Oliver Granert

Changes in activity of striato-thalamo-cortical network precede generalized spike wave discharges.

The pathophysiology of generalized spike wave discharges (GSW) is not completely understood. Thalamus, basal ganglia and neocortex have been implicated in the generation of GSW, yet the specific role of each structure remains to be clarified. In six children with idiopathic generalized epilepsy (IGE), we performed combined EEG-fMRI to identify GSW-related changes in blood oxygen level-dependent (BOLD) signal in the striato-thalamo-cortical network. In all patients, within-subject analysis demonstrated BOLD signal changes that preceded the GSW. An increase in BOLD signal in the medial thalamus started 6 s before the onset of the GSW. Decreases in cortical BOLD signal were mainly found in frontoparietal areas and precuneus starting 6 to 3 s before the GSW. All patients showed a decrease in BOLD signal in the head of the caudate nucleus with a variable onset. The temporospatial pattern of BOLD signal changes suggests that GSW on the cortical surface is preceded by a sequence of neuronal events in the thalamo-cortical-striatal network. Approximately 6 s before the GSW, the thalamus shows an increase in neuronal activity along with regional decreases in cortical activity. These changes in thalamo-cortical activity are followed by a deactivation of the caudate nucleus. These early changes in BOLD signal may reflect changes in neuronal activity that contribute to the generation of GSW and may contribute to the transition from a normal to a generalized hypersynchronous pattern of neuronal activity. Our preliminary findings warrant further studies on a larger number of patients to explore the influence of age, medication and type of epileptic syndrome.

Simultaneous EEG-fMRI in drug-naive children with newly diagnosed absence epilepsy.

Purpose: In patients with idiopathic generalized epilepsy (IGE), blood oxygen level dependent (BOLD) EEG during functional MRI (EEG‐fMRI) has been successfully used to link changes in regional neuronal activity to the occurrence of generalized spike‐and‐wave (GSW) discharges. Most EEG‐fMRI studies have been performed on adult patients with long‐standing epilepsy who were on antiepileptic medication. Here, we applied EEG‐fMRI to investigate BOLD signal changes during absence seizures in children with newly diagnosed childhood absence epilepsy (CAE).

Relation of lead trajectory and electrode position to neuropsychological outcomes of subthalamic neurostimulation in Parkinson’s disease: results from a randomized trial

Deep brain stimulation of the subthalamic nucleus improves motor functions in patients suffering from advanced Parkinsons disease but in some patients, it is also associated with a mild decline in cognitive functioning about one standard deviation from the preoperative state. We assessed the impact of the cortical lead entry point, the subcortical electrode path and the position of the active electrode contacts on neuropsychological changes after subthalamic nucleus-deep brain stimulation compared to a control group of patients receiving best medical treatment. Sixty-eight patients with advanced Parkinsons disease were randomly assigned to have subthalamic nucleus-deep brain stimulation or best medical treatment for Parkinsons disease. All patients had a blinded standardized neuropsychological exam (Mattis Dementia Rating scale, backward digit span, verbal fluency and Stroop task performance) at baseline and after 6 months of treatment. Patients with subthalamic nucleus-deep brain stimulation were defined as impaired according to a mild decline of one or more standard deviations compared to patients in the best medical treatment group. The cortical entry point of the electrodes, the electrode trajectories and the position of the active electrode contact were transferred into a normalized brain volume by an automated, non-linear registration algorithm to allow accurate statistical group analysis using pre- and postoperative magnetic resonance imaging data. Data of 31 patients of the subthalamic nucleus-deep brain stimulation group and 31 patients of the best medical treatment group were analysed. The subthalamic nucleus-deep brain stimulation group showed impaired semantic fluency compared with the best medical treatment group 6 months after surgery (P = 0.02). Electrode trajectories intersecting with caudate nuclei increased the risk of a decline in global cognition and working memory performance. Statistically, for every 0.1 ml overlap with a caudate nucleus, the odds for a decline >1 standard deviation increased by a factor of 37.4 (odds ratio, confidence interval 2.1-371.8) for the Mattis Dementia Rating Scale and by a factor of 8.8 (odds ratio, confidence interval 1.0-70.9) for the backward digit span task. Patients with subthalamic nucleus-deep brain stimulation who declined in semantic verbal fluency, Stroop task and the backward digit span task performance showed a position of the active electrode outside the volume built by the active electrodes of stable performers. Passage of the chronic stimulation lead through the head of the caudate increases the risk of global cognitive decline and working memory performance after subthalamic nucleus-deep brain stimulation in Parkinsons disease. Therefore the electrode path should be planned outside the caudate nuclei, whenever possible. This study also stresses the importance of precise positioning of the active stimulating contact within the subthalamic volume to avoid adverse effects on semantic verbal fluency and response inhibition.

Manual activity shapes structure and function in contralateral human motor hand area

From longitudinal voxel-based morphometry (VBM) studies we know that relatively short periods of training can increase regional grey matter volume in trained cortical areas. In 14 right-handed patients with writers cramp, we employed VBM to test whether suppression (i.e., immobilization) or enhancement (i.e., training) of manual activity lead to opposing changes in grey matter in the contralateral primary motor hand area (M1(HAND)). We additionally used transcranial magnetic stimulation (TMS) to evaluate concurrent changes in regional excitability. Patients were recruited from a clinical trial which was designed to improve handwriting-associated dystonia. Initially the dystonic hand was immobilized for 4 weeks with the intention to reverse faulty plasticity. After immobilization, patients accomplished a motor re-training for 8 weeks. T1-weighted MRIs of the whole brain and single-pulse TMS measurements of the resting motor threshold (RMT) were performed every 4 weeks. Immobilization of the right hand resulted in a relative grey matter decrease in the contralateral left M1(HAND) along with a decrease in corticomotor excitability as indexed by an increase in RMT. Subsequent training reversed the effects of immobilization, causing an increase in regional grey matter density and excitability of left M1(HAND). The relative changes in grey matter correlated with the relative shifts in RMT. This prospective within-subject VBM study in task-specific hand dystonia shows that the grey matter density of M1(HAND) is dynamically shaped by the level of manual activity. This bi-directional structural plasticity is functionally relevant as local grey matter changes are mirrored by changes in regional excitability.

fMRI activation during spike and wave discharges evoked by photic stimulation.

Photoparoxysmal response (PPR) is an electroencephalographic (EEG) trait characterized by the occurrence of epileptiform discharges in response to visual stimulation. Studying this trait helps to learn about mechanisms of epileptogenicity. While simultaneous recordings of EEG and functional MRI (EEG-fMRI) in patients with spontaneous generalised spike-wave discharges (GSW) have revealed activation of the thalamus and deactivation in frontoparietal areas, EEG-fMRI studies on evoked GSW such as PPR are lacking. In this EEG-fMRI study, 30 subjects with reported generalised PPR underwent intermittent photic stimulation (IPS) in a 3 T MR scanner. PPR was elicited in 6 subjects, four diagnosed with idiopathic generalised epilepsy and two with tension-type headache. Because PPR is preceded by synchronization of cortical gamma oscillations, blood oxygenation level-dependent (BOLD) signal changes were analysed at the onset of the PPR (standard regressor) and 3 s before the onset of PPR (early regressor) in one model. In all subjects, IPS led to a significant activation of the visual cortex. Based on the early regressor, PPR associated activation was found in the parietal cortex adjacent to the intraparietal sulcus in five and in the premotor cortex in all 6 subjects. The standard regressor revealed deactivation in early activated areas in all subjects and thalamic activation in one subject. In contrast to spontaneous GSW, these results suggest that PPR is a cortical phenomenon with an involvement of the parietal and frontal cortices. Pronounced haemodynamic changes seen with the early regressor could mirror gamma activity that is known to precede PPR.

Sensorimotor skills and focal dystonia are linked to putaminal grey-matter volume in pianists

Background Focal hand dystonia has been associated with morphometric changes and distorted somatotopic representations in the putamen. Objective The authors used voxel-based morphometry (VBM) to identify regions in the putamen where grey-matter volume is associated with musicians dystonia (MD) or the skill level of piano playing in professional pianists. Methods In 11 pianists with MD affecting the right hand and 12 healthy pianists without dystonia, the authors performed high-resolution T1-weighted MRI of the brain. The authors also measured the temporal variability of key strokes during scale playing with the right hand to characterise the individual skill level of piano playing. Statistical comparisons of the normalised and smoothed grey-matter maps were performed to test for dystonia and performance-related structural changes in the putamen. Results During scale playing, the timing of consecutive key strokes was more variable in MD patients than in non-dystonic pianists. Regional grey-matter volume in the middle part of left and right putamen increased with timing variability during piano playing in pianists with and without MD. Between-group comparisons revealed that MD patients had a larger grey-matter volume in the right middle putamen compared with healthy musicians. Conclusion In highly trained pianists with and without MD, the volume of the associative motor territory in the middle putamen reflects both the skill level of piano playing and the presence of dystonia. While a smaller volume is associated with better timing skills, a relative expansion is correlated with the presence of focal task-specific hand dystonia.

Brain changes associated with postural training in patients with cerebellar degeneration: a voxel-based morphometry study.

Recent research indicates that physiotherapy can improve motor performance of patients with cerebellar degeneration. Given the known contributions of the cerebellum to motor learning, it remains unclear whether such observable changes in performance are mediated by the cerebellum or cerebral brain areas involved in motor control and learning. The current study addressed this question by assessing the increase in gray matter volume due to sensorimotor training in cerebellar patients using voxel-based morphometry. Nineteen human subjects with pure cerebellar degeneration and matched healthy controls were trained for 2 weeks on a balance task. Postural and clinical assessments along with structural magnetic resonance imaging were performed pretraining and post-training. The main findings were as follows. First, training enhanced balance performance in cerebellar patients. Second, in contrast to controls patients revealed significantly more post-training gray matter volume in the dorsal premotor cortex. Third, training-related increase in gray matter volume was observed within the cerebellum and was more pronounced in controls than in patients. However, statistically cerebellar changes were at the trend level and thus require additional, independent confirmation. We conclude that sensorimotor training of patients with cerebellar neurodegeneration induces gray matter changes primarily within nonaffected neocortical regions of the cerebellar-cortical loop. Residual function of the cerebellum appears to be exploited suggesting either a recovery from degeneration or intact processes of cerebellar plasticity in the remaining healthy tissue.

ORIGINAL RESEARCH—ANATOMY/PHYSIOLOGY: Assessment of Sexual Orientation Using the Hemodynamic Brain Response to Visual Sexual Stimuli

INTRODUCTION The assessment of sexual orientation is of importance to the diagnosis and treatment of sex offenders and paraphilic disorders. Phallometry is considered gold standard in objectifying sexual orientation, yet this measurement has been criticized because of its intrusiveness and limited reliability. AIM To evaluate whether the spatial response pattern to sexual stimuli as revealed by a change in blood oxygen level-dependent (BOLD) signal can be used for individual classification of sexual orientation. METHODS We used a preexisting functional MRI (fMRI) data set that had been acquired in a nonclinical sample of 12 heterosexual men and 14 homosexual men. During fMRI, participants were briefly exposed to pictures of same-sex and opposite-sex genitals. Data analysis involved four steps: (i) differences in the BOLD response to female and male sexual stimuli were calculated for each subject; (ii) these contrast images were entered into a group analysis to calculate whole-brain difference maps between homosexual and heterosexual participants; (iii) a single expression value was computed for each subject expressing its correspondence to the group result; and (iv) based on these expression values, Fishers linear discriminant analysis and the kappa-nearest neighbor classification method were used to predict the sexual orientation of each subject. MEAN OUTCOME MEASURE Sensitivity and specificity of the two classification methods in predicting individual sexual orientation. RESULTS Both classification methods performed well in predicting individual sexual orientation with a mean accuracy of >85% (Fishers linear discriminant analysis: 92% sensitivity, 85% specificity; kappa-nearest neighbor classification: 88% sensitivity, 92% specificity). CONCLUSION Despite the small sample size, the functional response patterns of the brain to sexual stimuli contained sufficient information to predict individual sexual orientation with high accuracy. These results suggest that fMRI-based classification methods hold promise for the diagnosis of paraphilic disorders (e.g., pedophilia).

Mapping brain activity on the verge of a photically induced generalized tonic–clonic seizure

In a photosensitive patient intermittent photic stimulation (IPS) accidentally provoked a generalized tonic–clonic seizure during simultaneous recordings of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). Before seizure onset, IPS consistently induced generalized photoparoxysmal responses (PPRs). These PPRs were associated with increases in blood oxygen level dependent (BOLD) signal in the visual cortex, the thalamus, and both superior colliculi, and a decrease in BOLD signal in the frontoparietal areas. The BOLD signal in the visual cortex increased in magnitude during consecutive epochs of IPS associated with PPRs. We propose that repeated IPS led to an excessive amount of neuronal activity in the visual cortex that evoked PPRs and finally exceeded a critical threshold and triggered a generalized seizure.

Activities of daily living, cerebral glucose metabolism, and cognitive reserve in Lewy body and Parkinson's disease.

Aims: (1) To investigate the neural substrate of impaired activities of daily living (ADL) in Lewy body-associated disorders, such as dementia with Lewy bodies, classical Parkinson’s disease, and Parkinson’s disease dementia, and (2) to explore the effect of education on the relationship between cerebral metabolic changes and ADL performance. Methods: Fifty-four patients with Lewy body-associated disorders underwent an extensive clinical evaluation including cerebral positron emission tomography with 18F-fluoro-2-deoxy-glucose scanning. First, those brain areas were identified where ADL performance and glucose metabolism were significantly correlated. Second, brain regions were detected where the association between metabolic changes and ADL performance differed significantly between patients with a low and a high educational background. Results: There was a significant association between glucose hypometabolism and impaired ADL performance in the prefrontal, temporoparietal, and occipital association cortices and the precuneus. However, there was a significantly stronger association between hypometabolism and impaired ADL in the low education group compared with the high education group in the right middle occipital gyrus. Conclusions: The study suggests (1) that brain metabolic alterations are significantly associated with the loss of everyday functioning in Lewy body-associated disorders and (2) that education modifies this association.