 months after the implantation of the devices in the subarachnoid space. CONCLUSION: We confirm the biocompatibility of novel SCBI-based stretchable electrode devices and demonstrate their suitability for recording electrical brain activity in pre-clinical settings.

Enhanced thalamo-hippocampal synchronization during focal limbic seizures.

OBJECTIVE: The key factors that promote the termination of focal seizures have not been fully clarified. The buildup of neuronal synchronization during seizures has been proposed as one of the possible activity-dependent, self-limiting mechanisms. We investigate if increased thalamo-cortical coupling contributes to enhance synchronization during the late phase of focal seizure-like events (SLEs) generated in limbic regions. METHODS: Recordings were simultaneously performed in the nucleus reuniens of the thalamus, in the hippocampus and in the entorhinal cortex of the isolated guinea pig brain during focal bicuculline-induced SLEs with low voltage fast activity at onset. RESULTS: Spectral coherence and cross-correlation analysis demonstrated a progressive thalamo-cortical entrainment and synchronization in the generation of bursting activity that characterizes the final part of SLEs. The hippocampus is the first activated structure at the beginning of SLE bursting phase and thalamo-hippocampal synchronization is progressively enhanced as SLE develops. The thalamus takes the lead in generating the bursting discharge as SLE end approaches. SIGNIFICANCE: As suggested by clinical studies performed during pre-surgical intracranial monitoring, our data confirm a role of the midline thalamus in leading the synchronous bursting activity at the end of focal seizures in the mesial temporal regions.

Potassium dynamics and seizures: Why is potassium ictogenic?

Potassium channels dysfunction and altered genes encoding for molecules involved in potassium homeostasis have been associated with human epilepsy. These observations are in agreement with a control role of extracellular potassium on neuronal excitability and seizure generation. Epileptiform activity, in turn, regulates potassium homeostasis through mechanisms that are still not well established. We review here how potassium-associated processes are regulated in the brain and examine the mechanisms that support the role of potassium in triggering epileptiform activities.

A Novel Focal Seizure Pattern Generated in Superficial Layers of the Olfactory Cortex.

Seizure patterns identified in focal epilepsies caused by diverse etiologies are likely due to different pathogenic mechanisms. We describe here a novel, region-specific focal seizure pattern that mimics seizure activity observed in a subpopulation of patients submitted to presurgical monitoring with intracerebral electrodes. Distinctive seizure-like events (SLEs) are induced in the olfactory regions by acute treatment of both tangential brain slices and the isolated guinea pig brain with the potassium channel blocker 4-aminopyridine. Analysis of field potentials, intracellular activities, and extracellular potassium changes demonstrates that SLEs in the piriform cortex initiate in the superficial layer 1 lacking principal neurons with an activity-dependent increase of extracellular potassium. SLE progression (but not onset) does not require the participation of synaptic transmission and is mediated by diffusion of potassium to deep cortical layers. The novel seizure pattern here described is not observed in other cortical regions; it is proposed to rely on the peculiar organization of the superficial piriform cortex layers, which are characterized by unmyelinated axons and perisynaptic astroglial envelopes. This study reveals a sequence of ictogenic events in the olfactory cortex that were never described before in other cortical structures and supports the notion that altered potassium homeostasis and unmyelinated fibers may represent a potential vehicle for focal ictogenesis.SIGNIFICANCE STATEMENT We describe a novel seizure pattern peculiar of the olfactory cortex that resembles focal seizures with low-voltage fast activity at onset observed in humans. The findings suggest that network mechanisms responsible for seizure onset can be region specific.

High-frequency oscillations and seizure-like discharges in the entorhinal cortex of the in vitro isolated guinea pig brain.

We analyzed the patterns of seizure-like activity and associated high-frequency oscillations (HFOs) induced by the K+ channel blocker 4-aminopyridine (4AP, 50µM) or the GABAA receptor antagonist bicuculline methiodide (BMI, 50µM) in the in vitro isolated guinea pig brain preparation. Extracellular field recordings were obtained from the medial entorhinal cortex (EC) using glass pipettes or silicon probes; 4AP or BMI were applied through the basilar artery. Ripples (80-200Hz) or fast ripples (250-500Hz) occurred at higher rates shortly before ictal events induced by 4AP or BMI, respectively. In addition, during the ictal period, ripples were mostly associated with 4AP-induced ictal events whereas fast ripples predominated during ictal discharges induced by BMI. Finally, ripples occurred at higher rates during the clonic phase of 4AP-induced ictal events compared to the tonic phase, while higher rates of fast ripples characterized the clonic phase in both 4AP- and BMI-induced ictal discharges. These differences in HFO occurrence presumably reflect the diverse action of these two convulsants on GABAA receptor signaling.

The in vitro isolated whole guinea pig brain as a model to study epileptiform activity patterns.

BACKGROUND: Research on ictogenesis is based on the study of activity between seizures and during seizures in animal models of epilepsy (chronic condition) or in in vitro slices obtained from naïve non-epileptic brains after treatment with pro-convulsive drugs, manipulations of the extracellular medium and specific stimulation protocols. NEW METHOD: The in vitro isolated guinea pig brain retains the functional connectivity between brain structures and maintains interactions between neuronal, glial and vascular compartments. It is a close-to-in vivo preparation that offers experimental advantages not achieved with the use of other experimental models. Neurophysiological and imaging techniques can be utilized in this preparation to study brain activity during and between seizures induced by pharmacological or functional manipulations. RESULTS: Cellular and network determinants of interictal and ictal discharges that reproduce abnormal patterns observed in human focal epilepsies and the associated changes in extracellular ion and blood-brain permeability can be identified and analyzed in the isolated guinea pig brain. COMPARISON WITH EXISTING METHODS: Ictal and interictal patterns recorded in in vitro slices may show substantial differences from seizure activity recorded in vivo due to slicing procedure itself. The isolated guinea pig brain maintained in vitro by arterial perfusion combines the typical facilitated access of in vitro preparations, that are difficult to approach during in vivo experiments, with the preservation of larger neuronal networks. CONCLUSIONS: The in vitro whole isolated guinea pig brain preparation offers an unique experimental model to study systemic and neurovascular changes during ictogenesis.

Synchronous inhibitory potentials precede seizure-like events in acute models of focal limbic seizures.

Interictal spikes in models of focal seizures and epilepsies are sustained by the synchronous activation of glutamatergic and GABAergic networks. The nature of population spikes associated with seizure initiation (pre-ictal spikes; PSs) is still undetermined. We analyzed the networks involved in the generation of both interictal and PSs in acute models of limbic cortex ictogenesis induced by pharmacological manipulations. Simultaneous extracellular and intracellular recordings from both principal cells and interneurons were performed in the medial entorhinal cortex of the in vitro isolated guinea pig brain during focal interictal and ictal discharges induced in the limbic network by intracortical and brief arterial infusions of either bicuculline methiodide (BMI) or 4-aminopyridine (4AP). Local application of BMI in the entorhinal cortex did not induce seizure-like events (SLEs), but did generate periodic interictal spikes sensitive to the glutamatergic non-NMDA receptor antagonist DNQX. Unlike local applications, arterial perfusion of either BMI or 4AP induced focal limbic SLEs. PSs just ahead of SLE were associated with hyperpolarizing potentials coupled with a complete blockade of firing in principal cells and burst discharges in putative interneurons. Interictal population spikes recorded from principal neurons between two SLEs correlated with a depolarizing potential. We demonstrate in two models of acute limbic SLE that PS events are different from interictal spikes and are sustained by synchronous activation of inhibitory networks. Our findings support a prominent role of synchronous network inhibition in the initiation of a focal seizure.

Simultaneous enhancement of excitation and postburst inhibition at the end of focal seizures.

OBJECTIVE: Comprehension of the events that lead to seizure termination contributes to the development of strategies to confine propagation of ictal discharges. It is commonly assumed that the inhibitory control fails during seizures and recovers after the end of the ictal event. We examine the possibility that a progressive increase of inhibition that counters an increase in the strength of excitation contributes to terminating a focal seizure. METHODS: We analyzed seizures acutely induced by pharmacological manipulations (bicuculline and 4-aminopyridine) in the entorhinal cortex and in the hippocampus of the in vitro isolated guinea pig brain. RESULTS: As seizures ended, extracellular and intracellular recordings showed periodic bursting that progressively decreased in frequency. During the late bursting phase, the duration, number, and rate of occurrence of spikes within single bursts remained constant, whereas cumulative spike amplitude (index of excitation during a burst) and interburst interval (index of inhibition between bursts) progressively increased. The increment of average/cumulative burst excitation and interburst interval toward seizure end was confirmed in human focal seizures recorded with intracerebral electrodes in patients with drug-resistant partial epilepsies. A postburst refractory period of circa 2 seconds that increases with time toward the end of the seizure was confirmed in the experimental model by probing interburst epochs in the CA1 region with local dentate gyrus stimulation just suprathreshold for burst generation. INTERPRETATION: Our findings support the concept that focal seizures are terminated by the simultaneous and opposing enhancement of excitation (burst activity) in addition to postburst inhibition. We hypothesize that a seizure stops when postburst inhibition becomes large enough to prevent reactivation of excitation.