Terence J O'Brien

Publications of Terence J O'Brien

• Should patients be routinely assessed for cerebral vasospasm after temporal lobe epilepsy surgery?

  Authors: Terence J O'Brien, Gregory D Cascino

  Neurology. 03/2012;

  Temporal lobe epilepsy (TLE) is the most common form of epilepsy that is resistant to antiepileptic drug treatment. Resective epilepsy surgery offers a substantially greater prospect of achievingTemporal lobe epilepsy (TLE) is the most common form of epilepsy that is resistant to antiepileptic drug treatment. Resective epilepsy surgery offers a substantially greater prospect of achieving seizure control than continued medical therapy, and is associated with better quality of life outcomes.(1) The nature of the resection performed in patients undergoing epilepsy surgery for drug-resistant TLE varies among centers and surgeons. The most common type of resection is an "anterior temporal lobectomy" based on the procedure developed by Falconer and colleagues in the 1960s.(2) This involves the excision of the mesial temporal structures, the anterior temporal pole, and 3-6.5 cm of the lateral temporal neocortex (usually sparing the superior temporal gyrus). More recently, some surgeons have adopted the "selective amygdalohippocampectomy" approach, first described by Wieser and Yasargil.(3) This procedure attempts to restrict the resection to the mesial temporal structures, via a pterional craniotomy and transsylvian approach, while minimizing the possibility of reduced function due to resection of anterior and lateral temporal structures,(3) especially neurocognitive deficits, as compared to the standard anterior temporal lobectomy procedure.(4) However, performing a selective amygdalohippocampectomy is technically challenging, and patients undergoing this procedure have a high incidence of cerebral vasospasm (CVS), possibly as a result of mechanical irritation of blood vessels and increased intracranial bleeding. CVS may occur in up to 50% of patients following a selective amygdalohippocampectomy, and can be associated with increased neurologic morbidity.(5) However, CVS may also occur following anterior temporal lobectomy(6); the incidence or clinical consequences have not been directly compared between the 2 types of epilepsy surgery procedures.

• Identification of new epilepsy treatments: Issues in preclinical methodology.

  Authors: Aristea S Galanopoulou, Paul S Buckmaster, Kevin J Staley, Solomon L Moshé, Emilio Perucca, Jerome Engel, Wolfgang Löscher, Jeffrey L Noebels, Asla Pitkänen, James Stables, H Steve White, Terence J O'Brien, Michele Simonato For The American Epilepsy Society Basic Science Committee And T...

  Epilepsia. 03/2012; 53(3):571-582.

  Preclinical research has facilitated the discovery of valuable drugs for the symptomatic treatment of epilepsy. Yet, despite these therapies, seizures are not adequately controlled in a third of allPreclinical research has facilitated the discovery of valuable drugs for the symptomatic treatment of epilepsy. Yet, despite these therapies, seizures are not adequately controlled in a third of all affected individuals, and comorbidities still impose a major burden on quality of life. The introduction of multiple new therapies into clinical use over the past two decades has done little to change this. There is an urgent demand to address the unmet clinical needs for: (1) new symptomatic antiseizure treatments for drug-resistant seizures with improved efficacy/tolerability profiles, (2) disease-modifying treatments that prevent or ameliorate the process of epileptogenesis, and (3) treatments for the common comorbidities that contribute to disability in people with epilepsy. New therapies also need to address the special needs of certain subpopulations, that is, age- or gender-specific treatments. Preclinical development in these treatment areas is complex due to heterogeneity in presentation and etiology, and may need to be formulated with a specific seizure, epilepsy syndrome, or comorbidity in mind. The aim of this report is to provide a framework that will help define future guidelines that improve and standardize the design, reporting, and validation of data across preclinical antiepilepsy therapy development studies targeting drug-resistant seizures, epileptogenesis, and comorbidities.

• Focal administration of neuropeptide Y into the S2 somatosensory cortex maximally suppresses absence seizures in a genetic rat model.

  Authors: Leena van Raay, Valentina Jovanovska, Margaret J Morris, Terence J O'Brien

  Epilepsia. 03/2012; 53(3):477-84.

  Purpose:  Neuropeptide Y (NPY) is an inhibitory neurotransmitter that suppresses focal and generalized seizures in animal models. In this study, we investigated the sites within the thalamocorticalPurpose:  Neuropeptide Y (NPY) is an inhibitory neurotransmitter that suppresses focal and generalized seizures in animal models. In this study, we investigated the sites within the thalamocortical circuit that NPY acts to suppress seizures in genetic absence epilepsy rats from Strasbourg (GAERS). Methods:  In conscious freely moving GAERS, NPY was administered via intracerebral microcannulae implanted bilaterally into one of the following regions: primary somatosensory cortex (S1), secondary somatosensory cortex (S2), the primary motor cortex (M1), caudal nucleus reticular thalamus (nRT), or ventrobasal thalamus (VB). Animals received vehicle and up to three doses of NPY, in a randomized order. Electroencephalography (EEG) recordings were carried out for 30 min prior to injection and 90 min after the injection of NPY or vehicle. Key Findings:  Focal microinjections of NPY into the S2 cortex suppressed seizures in a dose-dependent manner, with the response being significantly different at the highest dose (1.5 mm) compared to vehicle for total time in seizures postinjection (7.2 ± 3.0% of saline, p < 0.01) and average number of seizures (9.4 ± 4.9% of saline, p < 0.05). In contrast NPY microinjections into the VB resulted in an aggravation of seizures. Significance:  NPY produces contrasting effects on absence-like seizures in GAERS depending on the site of injection within the thalamocortical circuit. The S2 is the site at which NPY most potently acts to suppress absence-like seizures in GAERS, whereas seizure-aggravating effects are seen in the VB. These results provide further evidence to support the proposition that these electroclinically "generalized" seizures are being driven by a topographically restricted region within the somatosensory cortex.

• T-type calcium channel blockers that attenuate thalamic burst firing and suppress absence seizures.

  Authors: Elizabeth Tringham, Kim L Powell, Stuart M Cain, Kristy Kuplast, Janette Mezeyova, Manjula Weerapura, Cyrus Eduljee, Xinpo Jiang, Paula Smith, Jerrie-Lynn Morrison, Nigel C Jones, Emma Braine, Gil Rind, Molly Fee-Maki, David Parker, Hassan Pajouhesh, Manjeet Parmar, Terence J O'Brien, Terrance P Snutch

  Science translational medicine. 02/2012; 4(121):121ra19.

  Absence seizures are a common seizure type in children with genetic generalized epilepsy and are characterized by a temporary loss of awareness, arrest of physical activity, and accompanyingAbsence seizures are a common seizure type in children with genetic generalized epilepsy and are characterized by a temporary loss of awareness, arrest of physical activity, and accompanying spike-and-wave discharges on an electroencephalogram. They arise from abnormal, hypersynchronous neuronal firing in brain thalamocortical circuits. Currently available therapeutic agents are only partially effective and act on multiple molecular targets, including γ-aminobutyric acid (GABA) transaminase, sodium channels, and calcium (Ca(2+)) channels. We sought to develop high-affinity T-type specific Ca(2+) channel antagonists and to assess their efficacy against absence seizures in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model. Using a rational drug design strategy that used knowledge from a previous N-type Ca(2+) channel pharmacophore and a high-throughput fluorometric Ca(2+) influx assay, we identified the T-type Ca(2+) channel blockers Z941 and Z944 as candidate agents and showed in thalamic slices that they attenuated burst firing of thalamic reticular nucleus neurons in GAERS. Upon administration to GAERS animals, Z941 and Z944 potently suppressed absence seizures by 85 to 90% via a mechanism distinct from the effects of ethosuximide and valproate, two first-line clinical drugs for absence seizures. The ability of the T-type Ca(2+) channel antagonists to inhibit absence seizures and to reduce the duration and cycle frequency of spike-and-wave discharges suggests that these agents have a unique mechanism of action on pathological thalamocortical oscillatory activity distinct from current drugs used in clinical practice.

• Targeting hyperphosphorylated tau with sodium selenate suppresses seizures in rodent models.

  Authors: Nigel C Jones, Thanh Nguyen, Niall M Corcoran, Dennis Velakoulis, Tracy Chen, Robert Grundy, Terence J O'Brien, Christopher M Hovens

  Neurobiology of disease. 12/2011; 45(3):897-901.

  Tau hyperphosphorylation has been implicated in the pathogenesis of a variety of forms of human epilepsy. Here we investigated whether treatment with sodium selenate, a drug which reducesTau hyperphosphorylation has been implicated in the pathogenesis of a variety of forms of human epilepsy. Here we investigated whether treatment with sodium selenate, a drug which reduces pathological hyperphosphorylated tau by enhancement of PP2A activity, would inhibit seizures in rodent models. In vitro, sodium selenate reduced tau phosphorylation in human neuroblastoma cells and reversed the increase in tau phosphorylation induced by the PP2A inhibitor, okadaic acid. Sodium selenate treatment was then tested against three different rodent seizure models. Firstly the propensity of 6-Hz electrical corneal stimulation to induce seizures in adult mice was assessed following acute treatment with different doses of sodium selenate. Secondly, the number of seizures induced by pentylenetetrazole (PTZ) was quantified in rats following chronic sodium selenate treatment via drinking water. Finally, amygdala kindled rats were chronically treated with sodium selenate in drinking water and the length and the severity of the seizures evoked by stimulation of the amygdala recorded. The results demonstrated a dose-dependent protection of sodium selenate against 6-Hz stimulation induced seizures, and significant reduction in the total number of seizures following PTZ injection. Amygdala kindled rats chronically treated with sodium selenate had significantly shorter seizure duration compared controls, with more pronounced effects observed as the duration of treatment increased. The results of this study indicate that targeting hyperphosphorylated tau by treatment with sodium selenate has anti-seizure effects in a broad range of rodent models, and may represent a novel approach to treatment of patients with epilepsy.

• Statistical parametric mapping demonstrates asymmetric uptake with Tc-99m ECD and Tc-99m HMPAO SPECT in normal brain.

  Authors: Benjamin H Brinkmann, David T Jones, Matt Stead, Noojan Kazemi, Terence J O'Brien, Elson L So, Hal Blumenfeld, Brian P Mullan, Gregory A Worrell

  Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 09/2011; 32(1):190-8.

  Tc-99m ethyl cysteinate diethylester (ECD) and Tc-99m hexamethyl propylene amine oxime (HMPAO) are commonly used for single-photon emission computed tomography (SPECT) studies of a variety ofTc-99m ethyl cysteinate diethylester (ECD) and Tc-99m hexamethyl propylene amine oxime (HMPAO) are commonly used for single-photon emission computed tomography (SPECT) studies of a variety of neurologic disorders. Although these tracers have been very helpful in diagnosing and guiding treatment of neurologic disease, data describing the distribution and laterality of these tracers in normal resting brain are limited. Advances in quantitative functional imaging have demonstrated the value of using resting studies from control populations as a baseline to account for physiologic fluctuations in cerebral perfusion. Here, we report results from 30 resting Tc-99m ECD SPECT scans and 14 resting Tc-99m HMPAO scans of normal volunteers with no history of neurologic disease. Scans were analyzed with regions of interest and with statistical parametric mapping, with comparisons performed laterally (left vs. right), as well as for age, gender, and handedness. The results show regions of significant asymmetry in the normal controls affecting widespread areas in the cerebral hemispheres, but most marked in superior parietotemporal region and frontal lobes. The results have important implications for the use of normal control SPECT images in the evaluation of patients with neurologic disease.

• The prescribing of antiepileptic drugs for pregnant Australian women.

  Authors: Frank J E Vajda, David Horgan, Samantha Hollingworth, Janet Graham, Alison A Hitchcock, Annie Roten, Terence J O'Brien, Cecile M Lander, Mervyn J Eadie

  The Australian & New Zealand journal of obstetrics & gynaecology. 09/2011; 52(1):49-53.

  Background:  It is not clear how widely it is appreciated in Australia that certain antiepileptic drugs, particularly valproate, are teratogenic. Aim:  The aim of the study is to assess trends in theBackground:  It is not clear how widely it is appreciated in Australia that certain antiepileptic drugs, particularly valproate, are teratogenic. Aim:  The aim of the study is to assess trends in the pattern of antiepileptic drug prescribing for pregnant women in Australia to determine whether drug use is optimal, particularly from the fetal viewpoint. Methods:  Analysis of data contained in the Australian Register of Antiepileptic Drugs, assessing trends in antiepileptic drug use correlated with pregnancy outcomes. Results:  Valproate was the only significant teratogen among the antiepileptic drugs in common use. There was a fetal malformation rate of 14.5% associated with its use in monotherapy, as compared with a rate of 3.15% in antiepileptic drug-unexposed pregnancies in women with epilepsy (OR = 5.23, 95% CI = 1.81, 15.09). The highest malformation rate associated with any other antiepileptic drug used in monotherapy was 5.0%, for carbamazepine. Neurologists had progressively prescribed valproate less frequently and in lower dosage than other classes of practitioner over the 10-year study period, with a parallel decrease in occurrence of fetal malformations in pregnancies referred to the Register. Other prescribers of valproate did not seem to have adopted these practices to the same extent and had not obtained similar degrees of reduction in the occurrence of fetal malformations. Conclusions:  Contemporary Australian obstetricians, even though they may not be valproate prescribers, when managing pregnancies in women taking valproate, need to be alert to the possibility that it may not be being used optimally from the fetal point of view, especially when not prescribed by neurologists.

• Confounding neurodegenerative effects of manganese for in vivo MR imaging in rat models of brain insults.

  Authors: Viviane Bouilleret, Lisa Cardamone, Cyril Liu, Amelia S Koe, Ke Fang, John P Williams, Damian E Myers, Terence J O'Brien, Nigel C Jones

  Journal of magnetic resonance imaging : JMRI. 07/2011; 34(4):774-84.

  To examine the long-term consequences of manganese exposure due to the use of manganese-enhanced magnetic resonance imaging (MEMRI) in a model of closed head injury, the fluid-percussion injury (FPI)To examine the long-term consequences of manganese exposure due to the use of manganese-enhanced magnetic resonance imaging (MEMRI) in a model of closed head injury, the fluid-percussion injury (FPI) model. Two groups of adult male Wistar rats (n = 72) were studied with either MEMRI, whereby rats receive MnCl(2) (100 mg/kg intraperitoneally) 24 hours prior to scanning, or standard MRI (sMRI) with no contrast agent. Rats from both groups underwent FPI or sham injury and were longitudinally assessed for 6 months for neurological toxicity using behavioral tests, EEG recording, and MRI scanning. Regardless of whether they received FPI, MEMRI animals showed progressive signs of cerebral toxicity compared with sMRI rats, including significantly reduced weight gain, progressive brain volume decrease, and increased anxiety and depressive-like behaviors. Long-term structural and functional consequences of using manganese as a contrast agent for MRI can confound experimental outcomes and must be taken into account when designing longitudinal imaging studies using manganese-enhanced MRI.

• Inhibition of dynamin by dynole 34-2 induces cell death following cytokinesis failure in cancer cells.

  Authors: Megan Chircop, Swetha Perera, Anna Mariana, Hui Lau, Maggie P C Ma, Jayne Gilbert, Nigel C Jones, Christopher P Gordon, Kelly A Young, Andrew Morokoff, Jennette Sakoff, Terence J O'Brien, Adam McCluskey, Phillip J Robinson

  Molecular cancer therapeutics. 07/2011; 10(9):1553-62.

  Inhibitors of mitotic proteins such as Aurora kinase and polo-like kinase have shown promise in preclinical or early clinical development for cancer treatment. We have reported that the MiTMAB classInhibitors of mitotic proteins such as Aurora kinase and polo-like kinase have shown promise in preclinical or early clinical development for cancer treatment. We have reported that the MiTMAB class of dynamin small molecule inhibitors are new antimitotic agents with a novel mechanism of action, blocking cytokinesis. Here, we examined 5 of the most potent of a new series of dynamin GTPase inhibitors called dynoles. They all induced cytokinesis failure at the point of abscission, consistent with inhibition of dynamin while not affecting other cell cycle stages. All 5 dynoles inhibited cell proliferation (MTT and colony formation assays) in 11 cancer cell lines. The most potent GTPase inhibitor, dynole 34-2, also induced apoptosis, as revealed by cell blebbing, DNA fragmentation, and PARP cleavage. Cell death was induced specifically following cytokinesis failure, suggesting that dynole 34-2 selectively targets dividing cells. Dividing HeLa cells were more sensitive to the antiproliferative properties of all 5 dynoles compared with nondividing cells, and nontumorigenic fibroblasts were less sensitive to cell death induced by dynole 34-2. Thus, the dynoles are a second class of dynamin GTPase inhibitors, with dynole 34-2 as the lead compound, that are novel antimitotic compounds acting specifically at the abscission stage.

• The rationale for pregnancy registers for women with epilepsy.

  Authors: Frank J E Vajda, Terence J O'Brien, Cecilie M Lander, Mervyn J Eadie

  The Medical journal of Australia. 07/2011; 195(1):8-9.

• Acute administration of typical and atypical antipsychotics reduces EEG gamma power, but only the preclinical compound LY379268 reduces the ketamine-induced rise in gamma power.

  Authors: Nigel C Jones, Maya Reddy, Paul Anderson, Michael R Salzberg, Terence J O'Brien, Didier Pinault

  The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP). 06/2011;

  A single non-anaesthetic dose of ketamine, a non-competitive NMDA receptor (NMDAR) antagonist with hallucinogenic properties, induces cognitive impairment and psychosis, and aggravates schizophreniaA single non-anaesthetic dose of ketamine, a non-competitive NMDA receptor (NMDAR) antagonist with hallucinogenic properties, induces cognitive impairment and psychosis, and aggravates schizophrenia symptoms in patients. In conscious rats an equivalent dose of ketamine induces key features of animal models of acute psychosis, including hyperlocomotor activity, deficits in prepulse inhibition and gating of auditory evoked potentials, and concomitantly increases the power of ongoing spontaneously occurring gamma (30-80 Hz) oscillations in the neocortex. This study investigated whether NMDAR antagonist-induced aberrant gamma oscillations could be modulated by acute treatment with typical and atypical antipsychotic drugs. Extradural electrodes were surgically implanted into the skull of adult male Wistar rats. After recovery, rats were subcutaneously administered either clozapine (1-5 mg/kg, n=7), haloperidol (0.05-0.25 mg/kg; n=8), LY379268 (a preclinical agonist at mGluR2/3 receptors: 0.3-3 mg/kg; n=5) or the appropriate vehicles, and 30 min later received ketamine (5 mg/kg s.c.). Quantitative measures of EEG gamma power and locomotor activity were assessed throughout the experiment. All three drugs significantly reduced the power of baseline EEG gamma oscillations by 30-50%, an effect most prominent after LY379268, and all inhibited ketamine-induced hyperlocomotor activity. However, only pretreatment with LY379268 attenuated trough-to-peak ketamine-induced gamma hyperactivity. These results demonstrate that typical and atypical antipsychotic drugs acutely reduce cortical gamma oscillations, an effect that may be related to their clinical efficacy.

• Utility and validity of a brief cognitive assessment tool in patients with epileptic and nonepileptic seizures.

  Authors: Mark Walterfang, Yves Choi, Terence J O'Brien, Nerissa Cordy, Raju Yerra, Sophia Adams, Dennis Velakoulis

  Epilepsy & behavior : E&B. 06/2011; 21(2):177-83.

  Cognitive impairment is not uncommon in patients with epilepsy, and may relate to the underlying pathophysiology of epilepsy, the effects of seizures, or epilepsy treatment. Formal neuropsychologicalCognitive impairment is not uncommon in patients with epilepsy, and may relate to the underlying pathophysiology of epilepsy, the effects of seizures, or epilepsy treatment. Formal neuropsychological testing is not available in many centers, and few cognitive screening tools have been validated in an epilepsy population. We aimed to ascertain the reliability and validity of a multidimensional cognitive screening instrument, the Neuropsychiatry Unit Cognitive Assessment Tool (NUCOG), in a mixed epilepsy population. One hundred sixty-one of 177 consecutive patients admitted to a video telemetry unit were assessed with the NUCOG and classified with respect to seizure semiology, and a subset (n=33) were formally neuropsychologically assessed. Scores did not differ between patients with epileptiform, those with nonepileptiform, and those with mixed EEGs on the NUCOG, nor between patients with focal and those with generalized epilepsies. Patients with a temporal lobe focus performed more poorly in general, and in memory specifically, than patients with an extratemporal focus. Scores on the NUCOG subscales Memory, Attention, and Executive Functioning correlated significantly with neuropsychological testing of these same domains, although patients were not impaired on measures of language or spatial function. The NUCOG appears to correlate strongly with neuropsychological functioning in a number of key cognitive areas affected in patients with epilepsy, and appears to robustly detect memory impairment in patients with temporal lobe epilepsy.

• Morphometric changes and molecular mechanisms in rat models of idiopathic generalized epilepsy with absence seizures.

  Authors: Nigel C Jones, Terence J O'Brien, Kim L Powell

  Neuroscience letters. 02/2011; 497(3):185-93.

  The idiopathic generalized epilepsies (IGEs), constituting approximately a quarter of all epilepsy cases, are presumed to arise primarily from genetic abnormalities. A minority of cases have beenThe idiopathic generalized epilepsies (IGEs), constituting approximately a quarter of all epilepsy cases, are presumed to arise primarily from genetic abnormalities. A minority of cases have been identified to be caused by mutations in a single gene, but in the vast majority, mutations in multiple genes are presumed to contribute to the development of epilepsy. Two rat models of IGE with absence seizures, the Genetic Epilepsy Rats from Strasbourg (GAERS) and Wistar Albino Glaxo from Rijswijk (WAG/Rij), have proven valuable for translational research. These models closely mimic the behavioural, electrophysiological, and pharmacological aspects of the human condition, with the epilepsy phenotype for both likely to have polygenic determinants. Research in these models, using molecular and in vivo imaging approaches, has provided important insights into the pathophysiology of IGE. Molecular and imaging techniques have the potential to provide researchers with tangible biomarkers of disease progression and the effects of intervention, and also to provide fundamental information about the causation and epileptogenic processes associated with IGE. This review discusses the published literature concerning the molecular changes and morphometric abnormalities identified in these models, as well as their potential relevance for human IGE.

• Early life stress enhancement of limbic epileptogenesis in adult rats: mechanistic insights.

  Authors: Gaurav Kumar, Nigel C Jones, Margaret J Morris, Sandra Rees, Terence J O'Brien, Michael R Salzberg

  PloS one. 01/2011; 6(9):e24033.

  Exposure to early postnatal stress is known to hasten the progression of kindling epileptogenesis in adult rats. Despite the significance of this for understanding mesial temporal lobe epilepsyExposure to early postnatal stress is known to hasten the progression of kindling epileptogenesis in adult rats. Despite the significance of this for understanding mesial temporal lobe epilepsy (MTLE) and its associated psychopathology, research findings regarding underlying mechanisms are sparse. Of several possibilities, one important candidate mechanism is early life 'programming' of the hypothalamic-pituitary-adrenal (HPA) axis by postnatal stress. Elevated corticosterone (CORT) in turn has consequences for neurogenesis and cell death relevant to epileptogenesis. Here we tested the hypotheses that MS would augment seizure-related corticosterone (CORT) release and enhance neuroplastic changes in the hippocampus. Eight-week old Wistar rats, previously exposed on postnatal days 2-14 to either maternal separation stress (MS) or control brief early handling (EH), underwent rapid amygdala kindling. We measured seizure-induced serum CORT levels and post-kindling neurogenesis (using BrdU). Three weeks post-kindling, rats were euthanized for histology of the hippocampal CA3c region (pyramidal cell counts) and dentate gyrus (DG) (to count BrdU-labelled cells and measure mossy fibre sprouting). As in our previous studies, rats exposed to MS had accelerated kindling rates in adulthood. Female MS rats had heightened CORT responses during and after kindling (p<0.05), with a similar trend in males. In both sexes total CA3c pyramidal cell numbers were reduced in MS vs. EH rats post-kindling (p = 0.002). Dentate granule cell neurogenesis in female rats was significantly increased post-kindling in MS vs. EH rats. These data demonstrate that early life stress results in enduring enhancement of HPA axis responses to limbic seizures, with increased hippocampal CA3c cell loss and augmented neurogenesis, in a sex-dependent pattern. This implicates important candidate mechanisms through which early life stress may promote vulnerability to limbic epileptogenesis in rats as well as to human MTLE and its associated psychiatric disorders.

• Progressive metabolic and structural cerebral perturbations after traumatic brain injury: an in vivo imaging study in the rat.

  Authors: Ying R Liu, Lisa Cardamone, R Edward Hogan, Marie-Claude Gregoire, John P Williams, Rod J Hicks, David Binns, Amelia Koe, Nigel C Jones, Damian E Myers, Terence J O'Brien, Viviane Bouilleret

  Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 11/2010; 51(11):1788-95.

  Traumatic brain injury (TBI) has a high incidence of long-term neurologic and neuropsychiatric morbidity. Metabolic and structural changes in rat brains were assessed after TBI using serial (18)F-FDGTraumatic brain injury (TBI) has a high incidence of long-term neurologic and neuropsychiatric morbidity. Metabolic and structural changes in rat brains were assessed after TBI using serial (18)F-FDG PET and 3-dimensional MRI in vivo. Rats underwent lateral fluid percussion injury (FPI; n = 16) or a sham procedure (n = 11). PET and MR images were acquired at 1 wk and at 1, 3, and 6 mo after injury. Morphologic changes were assessed using MRI-based regions of interest, and hippocampal shape changes were assessed with large-deformation high-dimensional mapping. Metabolic changes were assessed using region-of-interest analysis and statistical parametric mapping with the flexible factorial analysis. Anxiety-like behavior and learning were assessed at 1, 3, and 6 mo after injury. PET analyses showed widespread hypometabolism in injured rats, in particular involving the ipsilateral cortex, hippocampus, and amygdalae, present at 1 wk after FPI, most prominent at 1 mo, and then decreasing. Compared with the sham group, rats in the FPI group had decreased structural volume which progressively increased over 3-6 mo, occurring in the ipsilateral cortex, hippocampus, and ventricles after FPI (P < 0.05). Large-deformation high-dimensional mapping showed evolving hippocampal shape changes across the 6 mo after FPI. Injured rats displayed increased anxiety-like behavior (P < 0.05), but there were no direct correlations between the severity of the behavior abnormalities and functional or structural imaging changes. In selected brain structures, FPI induces early hypometabolism and delayed progressive atrophic changes that are dynamic and continue to evolve for months. These findings have implications for the understanding of the pathophysiology and evolution of long-term neurologic morbidity following TBI, and indicate an extended window for targeted neuroprotective interventions.

• Seizure-like thalamocortical rhythms initiate in the deep layers of the cortex in a co-culture model.

  Authors: Brendan E L Adams, Mervyn Kyi, Christopher A Reid, Damian E Myers, Shenghong Xu, David A Williams, Terence J O'Brien

  Experimental neurology. 11/2010; 227(1):203-9.

  The oscillatory rhythms underlying many physiological and pathological states, including absence seizures, require both the thalamus and cortices for full expression. A co-culture preparationThe oscillatory rhythms underlying many physiological and pathological states, including absence seizures, require both the thalamus and cortices for full expression. A co-culture preparation combining cortical and thalamic explants provides a unique model for investigating how such oscillations initiate and spread. Here we investigated the dynamics of synchronized thalamocortical activity by simultaneous measurement of field-potential recordings and rapid imaging of Ca(2+) transients by fluorescence methods. Spontaneous sustained hypersynchronized "seizure-like" oscillations required reciprocal cortico-thalamocortical connections. Isolated cortical explants can independently develop brief discharges, while thalamic explants alone were unable to do so. Rapid imaging of Ca(2+) transients demonstrated deep-layer cortical initiation of oscillatory network activity in both connected and isolated explants. Further, cortical explants derived from a rat model of genetic absence epilepsy showed increased bursting duration consistent with an excitable cortex. We propose that thalamocortical oscillatory network activity initiates in deep layers of the cortex with reciprocal thalamic interconnections enabling sustained hyper-synchronization.

• EEG dipole source localization of interictal spikes in non-lesional TLE with and without hippocampal sclerosis.

  Authors: Megan Oliva, Stefanie Meckes-Ferber, Annie Roten, Patricia Desmond, Rodney J Hicks, Terence J O'Brien

  Epilepsy research. 10/2010; 92(2-3):183-90.

  A subgroup of patients with non-lesional temporal lobe epilepsy (NLTLE) have no evidence of hippocampal sclerosis (HS) on MRI or on histopathology. It is controversial whether this represents aA subgroup of patients with non-lesional temporal lobe epilepsy (NLTLE) have no evidence of hippocampal sclerosis (HS) on MRI or on histopathology. It is controversial whether this represents a different clinicopathological syndrome from NLTLE with HS, or whether both subgroups represent different ends of the spectrum of mesial TLE. Here the EEG source localization dipoles were compared between NLTLE patients with HS (HS+) and without HS (HS-), and the relationship with post-surgical outcome was investigated. EEG dipole source localization of interictal epileptiform spikes recorded during prolonged video-EEG monitoring was performed from 22 consecutive HS+ and 12 HS- NLTLE patients. EEG was acquired using 29 scalp electrodes, including an inferior temporal row. Up to 13 spikes per patient were averaged and sources localized using a boundary element model based on the patients volumetric MRI. 21/34 patients (62%) had dipoles for the interictal spikes localized to the epileptogenic temporal lobe. The site of the intratemporal localization did not differ significantly between the HS+ and HS- patients, with the dipoles localizing to the mesial temporal region in 27% of HS+ and 25% of HS- patients. There was no significant relationship between the localization and orientation of the dipoles and the surgical outcome. The dipoles for interictal spikes do not differ between HS+ and HS- patients, suggesting that these subgroups of NLTLE patients do not have distinct cerebral generators.

• The use of computer-assisted-telephone-interviewing to diagnose seizures, epilepsy and idiopathic generalized epilepsy.

  Authors: Wendyl J D'Souza, Jim Stankovich, Terence J O'Brien, Simon Bower, Neil Pearce, Mark J Cook

  Epilepsy research. 09/2010; 91(1):20-7.

  Computer-assisted-telephone-interviewing (CATI), widely used in market research, could be a useful alternative for conducting diagnostic interviews in epilepsy epidemiology. We administered aComputer-assisted-telephone-interviewing (CATI), widely used in market research, could be a useful alternative for conducting diagnostic interviews in epilepsy epidemiology. We administered a diagnostic seizure questionnaire by CATI, interpreting the responses with standardized classification guidelines, compared against an epilepsy specialist's assessment, for agreement [Kappa statistic (kappa)], sensitivity, specificity, positive predictive value, negative predictive value and Youden's Index (YI). 99 outpatients with 382 lifetime events participated: 22 generalized-onset epilepsy [16 Idiopathic Generalized Epilepsy (IGE)], 59 partial-onset epilepsy, 12 non-epileptic and 6 uncertain. We observed almost perfect agreement in diagnosing epilepsy (kappa=0.94), seizure-onset types (kappa=0.84), simple or complex partial seizures (kappa=0.87), any generalized non-convulsive seizure (kappa=0.82), and IGE (kappa=0.82). Although substantial, agreement was not as close for secondarily generalized seizures (kappa=0.74), and generalized tonic-clonic seizures (kappa=0.79). This related more to under-recognition of individual generalized non-convulsive seizures rather than misinterpretation of partial seizures. Epilepsy diagnostic questionnaires administered by CATI and interpreted with standardized diagnostic guidelines can effectively classify epilepsy, most seizure types and IGE in outpatients with suspected seizures. Applying this diagnostic method in 'field' settings will allow firmer conclusions to be drawn on its wider epidemiological utility.

• Association between temporal lobe P-glycoprotein expression and seizure recurrence after surgery for pharmacoresistant temporal lobe epilepsy.

  Authors: Patrick Kwan, Hiu Ming Li, Eman Al-Jufairi, Rawia Abdulla, Michael Gonzales, Andrew H Kaye, Cassandra Szoeke, Ho Keung Ng, Ka Sing Wong, Terence J O'Brien

  Neurobiology of disease. 08/2010; 39(2):192-7.

  Surgery is recommended for pharmacoresistant temporal lobe epilepsy (TLE), but seizures recur in approximately one third of patients postsurgery. P-glycoprotein is an efflux multidrug transporterSurgery is recommended for pharmacoresistant temporal lobe epilepsy (TLE), but seizures recur in approximately one third of patients postsurgery. P-glycoprotein is an efflux multidrug transporter that is overexpressed in a range of epileptogenic pathologies. We hypothesized that increased expression of P-glycoprotein in the epileptogenic temporal lobe might be a marker for recurrence of pharmacoresistant seizures postsurgery. We performed immunohistochemistry on temporal lobe tissues resected from 69 patients who underwent anterior temporal lobectomy for pharmacoresistant TLE with histopathological proven hippocampal sclerosis. P-glycoprotein expression was rated by three pathologists independently. Patients with seizure recurrence (n=22) had greater number of positively stained capillaries (p=0.001) and higher P-glycoprotein immunoreactive score in capillaries (p=0.002) in the white matter of resected temporal lobe. The differences remained significant in multivariate analysis (p=0.002 and 0.006, respectively). The results suggest that P-glycoprotein expression in temporal lobe may be associated with seizure recurrence after surgery for pharmacoresistant TLE.

• Clinical characteristics and outcome in patients with psychogenic nonepileptic seizures.

  Authors: Simon G Jones, Terence J O' Brien, Sophia J Adams, Ramon Mocellin, Christine J Kilpatrick, Raju Yerra, John H Lloyd, Dennis Velakoulis

  Psychosomatic medicine. 04/2010; 72(5):487-97.

  To examine baseline clinical features of psychogenic nonepileptic seizures (PNES) in a large cohort and to investigate outcome over a period of up to 10 years. Studies investigating PNES have beenTo examine baseline clinical features of psychogenic nonepileptic seizures (PNES) in a large cohort and to investigate outcome over a period of up to 10 years. Studies investigating PNES have been limited by differences in diagnostic criteria, short follow-up periods, and the use of limited outcome measures. Patients with PNES were identified, using strict diagnostic criteria. Baseline neurological, neuropsychiatric, and neuroimaging data were obtained from medical records. Long-term outcome was assessed with ratings of seizures, psychopathology, and quality of life in a subset of the patients. Patients with PNES (n = 221) experienced long delays in diagnosis (mu, 5.6 years; standard deviation, 7.7 years) and high rates (>60%) of prolonged treatment with antiepileptic drugs. Compared with previous studies, a relatively low proportion (8.1% to 17.9%, depending on diagnostic criteria) had comorbid epilepsy. An unexpected finding was that 22.6% of PNES patients had magnetic resonance imaging abnormalities. Patients assessed at follow-up (n = 61) exhibited poor long-term outcomes with ongoing PNES, high rates of psychopathology, low rates of specialist follow-up, poor quality of life, and poor overall levels of functioning. These results demonstrate the need for earlier diagnosis of PNES and comorbidities and highlight the need for diagnostic and therapeutic approaches that combine neurological and psychiatric perspectives.