Activation of metabotropic glutamate 5 and NMDA receptors underlies the induction of persistent bursting and associated long-lasting changes in CA3 recurrent connections.

The aim of this study was to describe the induction and expression mechanisms of a persistent bursting activity in a horizontal slice preparation of the rat limbic system that includes the ventral part of the hippocampus and the entorhinal cortex. Disinhibition of this preparation by bicuculline led to interictal-like bursts in the CA3 region that triggered synchronous activity in the entorhinal cortex. Washout of bicuculline after a 1 hr application resulted in a maintained production of hippocampal bursts that continued to spread to the entorhinal cortex. Separation of CA3 from the entorhinal cortex caused the activity in the latter to become asynchronous with CA3 activity in the presence of bicuculline and disappear after washout; however, in CA3, neither the induction of bursting nor its persistence were affected. Associated with the CA3 persistent bursting, a strengthening of recurrent collateral excitatory input to CA3 pyramidal cells and a decreased input to CA3 interneurons was found. Both the induction of the persistent bursting and the changes in synaptic strength were prevented by antagonists of metabotropic glutamate 5 (mGlu5) or NMDA receptors or protein synthesis inhibitors and did not occur in slices from mGlu5 receptor knock-out mice. The above findings suggest potential synaptic mechanisms by which the hippocampus switches to a persistent interictal bursting mode that may support a spread of interictal-like bursting to surrounding temporal lobe regions.

Focal Epilepsy: MR Imaging of Nonhemodynamic Field Effects by Using a Phase-cycled Stimulus-induced Rotary Saturation Approach with Spin-Lock Preparation.

Purpose To investigate whether nonhemodynamic resonant saturation effects can be detected in patients with focal epilepsy by using a phase-cycled stimulus-induced rotary saturation (PC-SIRS) approach with spin-lock (SL) preparation and whether they colocalize with the seizure onset zone and surface interictal epileptiform discharges (IED). Materials and Methods The study was approved by the local ethics committee, and all subjects gave written informed consent. Eight patients with focal epilepsy undergoing presurgical surface and intracranial electroencephalography (EEG) underwent magnetic resonance (MR) imaging at 3 T with a whole-brain PC-SIRS imaging sequence with alternating SL-on and SL-off and two-dimensional echo-planar readout. The power of the SL radiofrequency pulse was set to 120 Hz to sensitize the sequence to high gamma oscillations present in epileptogenic tissue. Phase cycling was applied to capture distributed current orientations. Voxel-wise subtraction of SL-off from SL-on images enabled the separation of T2* effects from rotary saturation effects. The topography of PC-SIRS effects was compared with the seizure onset zone at intracranial EEG and with surface IED-related potentials. Bayesian statistics were used to test whether prior PC-SIRS information could improve IED source reconstruction. Results Nonhemodynamic resonant saturation effects ipsilateral to the seizure onset zone were detected in six of eight patients (concordance rate, 0.75; 95% confidence interval: 0.40, 0.94) by means of the PC-SIRS technique. They were concordant with IED surface negativity in seven of eight patients (0.88; 95% confidence interval: 0.51, 1.00). Including PC-SIRS as prior information improved the evidence of the standard EEG source models compared with the use of uninformed reconstructions (exceedance probability, 0.77 vs 0.12; Wilcoxon test of model evidence, P < .05). Nonhemodynamic resonant saturation effects resolved in patients with favorable postsurgical outcomes, but persisted in patients with postsurgical seizure recurrence. Conclusion Nonhemodynamic resonant saturation effects are detectable during interictal periods with the PC-SIRS approach in patients with epilepsy. The method may be useful for MR imaging-based detection of neuronal currents in a clinical environment. (©) RSNA, 2016 Online supplemental material is available for this article.

The impact of antibiotic associated diarrhea on health related quality of life in hospitalized patients

Objective. To determine the impact of antibiotic associated diarrhea (AAD) on health related quality of life (HRQOL) in hospitalized patients compared to matched controls without diarrhea. ^ Methods. This is a hospital-based, matched case-control study using secondary data from a prospective cohort trial of patients receiving broad-spectrum antibiotics. One hundred and seventy-eight patients were recruited of whom 18 (10%) reported having antibiotic associated diarrhea. Two non-diarrhea controls were selected for each case with diarrhea giving a final sample of 18 cases and 36 controls. Responses from Short Form (SF) 36 questionnaire were aggregated into eight domains including physical functioning (PF), role-functioning physical (RP), bodily pain (BP), general health (GH), social functioning (SF), vitality (VT), role-functioning emotional (RE), and mental health (MH). The eight domains were compared between cases and controls. A GI targeted HRQOL measure was administered to 13 patients with AAD. Responses from the disease-specific instrument were combined in eight subscale scores: dysphoria, interference with activity, body image, health worry, food avoidance, social reaction, sex, and relationships. ^ Results. The sample consisted of 41 females (75.9%) and 13 males (24.1%) aged 53.5 ± 14.4 years (range: 21-76 years). Twenty five patients (46%) were Caucasian, 15 (27%) were African American, 13(24%) were Hispanic and 1(2%) was Asian. In univariate analysis, no significant differences in quality of life outcomes were observed in each of the SF36 domains between the case patients and matched controls. There were trends for decreased scores on the role-functioning physical, bodily pain, general health, social functioning, mental health, and mental summary domains. In total, 7 of 8 domain scores were lower in patients with AAD and 5 of 8 domain scores were lower by more than 5 points (considered clinically significant). Controlling for age, patients with antibiotic associated diarrhea had significantly lower general health, vitality, and mental health scale scores (p<0.05 each). The disease-specific scores were significantly lower in patients with AAD than those in published norms for irritable bowel syndrome patients. ^ Conclusion. In this small sample, several areas of decreased QOL in patients with AAD compared to matched controls were noted. A larger sample size to validate these results is necessary.^

Desarrollo de una herramienta para el análisis de imágenes cerebrales multimodales

En la actualidad, el desarrollo de las tecnologías de adquisición y análisis de imagen médica permiten la implementación de aplicaciones con fines clínicos y de investigación que resulten en un mejor conocimiento de la fisiopatología humana y, en la práctica, un mejor tratamiento a los pacientes. Utilizando imágenes de resonancia magnética nuclear y de tomografía por emisión de fotón único (SPECT), se han desarrollado los algoritmos de registro necesarios para ser integrados en dos procedimientos de uso clínico. En el primero de estos procedimientos, el objetivo es la localización del foco epileptogénico en casos de epilepsia fármacorresistente mediante el protocolo denominado SISCOM. En este contexto, se ha implementado un algoritmo de registro rígido para el corregistro de Resonancia Magnética e imagen SPECT interictal, así como un algoritmo de registro afín que ayuda a la segmentación de imágenes SPECT. Así mismo, se han validado y caracterizado ambos algoritmos y la librería sobre la que se han desarrollado. El segundo procedimiento tiene por objeto la cuantificación de neurotransmisores dopaminérgicos para el diagnóstico de Enfermedad de Parkinson. En este contexto, se ha implementado un algoritmo de registro SPECT-template necesario para realizar correctamente la cuantificación.

FocusDET, a new toolbox for SISCOM analysis. Evaluation of the registration accuracy using monte carlo simulation

Subtraction of Ictal SPECT Co-registered to MRI (SISCOM) is an imaging technique used to localize the epileptogenic focus in patients with intractable partial epilepsy. The aim of this study was to determine the accuracy of registration algorithms involved in SISCOM analysis using FocusDET, a new user-friendly application. To this end, Monte Carlo simulation was employed to generate realistic SPECT studies. Simulated sinograms were reconstructed by using the Filtered BackProjection (FBP) algorithm and an Ordered Subsets Expectation Maximization (OSEM) reconstruction method that included compensation for all degradations. Registration errors in SPECT-SPECT and SPECT-MRI registration were evaluated by comparing the theoretical and actual transforms. Patient studies with well-localized epilepsy were also included in the registration assessment. Global registration errors including SPECT-SPECT and SPECT-MRI registration errors were less than 1.2 mm on average, exceeding the voxel size (3.32 mm) of SPECT studies in no case. Although images reconstructed using OSEM led to lower registration errors than images reconstructed with FBP, differences after using OSEM or FBP in reconstruction were less than 0.2 mm on average. This indicates that correction for degradations does not play a major role in the SISCOM process, thereby facilitating the application of the methodology in centers where OSEM is not implemented with correction of all degradations. These findings together with those obtained by clinicians from patients via MRI, interictal and ictal SPECT and video-EEG, show that FocusDET is a robust application for performing SISCOM analysis in clinical practice.

Operative GABAergic inhibition in hippocampal CA1 pyramidal neurons in experimental epilepsy

Patch–clamp recordings of CA1 interneurons and pyramidal cells were performed in hippocampal slices from kainate- or pilocarpine-treated rat models of temporal lobe epilepsy. We report that γ-aminobutyric acid (GABA)ergic inhibition in pyramidal neurons is still functional in temporal lobe epilepsy because: (i) the frequency of spontaneous GABAergic currents is similar to that of control and (ii) focal electrical stimulation of interneurons evokes a hyperpolarization that prevents the generation of action potentials. In paired recordings of interneurons and pyramidal cells, synchronous interictal activities were recorded. Furthermore, large network-driven GABAergic inhibitory postsynaptic currents were present in pyramidal cells during interictal discharges. The duration of these interictal discharges was increased by the GABA type A antagonist bicuculline. We conclude that GABAergic inhibition is still present and functional in these experimental models and that the principal defect of inhibition does not lie in a complete disconnection of GABAergic interneurons from their glutamatergic inputs.

Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes

The neurosteroid 3α-hydroxysteroid-5α-pregnan-20-one (allopregnanolone) acts as a positive allosteric modulator of γ-aminobutyric acid at γ-aminobutyric acid type A receptors and hence is a powerful anxiolytic, anticonvulsant, and anesthetic agent. Allopregnanolone is synthesized from progesterone by reduction to 5α-dihydroprogesterone, mediated by 5α-reductase, and by reduction to allopregnanolone, mediated by 3α-hydroxysteroid dehydrogenase (3α-HSD). Previous reports suggested that some selective serotonin reuptake inhibitors (SSRIs) could alter concentrations of allopregnanolone in human cerebral spinal fluid and in rat brain sections. We determined whether SSRIs directly altered the activities of either 5α-reductase or 3α-HSD, using an in vitro system containing purified recombinant proteins. Although rats appear to express a single 3α-HSD isoform, the human brain contains several isoforms of this enzyme, including a new isoform we cloned from human fetal brains. Our results indicate that the SSRIs fluoxetine, sertraline, and paroxetine decrease the Km of the conversion of 5α-dihydroprogesterone to allopregnanolone by human 3α-HSD type III 10- to 30-fold. Only sertraline inhibited the reverse oxidative reaction. SSRIs also affected conversions of androgens to 3α- and 3α, 17β-reduced or -oxidized androgens mediated by 3α-HSD type IIBrain. Another antidepressant, imipramine, was without any effect on allopregnanolone or androstanediol production. The region-specific expression of 3α-HSD type IIBrain and 3α-HSD type III mRNAs suggest that SSRIs will affect neurosteroid production in a region-specific manner. Our results may thus help explain the rapid alleviation of the anxiety and dysphoria associated with late luteal phase dysphoria disorder and major unipolar depression by these SSRIs.

Health-related quality of life and determinant factors in celiac disease. A population-based analysis of adult patients in Spain

Background: Celiac disease (CD) has a negative impact on the health-related quality of life (HRQL) of affected patients. Although HRQL and its determinants have been examined in Spanish CD patients specifically recruited in hospital settings, these aspects of CD have not been assessed among the general Spanish population. Methods: An observational, transversal study of a non-randomized, representative sample of adult celiac patients throughout all of Spain's Autonomous Regions. Subjects were recruited through celiac patient associations. A Spanish version of the self-administered Celiac Disease-Quality of Life (CD-QOL) questionnaire was used. Determinant factors of HRQL were assessed with the aid of multivariate analysis to control for confounding factors. Results: We analyzed the responses provided by 1,230 patients, 1,092 (89.2%) of whom were women. The overall mean value for the CD-QOL index was 56.3 ± 18.27 points. The dimension that obtained the most points was dysphoria, with 81.3 ± 19.56 points, followed by limitations with 52.3 ± 23.43 points; health problems, with 51.6 ± 26.08 points, and inadequate treatment, with 36.1 ± 21.18 points. Patient age and sex, along with time to diagnosis, and length of time on a gluten-free diet were all independent determinant factors of certain dimensions of HRQL: women aged 31 to 40 expressed poorer HRQL while time to diagnosis and length of time on a gluten-free diet were determinant factors for better HRQL scores. Conclusions: The HRQL of adult Spanish celiac subjects is moderate, improving with the length of time patients remain on a gluten-free diet.

Does naltrexone treatment lead to depression? Findings from a randomized controlled trial in subjects with opioid dependence

Objective: Dysphoria and depression have been cited as side effects of the opioid antagonist naltrexone. We aimed to assess whether depressive symptoms are a clinically relevant side effect in a population receiving naltrexone as a treatment for opioid dependence. Methods: We carried out a randomized controlled, open-label trial comparing rapid opiate detoxification under anesthesia and naltrexone treatment with continued methadone maintenance at the Alcohol and Drug Service, Royal Brisbane and Women's Hospital, Brisbane, Australia. The study subjects were patients stabilized on methadone maintenance treatment for heroin dependence who wished to transfer to naltrexone treatment. The Beck Depression Inventory, State-Trait Anxiety Inventory and Opiate Treatment Index subscales for heroin use and social functioning were used at baseline and follow-up assessments at 1, 2, 3 and 6 months. Results: Forty-two participants were allocated to receive naltrexone treatment, whereas 38 continued methadone maintenance as the control condition. Participants who received naltrexone did not exhibit worsening of depressive symptoms. In participants attending all follow-up assessments, there was a trend for those receiving naltrexone to exhibit an improvement in depression over time compared with the control group. Participants who were adherent to naltrexone treatment exhibited fewer depressive symptoms than those who were nonadherent. Conclusions: These results suggest that depression need not be considered a common adverse effect of naltrexone treatment or a treatment contraindication and that engaging with or adhering to naltrexone treatment may be associated with fewer depressive symptoms.

Postcesarean pelvic floor dysfunction contributes to undisclosed psychosocial morbidity

OBJECTIVE: To estimate the prevalence and severity of postcesarean pelvic dysfunction. STUDY DESIGN: Using biopsychosocial interviewing at home, 184 postcesarean primiparas were compared to 100 vaginally delivered women regarding symptoms of stress incontinence, anal incontinence and dyspareunia. Delivery details were confirmed from medical records. RESULTS: Comparison of postcesarean vs. vaginally delivered women revealed stress incontinence in 33% vs. 54% and dyspareunia in 27% vs. 46%, both differences reaching statistical significance, unlike anal incontinence, which was manifest in 51% vs. 44%. When compared to emergency cesarean the relative risk of stress incontinence following an elective cesarean was 0.99 (0.71, 1.39), of dyspareunia 1.02 and of anal incontinence 1.05, indicating no statistically significant difference. Thirty (22%) stress incontinent and 4 (3%) fecally incontinent mothers used pads continuously, suggesting severe physical morbidity. Severe dysphoria (depression) was expressed by 41 (35%) stress incontinent mothers, 38 (30%) with dyspareunia and 34 (26%) with anal incontinence; the association of severe dysphoria with dyspareunia was statistically significant (OR = 2.504 [1.362, 4.602]). Few women came forward to seek help. CONCLUSION: Pelvic dysfunction was similar after elective or emergency cesarean. Compared to vaginal delivery, postcesarean stress incontinence and dyspareunia were less frequent but biopsychosocial morbidity could be severe.

Intentional forgetting in depressed states

The aim of this thesis was to extend previous research on intentional forgetting in depressed states. The first experiment used the think/no-think paradigm, and found that although dysphoric individuals were significantly worse at suppressing emotional (positive and negative) words than non-dysphoric individuals, both groups were unsuccessful at direct thought suppression. However, there was no effect of rumination on dysphoric individuals' ability to intentionally forget material. Furthermore, there was also no group differences in attentional measures of Stroop and IDEO. The second experiment involved modifying the TNT task, by including the use of substitute words in the suppression phase, in order to determine whether recalling substitute words during suppression would increase the level of forgetting. The findings from the study revealed that both dysphoric and non-dysphoric individuals were successful at intentionally forgetting neutral words using a thought substitution strategy. However, both groups were impaired at suppressing words in the direct thought substitution condition. The third experiment investigated the influence of thought substitution on intentional forgetting of emotional words in dysphoria. The study replicated experiment two, but used emotional (i.e. positive and depression-relevant) words instead of neutral words. The study found that dysphoric individuals were still impaired in their ability to suppress emotional material. Furthermore, dysphoric individuals were recalling significantly more depression­ relevant respond and previously-suppressed words. The fourth experiment examined the role of executive control in intentional forgetting. In the study, dysphoric and non­ dysphoric participants were categorised as having good or poor executive control based on their scores on the operation span with words task (OSPAN). The study found that non-dysphoric individuals with good control demonstrated successful suppression. However, dysphoric individuals with good control were unsuccessful at suppression. The fifth experiment investigated whether experimentally induced changes in mood state would alter an individual's ability to intentionally forget emotional material. Non-dysphoric healthy participants were given a positive or negative autobiographical memory and music mood induction. They completed two modified think/no-think tasks, one prior to the mood induction and one after the mood induction. The study found that transient negative mood state impaired intentional forgetting of depression-relevant material. Summary: Taken together, the findings suggest that individuals in a depressed mood are impaired in their ability to intentionally forget emotional material, even with the use of a thought substitution strategy. Furthermore, the findings implicate poor executive control and negative mood state in impaired intentional forgetting. An important theme emerging from the findings was the role of an inhibitory mechanism in intentional forgetting. The findings reported in this thesis suggest that thought substitution involves engaging an inhibitory control mechanism that contributes to successful intentional forgetting. The findings have clear implications on depressed individuals everyday functioning, and suggest that even with the presence of effective distraction, dysphoric indivduals are imapired in their ability to suppress emotional material. Furthermore, it is suggested that impaired intentional forgetting of emotional material may contribute to the maintenance of depressed mood, and could potentially worsen ongoing depression.

Magnetoencephalography in epilepsy

Magnetoencephalographic (MEG) signals, like electroencephalographic (EEG) measures, are the direct extracranial manifestations of neuronal activation. The two techniques can detect time-varying changes in electromagnetic activity with a sub-millisecond time resolution. Extra-cranial electromagnetic measures are the cornerstone of the non-invasive diagnostic armamentarium in patients with epilepsy. Their extremely high temporal resolution – comparable to intracranial recordings – is the basis for a precise definition of onset and propagation of ictal and interictal abnormalities. Given the cost of the infrastructure and equipment, MEG has yet to develop into a routinely applicable diagnostic tool in clinical settings. However, in recent years, an increasing number of patients with epilepsy have been investigated – usually in the context of presurgical evaluation of refractory epilepsies – and initial encouraging results have been reported. We will briefly review the principles and the technology behind MEG and its contribution in the diagnostic work-up of patients with epilepsy.

Sub-cortical sources of the somatosensory pathway are hypoactive in migraine interictally:a Functional Source Separation analysis

Background: Recent morpho-functional evidence pointed out that abnormalities in the thalamus could play a major role in the expression of migraine neurophysiological and clinical correlates. Whether this phenomenon is primary or secondary to its functional disconnection from the brainstem remains to be determined. We used a Functional Source Separation algorithm of EEG signal to extract the activity of the different neuronal pools recruited at different latencies along the somatosensory pathway in interictal migraine without aura (MO) patients. Methods: Twenty MO patients and 20 healthy volunteers (HV) underwent EEG recording. Four ad-hoc functional constraints, two sub-cortical (FS14 at brainstem and FS16 at thalamic level) and two cortical (FS20 radial and FS22 tangential parietal sources), were used to extract the activity of successive stages of somatosensory information processing in response to the separate left and right median nerve electric stimulation. A band-pass digital filter (450-750 Hz) was applied offline in order to extract high-frequency oscillatory (HFO) activity from the broadband EEG signal. Results: In both stimulated sides, significant reduced sub-cortical brainstem (FS14) and thalamic (FS16) HFO activations characterized MO patients when compared with HV. No difference emerged in the two cortical HFO activations between the two groups. Conclusions: Present results are the first neurophysiological evidence supporting the hypothesis that a functional disconnection of the thalamus from the subcortical monoaminergic system may underline the interictal cortical abnormal information processing in migraine. Further studies are needed to investigate the precise directional connectivity across the entire primary subcortical and cortical somatosensory pathway in interictal MO. Written informed consent to publication was obtained from the patient(s).

Impaired brainstem and thalamic high-frequency oscillatory EEG activity in migraine between attacks

INTRODUCTION: We investigated whether interictal thalamic dysfunction in migraine without aura (MO) patients is a primary determinant or the expression of its functional disconnection from proximal or distal areas along the somatosensory pathway. METHODS: Twenty MO patients and twenty healthy volunteers (HVs) underwent an electroencephalographic (EEG) recording during electrical stimulation of the median nerve at the wrist. We used the functional source separation algorithm to extract four functionally constrained nodes (brainstem, thalamus, primary sensory radial, and primary sensory motor tangential parietal sources) along the somatosensory pathway. Two digital filters (1-400 Hz and 450-750 Hz) were applied in order to extract low- (LFO) and high- frequency (HFO) oscillatory activity from the broadband signal. RESULTS: Compared to HVs, patients presented significantly lower brainstem (BS) and thalamic (Th) HFO activation bilaterally. No difference between the two cortical HFO as well as in LFO peak activations between the two groups was seen. The age of onset of the headache was positively correlated with HFO power in the right brainstem and thalamus. CONCLUSIONS: This study provides evidence for complex dysfunction of brainstem and thalamocortical networks under the control of genetic factors that might act by modulating the severity of migraine phenotype.

A phenomenology of crack abuse

The aim of this dissertation is to identify, describe, and explain the common experiences defining the crack abuser's life-world. Its method is phenomenological. Using basic cybernetic premises, a neurophysiologically oriented phenomenological framework concerning the constitution of thoughts, memories, and perceptions is first written. The framework is designed to hypothetically represent the neuropathology of crack abuse within a perspective that prescinds and describes the constitution, flow, and interdependence of experience. After the framework is written, the dissertation outlines the neuro-psychopharmacology of crack abuse and delimits crack abusers as a specific group within the more general population of cocaine users. It then represents the neuropathology of crack abuse within its phenomenological framework and uses the first-person accounts of forty-two crack dependents to actualize a phenomenological sketch of the crack abuser's life-world. The ethnographies afford the possibility of writing a “thick” description of the crack abuser's daily life—one that communicates the substance, order, and subjective and cultural dimensions of the dependent's defining experiences. ^ The dissertation's goals are successfully realized. The framework written and the ethnographies recorded and transcribed, the dissertation is able to identify, describe, and to a certain extent explain some of the common experiences defining the crack abusers life-world. The dissertation concludes that the crack abuser's life-world is organized around three primary and four secondary experiences. His primary experiences include: (1) an almost complete, yet fleeting, satisfaction of the ego's innate insufficiency and sublime, erotic-like stimulation of its core, (2) a fundamental inclination and expansion of the uniquely oriented euphoria-dysphoria dynamic that vivifies and orients the flow of consciousness, and (3) a change in the ego's innate structure. His secondary experiences include: (a) a characteristic aiming of projects, actions, and conduct toward the procurement and consumption of crack, (b) a denigration in the hold of legitimations and institutionalizations on the thematic field, (c) a strict alignment and a contraction in the scope of logical types pointing to the salient experiences within the stock of knowledge, and (d) for some crack abusers, ontological insecurity, despair, and exhaustion. ^