Lo J. Bour

Subthalamic nucleus versus globus pallidus bilateral deep brain stimulation for advanced Parkinson's disease (NSTAPS study): a randomised controlled trial

BACKGROUND Patients with advanced Parkinsons disease often have rapid swings between mobility and immobility, and many respond unsatisfactorily to adjustments in pharmacological treatment. We assessed whether globus pallidus pars interna (GPi) deep brain stimulation (DBS) gives greater functional improvement than does subthalamic nucleus (STN) DBS. METHODS We recruited patients from five centres in the Netherlands who were aged 18 years or older, had idiopathic Parkinsons disease, and had, despite optimum pharmacological treatment, at least one of the following symptoms: severe response fluctuations, dyskinesias, painful dystonias, or bradykinesia. By use of a computer-generated randomisation sequence, we randomly assigned patients to receive either GPi DBS or STN DBS (1:1), applying a minimisation procedure according to drug use (levodopa equivalent dose <1000 mg vs ≥1000 mg) and treatment centre. Patients and study assessors (but not those who assessed adverse events) were masked to treatment allocation. We had two primary outcomes: functional health as measured by the weighted Academic Medical Center Linear Disability Scale (ALDS; weighted by time spent in the off phase and on phase) and a composite score for cognitive, mood, and behavioural effects up to 1 year after surgery. Secondary outcomes were symptom scales, activities of daily living scales, a quality-of-life questionnaire, the occurrence of adverse events, and drug use. We used the intention-to-treat principle for all analyses. This trial is registered with www.controlled-trials.com, number ISRCTN85542074. FINDINGS Between Feb 1, 2007, and March 29, 2011, we enrolled 128 patients, assigning 65 to GPi DBS and 63 to STN DBS. We found no statistically significant difference in either of our primary outcomes: mean change in weighted ALDS (3·0 [SD 14·5] in the GPi group vs 7·7 [23·2] in the STN group; p=0·28) and the number of patients with cognitive, mood, and behavioural side-effects (36 [58%] of 62 patients in the GPi group vs 35 [56%] of 63 patients in the STN group; p=0·94). Secondary outcomes showed larger improvements in off-drug phase in the STN group compared with the GPi group in the mean change in unified Parkinsons disease rating scale motor examination scores (20·3 [16·3] vs 11·4 [16·1]; p=0·03), the mean change in ALDS scores (20·3 [27·1] vs 11·8 [18·9]; p=0·04), and medication (mean levodopa equivalent drug reduction: 546 [SD 561] vs 208 [521]; p=0·01). We recorded no difference in the occurrence of adverse events between the two groups. Other secondary endpoints showed no difference between the groups. INTERPRETATION Although there was no difference in our primary outcomes, our findings suggest that STN could be the preferred target for DBS in patients with advanced Parkinsons disease. FUNDING Stichting Internationaal Parkinson Fonds, Prinses Beatrix Fonds, and Parkinson Vereniging.

Directional steering: A novel approach to deep brain stimulation.

Objective: The aim of this study was to investigate whether directional steering through a novel 32-contact electrode is safe and can modulate the thresholds for beneficial and side effects of stimulation. Methods: The study is a single-center, performance and safety study. Double-blind intraoperative evaluations of the thresholds for therapeutic benefit and for side effects were performed in 8 patients with Parkinson disease while stimulating in randomized order in spherical mode and in 4 different steering modes with the 32-contact electrode, and in monopolar mode with a commercial electrode. In addition, simultaneous recordings of local field potentials through all 32 contacts were performed. Results: There were no adverse events related to the experimental device. For 13 of 15 side effects (87%), the threshold could be increased by ≥1 mA while steering in at least one direction in comparison to conventional spherical stimulation, thereby increasing the therapeutic window by up to 1.5 mA. Recording local field potentials through all 32 electrode contacts yielded spatiotemporal information on pathologic neuronal activity. Conclusions: Controlled steering of current through the brain may improve the effectiveness of deep brain stimulation (DBS), allow for novel applications, and provide a tool to better explore pathophysiologic activity in the brain. Classification of evidence: This study provides Class IV evidence that for patients with Parkinson disease, steering DBS current is well tolerated, increases the threshold for side effects, and may improve the therapeutic window of subthalamic nucleus DBS as compared with current standard spherical stimulation.

Blink reflex recovery curves in blepharospasm, torticollis spasmodica, and hemifacial spasm.

R1 and R2 blink reflex responses to single and paired stimuli were investigated in 23 control subjects: 21 patients with blepharospasm (BSP), 20 patients with torticollis spasmodica (TS), and 23 with hemifacial spasm (HFS). For paired stimuli, we compared measurements of area and peak responses at two and three times R2 threshold. R1 and R2 indices were calculated as the average of the recovery values at 0.5‐, 0.3‐, and 0.21‐s interstimulus intervals to test individual patients. Peak amplitude measurements at three times R2 threshold were optimal. The R2 index was abnormal in 67% of BSP patients, 37% of TS patients, and 50% of HFS patients on the affected side and 20% on the unaffected side. A normal R2 index in one third of patients with BSP may indicate that different pathophysiological mechanisms are involved in this type of focal dystonia.

Top-down-directed synchrony from medial frontal cortex to nucleus accumbens during reward anticipation

The nucleus accumbens and medial frontal cortex (MFC) are part of a loop involved in modulating behavior according to anticipated rewards. However, the precise temporal landscape of their electrophysiological interactions in humans remains unknown because it is not possible to record neural activity from the nucleus accumbens using noninvasive techniques. We recorded electrophysiological activity simultaneously from the nucleus accumbens and cortex (via surface EEG) in humans who had electrodes implanted as part of deep‐brain‐stimulation treatment for obsessive–compulsive disorder. Patients performed a simple reward motivation task previously shown to activate the ventral striatum. Spectral Granger causality analyses were applied to dissociate “top–down” (cortex → nucleus accumbens)‐ from “bottom–up” (nucleus accumbens → cortex)‐directed synchronization (functional connectivity). “Top–down”‐directed synchrony from cortex to nucleus accumbens was maximal over medial frontal sites and was significantly stronger when rewards were anticipated. These findings provide direct electrophysiological evidence for a role of the MFC in modulating nucleus accumbens reward‐related processing and may be relevant to understanding the mechanisms of deep‐brain stimulation and its beneficial effects on psychiatric conditions. Hum Brain Mapp, 2012.

A unique achiasmatic anomaly detected in non-albinos with misrouted retinal-fugal projections.

In mammals with binocular vision, projections of retinal sons to primary retino‐recipient nuclei establish a strict visuotopic and eye‐segregated arrangement. Normal primate visual pathway organization is characterized by orderly hemiretina separation in which nasal‐retinal axons cross at the optic chiasm and project to primary contralateral subcortical and cortical structures while temporal‐retinal fibres project ipsilaterally to corresponding visual structures. We report here, in two unrelated children, an unusual visual pathway malformation in which nasal‐retinal cortical projections, unable to decussate due to the inborn absence of an optic chiasm, erroneously route ipsilaterally to visual projection targets. We have termed this newly documented achiasmatic condition the non‐decussating retinal‐fugal fibre syndrome (Apkarian er al., Invest. Ophthalmol. Vis. Sci., 34, Suppl., 711, 1993).

Local field potentials and oscillatory activity of the internal globus pallidus in myoclonus–dystonia

The pathophysiology of myoclonus–dystonia (M–D), an autosomal dominantly inherited movement disorder characterized by myoclonic jerks and dystonic contractions, is largely unknown. In the present study, local field potential (LFP) activities in the globus pallidus internus (GPi) from two genetically proven M–D patients are investigated. Coherence analysis between GPi LFP activity and electromyographic muscle activity (EMG) and synchronization of GPi neuronal activity using event‐related spectral perturbation (ERSP) in a go–no‐go paradigm were studied. Significant increased coherence in the 3 to 15 Hz frequency band was detected between GPi LFP activity and several muscles, with the LFP leading the muscles. The ERSP analysis revealed synchronization in the 3 to 15 Hz frequency band within the GPi before the imperative cue of the go–no‐go task and desynchronization in the same band after the cue. The LFP recordings of the GPi in M–D show that the low‐frequency band previously described in dystonia is also involved in the dystonia plus syndrome M–D. The 3 to 15 Hz synchronization in the go–no‐go paradigm has not been described previously and may point to the existence of (myoclonus–)dystonia specific oscillatory activity in the GPi.

Neuropsychological and clinical correlates of antisaccade task performance in schizophrenia.

Objectives: To elucidate pathophysiologic mechanisms involved in abnormal antisaccade task performance in schizophrenia by investigating a possible relationship among antisaccade task performance, neuropsychological test results, and symptomatology in a group of young patients with recent-onset schizophrenia; to compare the effects of olanzapine and risperidone on antisaccades and reflexive saccades. Background: Patients with schizophrenia consistently perform worse than controls on the antisaccade task in which the subject is required to inhibit a reflexive saccade to a suddenly appearing visual target and look in the opposite direction. Methods: In 37 young (mean age 21 years), medicated patients with recent-onset schizophrenia the authors assessed antisaccades, reflexive saccades, neuropsychological test performance, and symptomatology. A subgroup of 18 patients was treated with olanzapine, and 15 patients were treated with risperidone. Reflexive-saccade and antisaccade task results were compared with those obtained in 13 control subjects. Results: The antisaccade error rate was significantly higher in the patients than in the control subjects. In the patients, poor working memory function was related to increased antisaccade error rate. Severity of disorganization symptoms at intake was related to prolonged mean latency of the correct antisaccades. Patients on risperidone had a prolonged mean latency in the reflexive saccade task compared with patients using olanzapine. Conclusions: Abnormal antisaccade task performance is already present in early schizophrenia and may reflect working memory dysfunction. In future studies, medication effects should be considered in interpreting eye movement test results of patients with schizophrenia.

Predicting Survival in Patients with Early Alzheimer’s Disease

We investigated whether an index based on clinical features, electroencephalogram and computed tomography is useful to predict survival in early Alzheimer’s disease. One hundred and sixty-three consecutively referred patients to an outpatient memory clinic and first diagnosed with Alzheimer’s disease (105 ‘probable’ and 58 ‘possible’, NINCDS-ADRDA criteria) were studied and outcome measure was death. Cox proportional hazards regression analysis and Kaplan-Meier survival curves were used to investigate relations between baseline parameters and survival. Eighty-four patients (51.5%) died during the follow-up period that extended to 5.8 years, with a median duration of survival after entry of 4.3 years. Baseline factors that were statistically significant and independently related to increased risk of mortality were high age, male sex, poor cognitive function as measured with the CAMCOG, low alpha and beta power on electroencephalogram, and temporoparietal atrophy on computed tomography scan. These results were independent of the diagnosis probable or possible Alzheimer’s disease. Based on the coefficients from the regression equation, we computed a survival index for each patient and we constructed three groups according to tertiles of this index. After 5.2 years of follow-up, survival curves showed a low mortality group with 81.7% patients alive (median survival at least 5.7 years), an intermediate mortality group with 35.9% patients alive (median survival 3.8 years), and a high mortality group with no patients alive (median survival 2.3 years). Log rank tests were statistically significant for comparisons between all three groups. We conclude that an overall index combining demographic, cognitive, electroencephalogram and computed tomography features is a strong predictor of survival in early Alzheimer’s disease.

Psychosis Prediction: Stratification of Risk Estimation With Information-Processing and Premorbid Functioning Variables

BACKGROUND The period preceding the first psychotic episode is regarded as a promising period for intervention. We aimed to develop an optimized prediction model of a first psychosis, considering different sources of information. The outcome of this model may be used for individualized risk estimation. METHODS Sixty-one subjects clinically at high risk (CHR), participating in the Dutch Prediction of Psychosis Study, were assessed at baseline with instruments yielding data on neuropsychology, symptomatology, environmental factors, premorbid adjustment, and neurophysiology. The follow-up period was 36 months. RESULTS At 36 months, 18 participants (29.5%) had made a transition to psychosis. Premorbid adjustment (P = .001, hazard ratio [HR] = 2.13, 95% CI = 1.39/3.28) and parietal P300 amplitude (P = .004, HR = 1.27, 95% CI = 1.08/1.45) remained as predictors in the Cox proportional hazard model. The resulting prognostic score (PS) showed a sensitivity of 88.9% and a specificity of 82.5%. The area under the curve of the PS was 0.91 (95% CI = 0.83-0.98, cross-validation: 0.86), indicating an outstanding ability of the model to discriminate between transition and nontransition. The PS was further stratified into 3 risk classes establishing a prognostic index. In the class with the worst social-personal adjustment and lowest P300 amplitudes, 74% of the subjects made a transition to psychosis. Furthermore, transition emerged on average more than 17 months earlier than in the lowest risk class. CONCLUSIONS Our results suggest that predicting a first psychotic episode in CHR subjects could be improved with a model including premorbid adjustment and information-processing variables in a multistep algorithm combining risk detection and stratification.

Antisaccade task performance in patients at ultra high risk for developing psychosis

Patients with schizophrenia consistently perform worse than healthy controls on the antisaccade task in which the subject is required to inhibit a reflexive saccade to a suddenly appearing visual target and look in the opposite direction. To our knowledge there is no research yet showing how patients at ultra high risk (UHR) for developing psychosis perform on the antisaccade task. The aim of the present study was to investigate antisaccade task performance in UHR patients. Patients were eligible for the study when they met criteria for one or more of the following groups: Attenuated symptoms or brief limited intermitted psychotic symptoms or a first-degree family member with a psychotic disorder and reduced functioning or basic symptoms. In 35 UHR patients we assessed antisaccades, neuropsychological test performance and symptomatology. Antisaccade task results were compared with those obtained in 42 age- and intelligence-matched patients with recent-onset schizophrenia and 28 matched healthy controls. Antisaccade error rate was significantly higher in the UHR patients than in the controls. Schizophrenia patients performed worse than the UHR patients and the control subjects. We found a trend towards higher antisaccade error rate at baseline in the UHR patients who later made the transition to psychosis compared to the UHR patients who did not make the transition to psychosis. Poor spatial working memory function was related to increased antisaccade errors in the UHR group. Abnormal antisaccade task performance is also present in patients at UHR for developing psychosis. Subsequent research needs to clarify if increased antisaccade error rate is predictive of a psychotic episode. In UHR patients, poor antisaccade performance may reflect working memory dysfunction.