Definition of DLPFC and M1 according to anatomical landmarks for navigated brain stimulation: inter-rater reliability, accuracy, and influence of gender and age.

The optimization of the targeting of a defined cortical region is a challenge in the current practice of transcranial magnetic stimulation (TMS). The dorsolateral prefrontal cortex (DLPFC) and the primary motor cortex (M1) are among the most usual TMS targets, particularly in its "therapeutic" application. This study describes a practical algorithm to determine the anatomical location of the DLPFC and M1 using a three-dimensional (3D) brain reconstruction provided by a TMS-dedicated navigation system from individual magnetic resonance imaging (MRI) data. The coordinates of the right and left DLPFC and M1 were determined in 50 normal brains (100 hemispheres) by five different investigators using a standardized procedure. Inter-rater reliability was good, with 95% limits of agreement ranging between 7 and 16 mm for the different coordinates. As expressed in the Talairach space and compared with anatomical or imaging data from the literature, the coordinates of the DLPFC defined by our algorithm corresponded to the junction between BA9 and BA46, while M1 coordinates corresponded to the posterior border of hand representation. Finally, we found an influence of gender and possibly of age on some coordinates on both rostrocaudal and dorsoventral axes. Our algorithm only requires a short training and can be used to provide a reliable targeting of DLPFC and M1 between various TMS investigators. This method, based on an image-guided navigation system using individual MRI data, should be helpful to a variety of TMS studies, especially to standardize the procedure of stimulation in multicenter "therapeutic" studies.

Men and women are different: diffusion tensor imaging reveals sexual dimorphism in the microstructure of the thalamus, corpus callosum and cingulum.

INTRODUCTION: Numerous magnetic resonance imaging (MRI) studies have addressed the question of morphological differences of the brain of men and women, reporting conflicting results regarding brain size and the ratio of gray and white matter. In the present study, we used diffusion tensor imaging (DTI) to delineate sex differences of brain white matter. METHODS: We investigated brain microstructure in 25 male and 25 female healthy subjects using a 3T MRI scanner. Whole-head DTI scans were analyzed without a-priori hypothesis using Tract-Based Spatial Statistics (TBSS) calculating maps of fractional anisotropy (FA), radial diffusivity (RD, a potential marker of glial alteration and changes in myelination) and axial diffusivity (AD, a potential marker of axonal changes). RESULTS: DTI revealed regional microstructural differences between the brains of male and female subjects. Those were prominent in the thalamus, corpus callosum and cingulum. Men showed significantly (p<0.0001) higher values of fractional anisotropy and lower radial diffusivity in these areas, suggesting that the observed differences are mainly due to differences in myelination. DISCUSSION: As a novel finding we showed widespread differences in thalamic microstructure that have not been described previously. Additionally, the present study confirmed earlier DTI studies focusing on sexual dimorphism in the corpus callosum and cingulum. All changes appear to be based on differences in myelination. The sex differences in thalamic microstructure call for further studies on the underlying cause and the behavioral correlates of this sexual dimorphism. Future DTI group studies may carefully control for gender to avoid confounding.

Intraoperative ultrasound in malformations of cortical development.

PURPOSE: Malformations of cortical development (MCD) are a common cause of medically refractory focal epilepsy. However, the intraoperative definition of MCD can be challenging. In this study we assess the feasibility of intraoperative ultrasound (IOUS) for the intraoperative localization of MCD. MATERIALS AND METHODS: Five epilepsy patients with at least one suspected lesion of MCD were operated with the aid of IOUS. IOUS was compared to preoperative MRI and histopathology. RESULTS: In three cases of focal cortical dysplasia (FCD) type IIB and one case of periventricular heterotopia, the lesions could be delineated well on IOUS and the configuration of the lesion corresponded to the appearance on MRI. However, only one of two FCD type I lesions could be detected on IOUS. CONCLUSION: IOUS can be helpful in defining FCD IIB as well as periventricular heterotopia intraoperatively, but this seems to be more difficult in FCD type I.

Auditory processing across the sleep-wake cycle: simultaneous EEG and fMRI monitoring in humans.

We combined fMRI and EEG recording to study the neurophysiological responses associated with auditory stimulation across the sleep-wake cycle. We found that presentation of auditory stimuli produces bilateral activation in auditory cortex, thalamus, and caudate during both wakefulness and nonrapid eye movement (NREM) sleep. However, the left parietal and, bilaterally, the prefrontal and cingulate cortices and the thalamus were less activated during NREM sleep compared to wakefulness. These areas may play a role in the further processing of sensory information required to achieve conscious perception during wakefulness. Finally, during NREM sleep, the left amygdala and the left prefrontal cortex were more activated by stimuli having special affective significance than by neutral stimuli. These data suggests that the sleeping brain can process auditory stimuli and detect meaningful events.

Sleep quality in a family with hereditary parkinsonism (PARK6).

OBJECTIVES: The autosomal recessive disorder PARK6 manifests as early-onset Parkinson's disease (PD) with a particularly mild progression. PARK6 is of particular scientific interest, since it is caused by loss-of-function mutations in the mitochondrial protein kinase PINK1 and may thus serve as a model for oxidative damage in PD and in other basal ganglia disorders. Sleep disturbances are very common in PD but have not yet been reported for PARK6 patients. The present study reports on sleep of a Spanish family with PARK6. Of the 5 siblings, 3 were homozygous and severely affected, and 2 were heterozygous and clinically asymptomatic. Research questions concerned possible differences in sleep recordings between homozygote and heterozygote siblings and similarities between PARK6 and sporadic PD sleep profiles. METHOD: The data from detailed clinical interviews of the patients and their bedpartners are reported and compared with polysomnographic data from second-night recordings. CONCLUSIONS: All siblings had good subjective and objective sleep quality. Restless legs syndrome and rapid eye movement (REM) sleep behaviour disorder (RBD) were not observed, suggesting that sleep disturbances are not commonly found in PARK6 patients. Good sleep quality and the absence of RBD might be a useful diagnostic guide in the differential diagnosis of sporadic PD versus PARK6.

Topiramate in add-on therapy: results from an open-label, observational study.

An open-label, observational prospective study assessed the effectiveness of topiramate (TPM) as add-on therapy. A total of 450 patients aged 12 and above with a diagnosis of epilepsy and at least one epileptic seizure during the 12-week retrospective baseline were to be documented. After baseline evaluation, topiramate was added. Ninety-five percent of patients had at least one baseline AED, most commonly Carbamazepine (53%) or Valproate (34%). In 5% TPM was started in monotherapy. Topiramate dose titration and target dose was determined by clinical response and side effect profile. Patients were intended to be followed for a total of 1 year which included 6 visits during which seizure frequency, adverse events, weight as well as clinical global impression were recorded. During the 12 weeks retrospective baseline, a median of 2.8 seizures per month were recorded which reduced significantly to 0.7 per month during the complete treatment phase (p < 0.0001). Seventy-two percent of patients had a > or =50% seizure reduction. Ten percent of patients were seizure free during the study. The most commonly reported adverse events were difficulties with memory (4.2%), somnolence (3.6%), and dizziness (2.7%). Overall, topiramate was well tolerated, and only 5% of patients discontinued treatment due to an adverse event. Retention in the study was higher than previously reported during randomized, dose controlled studies and is likely due to individualized doses as well as slower titration used.

The combined action of a passive exoskeleton and an EMG-controlled neuroprosthesis for upper limb stroke rehabilitation: First results of the RETRAINER project.

The combined use of Functional Electrical Stimulation (FES) and robotic technologies is advocated to improve rehabilitation outcomes after stroke. This work describes an arm rehabilitation system developed within the European project RETRAINER. The system consists of a passive 4-degrees-of-freedom exoskeleton equipped with springs to provide gravity compensation and electromagnetic brakes to hold target positions. FES is integrated in the system to provide additional support to the most impaired muscles. FES is triggered based on the volitional EMG signal of the same stimulated muscle; in order to encourage the active involvement of the patient the volitional EMG is also monitored throughout the task execution and based on it a happy or sad emoji is visualized at the end of each task. The control interface control of the system provides a GUI and multiple software tools to organize rehabilitation exercises and monitor rehabilitation progress. The functionality and the usability of the system was evaluated on four stroke patients. All patients were able to use the system and judged positively its wearability and the provided support. They were able to trigger the stimulation based on their residual muscle activity and provided different levels of active involvement in the exercise, in agreement with their level of impairment. A randomized controlled trial aimed at evaluating the effectiveness of the RETRAINER system to improve arm function after stroke is currently ongoing.

Long-term continuation of levetiracetam in patients with refractory epilepsy.

The long-term continuation (retention) rate, efficacy, and safety data of the new antiepileptic drug levetiracetam (LEV) was evaluated in all patients with epilepsy exposed to the drug during its developmental program (n = 1,422). The retention rate was estimated to be 60% after 1 year and 32% after 5 years. Thirty-nine percent (512/1,325) of patients had a seizure reduction of > or =50%, and 13% (183/1,422) became seizure-free for at least 6 months. LEV seems an effective and well tolerated new antiepileptic drug.

Cerebellar volumes in newly diagnosed and chronic epilepsy.

Cerebellar atrophy is assumed to be a common finding in patients suffering from epilepsy. Anticonvulsants as well as seizure activity itself have been considered to be responsible for it but many studies have addressed these questions in specialised centres for epilepsy thus having a referral bias towards patients with severe epileptic syndromes. The purpose of this study was: 1. To develop a quantitative method on 3D-MRI data to achieve volume or planimetric measurements (of cerebrum, cerebellum and cerebellar substructures). 2. To investigate the prevalence of cerebellar atrophy (and substructure atrophy) in a prospectively investigated population-based cohort of patients with newly diagnosed and chronic epilepsy. 3. To quantify cerebellar atrophy in clinic-based patients, who had had atrophy previously diagnosed on routine visual MRI assessment. 4. To correlate the measures of atrophy with clinical features in both patient groups. A total of 57 patients with either newly diagnosed or chronic active epilepsy and 36 control subjects were investigated with a newly developed semiautomated method for cerebral as well as cerebellar volume measurements and substructure planimetry, corrected for intracranial volume. We did not find any significant atrophy in the population-based cohort of patients with newly diagnosed epilepsy or with chronic epilepsy. Visually diagnosed cerebellar atrophy was mostly confirmed and quantified by volumetric analysis. The clinical data suggested a correlation between cerebellar atrophy and the duration of the seizure disorder and also the total number of lifetime seizures experienced and the frequency of generalised tonic-clonic seizures per year. Volumetry on 3D-MRI yields reliable quantitative data which shows that cerebellar atrophy might be common in severe and/or longstanding epilepsy but not necessarily in unselected patient groups. The results do not support the proposition that cerebellar atrophy is a predisposing factor for epilepsy but rather are consistent with the view that cerebellar atrophy is the aftermath of epileptic seizures or anticonvulsant medication.

Fixation-off sensitivity as a model of continuous epileptiform discharges: electroencephalographic, neuropsychological and functional MRI findings.

A case of fixation-off sensitivity (FOS) in an asymptomatic adult is presented and studied as a model for continuous epileptiform discharges. Video-electroencephalographic (EEG) revealed continuous bilateral occipital spike wave discharges during elimination of central vision, which were shown to be associated with transitory cognitive impairment demonstrated by neuropsychological testing. Functional MRI showed activation of parieto-occipital and frontal brain areas during the fixation-off discharges. This localization was confirmed with 64-channel EEG source analysis. The applied methods provided additional information on the pathophysiology of epileptiform discharges.

Modified approach for the selective treatment of temporal lobe epilepsy: transsylvian-transcisternal mesial en bloc resection.

OBJECT: The authors propose a novel surgical approach for amygdalohippocampectomy (AH) in patients with temporal lobe epilepsy. Via a transsylvian-transcisternal route, the parahippocampal gyrus is directly exposed from its medial aspect, thus allowing a standardized en bloc resection of the temporomesial epileptogenic structures--the amygdala, anterior hippocampus, parahippocampal gyrus, and subiculum. Additional anatomical studies have been performed for standardization of this approach. METHODS: From 1990 to 1996, 32 patients presenting with medically intractable mesial temporal lobe epilepsy underwent AH via the transsylvian-transcisternal approach. Preoperative computerized tomography and magnetic resonance imaging revealed temporomesial lesions in 16 patients. Histopathological examination revealed cavernous malformations in seven patients, low-grade astrocytomas in four, hamartomas in three, and gangliogliomas in two patients. Specimens obtained in patients with no lesions were diagnosed as hippocampal sclerosis in all cases. No patient experienced permanent morbidity. Nine percent of the patients developed a temporary partial oculomotor nerve palsy. Only one patient developed a postoperative visual field deficit with a contralateral quadrantanopsia. With respect to seizure outcome, all patients benefited from surgery. At follow-up evaluation (mean 26.4 months), 80% of the patients were free from seizures (Engel Class I). Eight patients in this group were no longer receiving medication. Seventeen percent had experienced only one to several seizures since surgery (Engel Class II) and 3% reported a worthwhile improvement (Engel Class III). CONCLUSIONS: In contrast to previously described standard techniques for AH, the transsylvian-transcisternal approach presented in this study offers improved anatomical orientation and intraoperative control over the mesial temporal lobe and preserves the lateral as well as the laterobasal temporal lobe.

Reproducible localization of interictal epileptiform discharges using EEG-triggered fMRI.

We report preliminary experiences using fMRI triggered by EEG to localize the site of interictal epileptiform activity. EEG was recorded in the scanner and monitored on-line; the recording quality was good enough to allow the clear identification of spikes in the EEG. Snap-shot EPI was performed 2-4 s after an epileptiform discharge ('spike') or after at least 10 s of background activity ('rest') was observed. A pixel-by-pixel t-test was performed between the 'rest' and the 'spike' images to determine areas of significant activation. Significant activation was obtained in a patient with epilepsy. To assess the reliability and reproducibility of the technique, the patient was scanned on four separate occasions with similar areas being activated in all the studies, confirming the validity of the result.

Coping with refractory epilepsy.

We investigated the coping behaviour and its correlation with demographic and illness-related data, depression, locus of control and psychosocial adaptation in 40 patients with intractable epilepsy with primarily or secondarily generalized tonic-clonic seizures. Three standardized self-reporting questionnaires were applied, which are the Freiburg Questionnaire of Coping with Illness (FKV), the von Zerssen Depression Scale (D-S), and the IPC-questionnaire measuring generalized locus of control beliefs; the Social Interview Schedule (SIS), a semi-structured interview, was used to measure the psychosocial adaptation. Active, problem-focused and compliance strategies were predominantly used and regarded as most helpful. Hence, the epileptic patients use similar coping patterns reported in patients with other non life-threatening chronic diseases. The level of depression was moderate and in the range of other chronic somatic diseases. The use of coping patterns, which are regarded as maladaptive, was correlated with distinct depression, a small degree of internal locus of control beliefs and poor psychosocial adaption. These results indicate the possibility to improve psychosocial adjustment by supporting effective strategies.

Recovery of visual field constriction following discontinuation of vigabatrin.

Epilepsy patients treated with vigabatrin may develop symptomatic or asymptomatic concentric visual field constriction due to GABA-associated retinal dysfunction. The prevalence and course of this side effect are not established yet; in previously reported adult patients the visual disturbances seem to be irreversible. We present two patients with a significant improvement of visual field constriction and retinal function after the discontinuation of vigabatrin. These findings suggest that vigabatrin-associated retinal changes are at least partly reversible in some patients, and that these patients may benefit significantly from a withdrawal of vigabatrin. Larger scale clinical studies are needed to identify predictive factors both for the occurrence and reversibility of vigabatrin-associated visual field defects.

Spatio-temporal imaging of focal interictal epileptiform activity using EEG-triggered functional MRI.

EEG-triggered, blood oxygen level-dependent functional MRI (BOLD-fMRI) was used in 24 patients with localization-related epilepsy and frequent interictal epileptiform discharges (spikes) to identify those brain areas involved in generating the spikes, and to study the evolution of the BOLD signal change over time. The location of the fMRI activation was compared with the scalp EEG spike focus and the structural MR abnormality. Twelve patients (50%) had an fMRI activation concordant with the EEG focus and structural brain abnormalities where present (n = 7). In 2 other patients, the fMRI activation was non-concordant with electroclinical findings. The remaining 10 patients (41.7%) showed no significant fMRI activation. These patients had significantly lower mean spike amplitudes compared to those with positive fMRI results (p = 0.03). The time course of the BOLD response was studied in 3 patients and this revealed a maximum signal change 1.5 to 7.5 sec after the spike. In conclusion, EEG-triggered fMRI can directly identify the generators of interictal epileptiform activity, with high spatial resolution, in selected patients with frequent spikes. The superior spatial resolution obtainable through EEG-triggered fMRI may provide an additional non-invasive tool in the presurgical evaluation of patients with intractable focal seizures.

Where the BOLD signal goes when alpha EEG leaves.

Previous studies using simultaneous EEG and fMRI recordings have yielded discrepant results regarding the topography of brain activity in relation to spontaneous power fluctuations in the alpha band of the EEG during eyes-closed rest. Here, we explore several possible explanations for this discrepancy by re-analyzing in detail our previously reported data. Using single subject analyses as a starting point, we found that alpha power decreases are associated with fMRI signal increases that mostly follow two distinct patterns: either 'visual' areas in the occipital lobe or 'attentional' areas in the frontal and parietal lobe. On examination of the EEG spectra corresponding to these two fMRI patterns, we found greater relative theta power in sessions yielding the 'visual' fMRI pattern during alpha desynchronization and greater relative beta power in sessions yielding the 'attentional' fMRI pattern. The few sessions that fell into neither pattern featured the overall lowest theta and highest beta power. We conclude that the pattern of brain activation observed during spontaneous power reduction in the alpha band depends on the general level of brain activity as indexed over a broader spectral range in the EEG. Finally, we relate these findings to the concepts of 'resting state' and 'default mode' and discuss how - as for sleep - EEG-based criteria might be used for staging brain activity during wakefulness.

Right hemispheric language dominance in a right-handed male with a right frontal tumor shown by functional transcranial Doppler sonography.

BACKGROUND: A 38-year-old, right-handed man with late-onset right frontal epilepsy due to a ganglioglioma and atypical right hemispheric language dominance is described. METHODS: Language dominance was investigated with functional transcranial Doppler sonography (fTCD), and language localization with functional magnetic resonance imaging (fMRI). RESULTS: During a word generation task, fTCD showed atypical right hemispheric language dominance, which was confirmed by fMRI using a semantic word comparison and a word stem completion task. This information helped to guide the resective procedure, which left the patient seizure-free and did not induce new deficits. CONCLUSION: Functional TCD appears to be a useful and reliable screening tool for determining hemispheric language dominance, even in patients with atypical language representation. Functional MRI may be used to confirm fTCD results and further localize eloquent cortex.

Stages of sleep pathology in spinocerebellar ataxia type 2 (SCA2).

BACKGROUND: Autosomal dominant spinocerebellar ataxia type 2 (SCA2) bears clinical and neuropathologic similarities to sporadic multisystem atrophy (MSA) or Parkinson disease, in which sleep pathology is well documented. However, those clinical entities have a marked variability of the reported sleep disturbances, and their etiology is heterogeneous. In contrast, the study of SCA2 provides an opportunity to examine a molecularly homogeneous patient group, in which disease stages can be defined not only based on disease duration and ataxia scores, but also with regard to modulatory effects of mutation size. OBJECTIVE: To examine the presence and progression of sleep pathology in SCA2. METHODS: We analyzed eight patients with disease durations of 3 to 31 years, all with medium size SCA2 expansions (CAG 38 to 49), using clinical scores, sleep interviews, and video-polysomnography (VPSG) recordings. RESULTS: Almost all patients reported good subjective sleep quality and negated incidents of REM behavior disorder (RBD). At early disease stages, however, REM without atonia in four patients' VPSG suggested subclinical RBD. This was accompanied by a consistent reduction of REM density. In three patients at later SCA2 stages, REM sleep was undetectable, whereas slow wave sleep (SWS) was markedly increased at the cost of light sleep. Periodic leg movements, apnea, or hypopnea were not prominent. CONCLUSIONS: Progressive loss of dream recall in spinocerebellar ataxia type 2 was found and correlated with stages of REM more than non-REM pathology in video-polysomnography. These stages correspond to the progressive atrophy from the pons, nigrostriatal projection, and locus ceruleus to the thalamus.

Simultaneous assessment of brain tissue oxygenation and cerebral perfusion during orthostatic stress.

Simultaneous registration of cerebral tissue oxygenation parameters obtained by near infrared spectroscopy (NIRS), intracranial blood flow velocity (CBFV) measured by transcranial Doppler sonography (TCD) and basic cardiovascular parameters was carried out during a passive 80 degrees head-up tilt table test in 15 patients with a history of orthostatic syncope and 20 control subjects. In normals, the cardiovascular parameters showed a specific course after changing to a vertical position: the heart rate increased, the mean arterial blood pressure remained unchanged, and the CBFV decreased. The NIRS measurements showed an increase in deoxyhemoglobin (HHb) and a decline in oxyhemoglobin (O(2)Hb) and the regional oxygen saturation (RSAT). Patients had a significantly more prominent decline in arterial blood pressure (p < 0.001), CBFV (p < 0.001) and RSAT (p = 0.04). Five patients experienced symptoms of (pre)syncope during the experiment, which were associated with a further sudden and marked (>10%) drop of O(2)Hb. The results indicate that the combination of TCD and NIRS increases the understanding of hemodynamic and metabolic changes during orthostatic stress, which may lead to individually suited therapeutic procedures.