Alexander B. Kowski

Dopaminergic projections from the VTA substantially contribute to the mesohabenular pathway in the rat.

Recent evidence suggests that the lateral habenular complex (LHb) is a source of negative reward signals in midbrain dopaminergic neurons. LHb activity, in turn, is modulated by locally released dopamine, which is largely derived from the ventral tegmental area (VTA) via the mesohabenular pathway. Unfortunately, the presumed importance of this modulation has not been appreciated so far, as its intensity had been largely underestimated in previous reports. Consequently, the present study used contemporary techniques to reexamine the origin of dopaminergic fibers to the LHb. For this purpose, the retrograde tract-tracer gold-coupled wheatgerm agglutinin was injected into the LHb of fourteen rats. Four of these animals providing the most representative information were selected for detailed analysis. In total, 343 retrogradely labeled neurons were detected in the VTAs of these animals. By far most of them were found in the anterior VTA, accumulating in its ventral paramedian fields. About 47% (162) of retrogradely labeled cells displayed tyrosine hydroxylase immunoreactivity, suggesting that almost half of the mesohabenular neurons are dopaminergic. In addition, our data suggest that also incerto-hypothalamic and periventricular neurons contribute dopaminergic terminals to the LHb. The majority of LHb neurons, however, does not project to the origin of the mesohabenular pathway in the anterior VTA. Consequently, there might be no closed VTA-LHb-VTA loop. Instead, our data are in line with the idea that the anterior VTA via its projection to the medial part of the LHb may modulate the information flow from the limbic forebrain to monoaminergic midbrain nuclei.

Differential projections from subfields in the lateral preoptic area to the lateral habenular complex of the rat

The lateral habenular complex (LHb) constitutes an important link in the dorsal diencephalic conduction system conveying information from limbic forebrain structures to regulatory midbrain nuclei. In line with the considerable number of biological functions in which the habenula is thought to be involved, a complex subnuclear organization of the LHb has been suggested. However, the precise connectivity of habenular subnuclei remains to be identified. We hypothesize that axons from the lateral preoptic area (LPOA) project to distinct subnuclei of the LHb. As a result of an unexpected heterogeneity within the LPOA, we first examined its subregional morphology. Based on the analysis of several coronal series of sections, seven subfields were identified within the LPOA. Retrograde tracing experiments revealed that neurons projecting to the LHb were concentrated in the dorsal, ventral, and ventromedial subfields of the rostral LPOA and in the caudal LPOA. Anterograde tracing experiments confirmed that all LPOA subfields containing retrogradely labelled cells project to the LHb. Neurons in rostral subfields of the LPOA target predominantly the lateral area of the LHb, whereas caudal LPOA fibers innervate the medial LHb. Afferent labelling is most prominent within the magnocellular subnucleus in the LHbM, and only few fibers can be observed in the parvocellular subnucleus of the LHbM. The superior subnucleus of the LHbM and the oval subnucleus of the LHbL do not receive any fibers from the LPOA at all. This is the first comprehensive study so far to show that projections from LPOA subfields individually target subnuclei in the lateral habenular complex. J. Comp. Neurol. 507:1465–1478, 2008.

Cannabis and other illicit drug use in epilepsy patients

This study aimed to assess the prevalence of illicit drug use among epilepsy patients and its effects on the disease.

Deep hypothermia terminates status epilepticus - an experimental study

In search for novel treatment approaches in status epilepticus, the anticonvulsant effect of moderate and deep hypothermia was assessed in a rodent model. Self-sustaining status epilepticus (SSSE) characterized by spontaneous high-amplitude discharges recorded from the dentate gyrus was induced in male adult rats by electrical stimulation of the perforant path. After the end of stimulation, rats underwent cooling to 30 °C (n=7) and 20 °C (n=10) for 120 min and rewarming to 37 °C for another 60 min. Control SSSE animals (n=6) remained untreated for 180 min. Frequency of epileptiform discharges was assessed every 10 min. At the target temperature of 20 °C, SSSE was completely suppressed in four rats, this effect was not observed in any animal of the other two groups (p=0.043). On rewarming, seizure activity did not reoccur. Discharge frequency was significantly lower in the 20 °C group at most time points after 60 min of cooling. Following deep hypothermia, eight animals were rewarmed, all survived and moved spontaneously at 37 °C. These experimental data indicate the strong and enduring anticonvulsant and obviously safe properties of cooling down to 20 °C. Patients with status epilepticus refractory to first- and second-line anticonvulsants may benefit from deep cooling as an effective non-pharmacological adjunct to anesthetic anticonvulsants.

Specific adverse effects of antiepileptic drugs - a true-to-life monotherapy study

BACKGROUND In patients taking antiepileptic drugs (AEDs) for epilepsy, adverse effects (AEs) often lead to unfavorable quality of life, impaired adherence, and, eventually, discontinuation of pharmacological treatment. In a true-to-life sample of subjects from our academic epilepsy outpatient clinic, we aimed to identify predictors for overall high AE burden and for specific AEs focusing on patients on monotherapy. METHODS All patients ≥16years of age with epilepsy for ≥12months were routinely asked to complete the Liverpool Adverse Event Profile (LAEP) just before their appointment. Demographic, epilepsy, and treatment variables were derived from our comprehensive outpatient database. RESULTS Out of 841 patients, 438 (61% female, mean age: 44.7±17.1years) on monotherapy were included in this study. Levetiracetam (n=151), lamotrigine (n=167), valproic acid (n=73), or controlled-release carbamazepine (n=47) were the most commonly used antiepileptic drugs (AEDs). Independent predictors for general high AE burden (LAEP score≥45) were duration of epilepsy, lack of 12-month seizure freedom, and partial epilepsy, but none of the four individual AEDs. The most frequent LAEP-defined specific AEs were sleepiness, difficulty concentrating, tiredness, and memory problems. The three most frequent independent predictors for each of the 19 AEs were lack of 12-month seizure freedom (13/19 AEs), individual AED (7/19 AEs), and partial epilepsy (6/19 AEs). Levetiracetam was independently associated with anger/aggression, nervousness/agitation, upset stomach, depression, and sleep disturbance; lamotrigine with nervousness/agitation, upset stomach, and difficulty concentrating; and valproic acid with upset stomach and shaky hands. CONCLUSION Individual AEDs independently predicted some specific AEs, but not overall high AE burden. Our findings may help to characterize patients with epilepsy who are at high risk for specific AEs. Dose reduction or change to another AED may reduce LAEP score and potential nonadherence.

Nucleus accumbens stimulation in partial epilepsy--a randomized controlled case series.

Neuromodulative treatment options are warranted in patients with difficult‐to‐treat epilepsy. However, acquisition of controlled data on deep brain stimulation has so far been achieved only for the centromedian and anterior thalamic nucleus. In a case series of four patients with intractable partial epilepsy, a randomized controlled cross‐over protocol was used to get insight into efficacy and safety of 3‐month nucleus accumbens stimulation. Seizure frequency, neurocognitive testing, “Liverpool Seizure Severity Score,” “Quality of Life in Epilepsy Inventory,” “Beck Depression Inventory,” and “Mini International Neuropsychiatric Interview” were obtained at every visit. In a subsequent open‐label phase, nucleus accumbens stimulation responders underwent concomitant anterior thalamic nucleus stimulation, whereas nonresponders received solely thalamic stimulation. Under nucleus accumbens stimulation, three of four patients had ≥50% reduction in frequency of disabling seizures without further improvement with additional anterior thalamic nucleus stimulation. Patient‐reported outcome and neurocognitive testing remained unchanged. Accumbens stimulation is safe and seems to be a suitable option in intractable partial epilepsy. The current findings require substantiation by an adequately powered multicenter study.

Long-term outcome in epilepsy with grand mal on awakening: Forty years of follow-up

Epilepsy with grand mal on awakening (EGMA) is a well‐defined subtype of idiopathic generalized epilepsy. Patients with follow‐up of at least 20 years were assessed retrospectively regarding 5‐year terminal seizure remission. Forty‐two patients were included (mean age = 60 ± 13 years). After follow‐up of 40 ± 13 years, 26 patients (62%) were in remission, 5 without antiepileptic drugs. Age at investigation (odds ratio = 0.939, 95% confidence interval = 0.887–0.994, p = 0.029) independently predicted lacking remission. Nineteen patients (45.2%) had withdrawn from antiepileptic drugs at least once; 12 of those (63.2%) had seizure relapse. EGMA has a favorable long‐term prognosis. With increasing age and treatment duration, antiepileptic drug withdrawal may be justified. Ann Neurol 2014;75:298–302

No unified reward prediction error in local field potentials from the human nucleus accumbens: evidence from epilepsy patients

Functional magnetic resonance imaging (fMRI), cyclic voltammetry, and single-unit electrophysiology studies suggest that signals measured in the nucleus accumbens (Nacc) during value-based decision making represent reward prediction errors (RPEs), the difference between actual and predicted rewards. Here, we studied the precise temporal and spectral pattern of reward-related signals in the human Nacc. We recorded local field potentials (LFPs) from the Nacc of six epilepsy patients during an economic decision-making task. On each trial, patients decided whether to accept or reject a gamble with equal probabilities of a monetary gain or loss. The behavior of four patients was consistent with choices being guided by value expectations. Expected value signals before outcome onset were observed in three of those patients, at varying latencies and with nonoverlapping spectral patterns. Signals after outcome onset were correlated with RPE regressors in all subjects. However, further analysis revealed that these signals were better explained as outcome valence rather than RPE signals, with gamble gains and losses differing in the power of beta oscillations and in evoked response amplitudes. Taken together, our results do not support the idea that postsynaptic potentials in the Nacc represent a RPE that unifies outcome magnitude and prior value expectation. We discuss the generalizability of our findings to healthy individuals and the relation of our results to measurements of RPE signals obtained from the Nacc with other methods.

Long‐term outcome in adolescent‐onset generalized genetic epilepsies

Until now, it has been unclear if the three subsyndromes of adolescent‐onset generalized genetic epilepsy (GGE) differ in long‐term prognosis. Therefore, this study aimed to compare long‐term seizure outcome in juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and epilepsy with generalized tonic–clonic seizures alone (EGTCS).

High frequency of intrathecal immunoglobulin synthesis in epilepsy so far classified cryptogenic.

The influence of the immune system on seizures and epileptogenesis has been increasingly considered, in particular the role of autoantibodies. In this study, we aimed to determine the frequency of intrathecal antibody synthesis in the cerebrospinal fluid (CSF) compartment of patients with epilepsy.