Idil Cavus

Extracellular metabolites in the cortex and hippocampus of epileptic patients

Interictal brain energy metabolism and glutamate–glutamine cycling are impaired in epilepsy and may contribute to seizure generation. We used the zero‐flow microdialysis method to measure the extracellular levels of glutamate, glutamine, and the major energy substrates glucose and lactate in the epileptogenic and the nonepileptogenic cortex and hippocampus of 38 awake epileptic patients during the interictal period. Depth electrodes attached to microdialysis probes were used to identify the epileptogenic and the nonepileptogenic sites. The epileptogenic hippocampus had surprisingly high basal glutamate levels, low glutamine/glutamate ratio, high lactate levels, and indication for poor glucose utilization. The epileptogenic cortex had only marginally increased glutamate levels. We propose that interictal energetic deficiency in the epileptogenic hippocampus could contribute to impaired glutamate reuptake and glutamate–glutamine cycling, resulting in persistently increased extracellular glutamate, glial and neuronal toxicity, increased lactate production together with poor lactate and glucose utilization, and ultimately worsening energy metabolism. Our data suggest that a different neurometabolic process underlies the neocortical epilepsies. Ann Neurol 2005;57:226–235

Influence of estradiol, stress, and 5-HT2A agonist treatment on Brain-Derived Neurotrophic Factor expression in female rats

BACKGROUND Estradiol affects neuronal plasticity, mood, and cognition. We examined the effects of the estrous cycle, acute and chronic estradiol treatments on BDNF mRNA expression in the hippocampus and cortex of female rats. The roles of 5-HT2A receptors and of stress on the BDNF mRNA regulation were also explored. METHODS BDNF mRNA levels were measured using in situ hybridization at proestrus and estrus, and following acute and chronic estradiol treatment of acutely and chronically ovariectomized (OVX) female rats. Some rats were pretreated with 5-HT2A agonist and antagonist, and another group was subjected to two-hour immobilization stress. RESULTS BDNF mRNA levels in the dentate gyrus and the medial prefrontal cortex were decreased during estrus, when estradiol levels are highest. Acute estradiol treatment decreased hippocampal BDNF mRNA in acutely OVX rats, but neither acute nor chronic estradiol had effect in chronically OVX rats. Estradiol pretreatment reduced the 5-HT2A receptor-mediated cortical upregulation in BDNF mRNA and did not effect the stress-induced down-regulation of BDNF mRNA in the dentate gyrus. CONCLUSIONS The duration of the estradiol treatment and the duration of the ovarian hormone deprivation are important factors in the regulation of BDNF synthesis and possibly in the functional outcome of estrogen treatment.

Neurometabolism in human epilepsy

Purpose: Because of the large and continuous energetic requirements of brain function, neurometabolic dysfunction is a key pathophysiologic aspect of the epileptic brain. Additionally, neurometabolic dysfunction has many self‐propagating features that are typical of epileptogenic processes, that is, where each occurrence makes the likelihood of further mitochondrial and energetic injury more probable. Thus abnormal neurometabolism may be not only a chronic accompaniment of the epileptic brain, but also a direct contributor to epileptogenesis.

Decreased hippocampal volume on MRI is associated with increased extracellular glutamate in epilepsy patients

Purpose: Temporal lobe epilepsy (TLE) is associated with smaller hippocampal volume and with elevated extracellular (EC) glutamate levels. We investigated the relationship between the hippocampal volume and glutamate in refractory TLE patients.

The interaction of neuroactive steroids and GABA in the development of neuropsychiatric disorders in women

A growing literature suggests that hormonal fluctuations occurring across the menstrual cycle, during and after pregnancy, and during the menopausal transition are associated with onset of affective disorders or exacerbation of existing disorders. This influence of the neuroendocrine system on psychiatric disorders is thought to be mediated by an abnormality in central nervous system response to neuroactive steroids such as estradiol, progesterone, and the progesterone derivative allopregnanolone (ALLO). This interplay is considerably complex as neuroactive steroids modulate the function of multiple neurotransmitter systems throughout various stages of development. While one could choose to study any number of steroid-neurotransmitter interactions, our group in addition to others has focused our investigative efforts on unraveling the contribution of neuroactive steroids to psychiatric syndromes and disorders via their modulation of gamma aminobutyric acid (GABA), the brains major inhibitory neurotransmitter. The goal of this article is two-fold: to synthesize the clinical and preclinical research focusing on the interplay between neuroactive steroids and GABA as they relate to neuropsychiatric and substance use disorders in women and to integrate data from our laboratory using proton magnetic resonance spectroscopy into this context.

Impaired Visual Cortical Plasticity in Schizophrenia

BACKGROUND Impaired cortical plasticity may be part of the core pathophysiology of schizophrenia (SZ). Long-term potentiation is a form of neuroplasticity that has been recently demonstrated in humans by showing that repetitive visual stimulation produces lasting enhancement of visual evoked potentials (VEP). Using this paradigm, we examined whether visual cortical plasticity is impaired in SZ. METHODS Electroencephalographic data were recorded from 19 SZ and 22 healthy control (HC) subjects during a visual long-term potentiation paradigm. Visual evoked potentials were elicited by standard visual stimuli (∼.83 Hz, 2-minute blocks) at baseline and at 2, 4, and 20 minutes following exposure to visual high-frequency stimulation (HFS) (∼8.8 Hz, 2 minutes) designed to induce VEP potentiation. To ensure attentiveness during VEP assessments, subjects responded with a button press to infrequent (10%) target stimuli. Visual evoked potentials were subjected to principal components analysis. Two negative-voltage components prominent over occipital-parietal electrode sites were evident at 92 msec (C1) and at 146 msec (N1b). Changes in C1 and N1b component scores from baseline to the post-HFS assessments were compared between groups. RESULTS High-frequency stimulation produced sustained potentiation of visual C1 and N1b in HCs but not in SZs. The HCs and SZs had comparable HFS-driven electroencephalographic visual steady state responses. However, greater visual steady state responses to the HFS predicted greater N1b potentiation in HCs but not in SZs. Schizophrenia patients with greater N1b potentiation decreased their reaction times to target stimuli. CONCLUSIONS Visual cortical plasticity is impaired in schizophrenia, consistent with hypothesized deficits in N-methyl-D-aspartate receptor function.

The corollary discharge in humans is related to synchronous neural oscillations

How do animals distinguish between sensations coming from external sources and those resulting from their own actions? A corollary discharge system has evolved that involves the transmission of a copy of motor commands to sensory cortex, where the expected sensation is generated. Through this mechanism, sensations are tagged as coming from self, and responsiveness to them is minimized. The present study investigated whether neural phase synchrony between motor command and auditory cortical areas is related to the suppression of the auditory cortical response. We recorded electrocorticograms from the human brain during a vocalizing/listening task. Neural phase synchrony between Brocas area and auditory cortex in the gamma band (35 to ∼50 Hz) in the 50-msec time window preceding speech onset was greater during vocalizing than during listening to a playback of the same spoken sounds. Because prespeech neural synchrony was correlated (r = −.83, p = .006), with the subsequent suppression of the auditory cortical response to the spoken sound, we hypothesize that phase synchrony in the gamma band between Brocas area and auditory cortex is the neural instantiation of the transmission of a copy of motor commands. We suggest that neural phase synchrony of gamma frequencies may contribute to transmission of corollary discharges in humans.

Review of microdialysis in brain tumors, from concept to application: First annual Carolyn Frye-Halloran symposium

In individuals with brain tumors, pharmacodynamic and pharmacokinetic studies of therapeutic agents have historically used analyses of drug concentrations in serum or cerebrospinal fluid, which unfortunately do not necessarily reflect concentrations within the tumor and adjacent brain. This review article introduces to neurological and medical oncologists, as well as pharmacologists, the application of microdialysis in monitoring drug metabolism and delivery within the fluid of the interstitial space of brain tumor and its surroundings. Microdialysis samples soluble molecules from the extracellular fluid via a semipermeable membrane at the tip of a probe. In the past decade, it has been used predominantly in neurointensive care in the setting of brain trauma, vasospasm, epilepsy,and intracerebral hemorrhage. At the first Carolyn Frye-Halloran Symposium held at Massachusetts General Hospital in March 2002, the concept of microdialysis was extended to specifically address its possible use in treating brain tumor patients. In doing so we provide a rationale for the use of this technology by a National Cancer Institute consortium, New Approaches to Brain Tumor Therapy, to measure levels of drugs in brain tissue as part of phase 1 trials.

The role of sex steroids in catamenial epilepsy and premenstrual dysphoric disorder: Implications for diagnosis and treatment

Despite our understanding of hormonal influences on central nervous system (CNS) function, there is still much to learn about the pathogenesis of menstrual cycle-linked disorders. A growing literature suggests that the influence of sex steroids on neurological and psychiatric disorders is in part mediated by an aberrant CNS response to neuroactive steroids. Although sex steroids such as estradiol, progesterone, and the progesterone derivative allopregnanolone (ALLO) influence numerous neurotransmitter systems, it is their potent effect on the brains primary inhibitory and excitatory neurotransmitters gamma-aminobutyric acid (GABA) and glutamate that links the study of premenstrual dysphoric disorder (PMDD) and catamenial epilepsy (CE). After providing an overview of these menstrual cycle-linked disorders, this article focuses on the preclinical and clinical research investigating the role of estradiol and progesterone (via ALLO) in the etiology of PMDD and CE. Through exploration of the phenomenological and neurobiological overlap between CE and PMDD, we aim to highlight areas for future research and development of treatments for menstrual cycle-linked neuropsychiatric disorders.

Long-term potentiation (LTP) of human sensory-evoked potentials

Long-term potentiation (LTP) is the principal candidate synaptic mechanism underlying learning and memory, and has been studied extensively at the cellular and molecular level in laboratory animals. Inquiry into the functional significance of LTP has been hindered by the absence of a human model as, until recently, LTP has only been directly demonstrated in humans in isolated cortical tissue obtained from patients undergoing surgery, where it displays properties identical to those seen in non-human preparations. In this brief review, we describe the results of paradigms recently developed in our laboratory for inducing LTP-like changes in visual-, and auditory-evoked potentials. We describe how rapid, repetitive presentation of sensory stimuli leads to a persistent enhancement of components of sensory-evoked potential in normal humans. Experiments to date, investigating the locus, stimulus specificity, and NMDA receptor dependence of these LTP-like changes suggest that they have the essential characteristics of LTP seen in experimental animals. The ability to elicit LTP from non-surgical patients will provide a human model system allowing the detailed examination of synaptic plasticity in normal subjects and may have future clinical applications in the assessment of cognitive disorders. Copyright