Tic related local field potentials in the thalamus and the effect of deep brain stimulation in Tourette syndrome: Report of three cases.

OBJECTIVE: Three patients with intractable Tourette syndrome (TS) underwent thalamic deep brain stimulation (DBS). To investigate the role of thalamic electrical activity in tic generation, local field potentials (LFP), EEG and EMG simultaneously were recorded. METHODS: Event related potentials and event related spectral perturbations of EEG and LFP, event related cross-coherences between EEG/LFP and LFP/LFP were analyzed. As time locking events, the tic onsets were used. Spontaneous tics were compared to voluntary tic mimicking. The effect of tic suppression and DBS on thalamic LFPs was evaluated. RESULTS: All three patients showed time-locked and prior to onset of spontaneous motor tics thalamic synchronization and thalamo-cortical cross-coherence. Also in three patients, not time-locked to motor tics, increased intra-thalamic coherences in the 1-8Hz frequency band were found. In one patient it was demonstrated that voluntary mimicked tics were preceded by premotor cortical and thalamic potentials. In this patient unilateral thalamic DBS contralaterally decreased the background thalamic activity. CONCLUSIONS: The present study in three cases with TS shows that spontaneous tics in TS are preceded by repetitive coherent thalamo-cortical discharges, indicating that preceding a tic the basal ganglia circuits are "charged up", ultimately leading to a motor tic. SIGNIFICANCE: Thalamic LFP recording may lead to more insight in underlying pathophysiological mechanisms in TS.

Impulse control behaviours in patients with Parkinson's disease after subthalamic deep brain stimulation: de novo cases and 3-year follow-up.

OBJECTIVE: To document the occurrence of impulse control behaviours (ICBs) in patients with Parkinson's disease after 3 years of continuous deep brain stimulation (DBS) of the subthalamic nucleus (STN). METHODS: Detailed neurological and ICB assessments were performed before STN DBS and up to 3 years after implant. RESULTS: 13 out of 56 patients (23.2%) had ICBs at baseline; they took higher doses of dopamine agonists (DAA). Three years after implant 11 had fully remitted with a 60.8% reduction of DAA medication; the remaining two, who had a similar medication reduction, had only compulsive eating, having recovered from hypersexuality. Six of the 43 patients without ICBs at baseline (14%) developed transient de novo ICBs after implant; none of them had ICBs at the 3-year observation. CONCLUSIONS: ICBs were abolished in patients 3 years after STN DBS and DAA dosages were lowered. New ICBs may occur after implant and are transient in most cases. Compulsive eating may be specifically related to STN stimulation.

Novelty processing and memory formation in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is characterized by a degeneration of nigrostriatal dopaminergic cells, resulting in dopamine depletion. This depletion is counteracted through dopamine replacement therapy (DRT). Dopamine has been suggested to affect novelty processing and memory, which suggests that these processes are also implicated in PD and that DRT could affect them. OBJECTIVE: To investigate word learning and novelty processing in patients with PD as indexed by the P2 and P3 event-related potential components, and the role of DRT in these processes. METHODS: 21 patients with PD and 21 matched healthy controls were included. Patients with PD were tested on and off DRT in two sessions in a counterbalanced design, and healthy controls were tested twice without intervention. Electroencephalogram (EEG) was measured while participants performed a word learning Von Restorff task. RESULTS: Healthy controls showed the typical Von Restorff effect, with better memory for words that were presented in novel fonts, than for words presented in standard font. Surprisingly, this effect was reversed in the patients with PD. In line with the behavioral findings, the P3 was larger for novel than for standard font words in healthy controls, but not in patients with PD. For both groups the P2 and P3 event-related components were larger for recalled versus forgotten words. DRT did not affect these processes. CONCLUSIONS: Learning of novel information is compromised in patients with PD. Likewise, the P2 and P3 components that predict successful memory encoding are reduced in PD patients. This was true both on and off DRT, suggesting that these findings reflect abnormalities in learning and memory in PD that are not resolved by dopaminergic medication.

Gray matter differences contribute to variation in cognitive performance in Parkinson's disease.

BACKGROUND AND PURPOSE: A substantial proportion of patients with Parkinson's disease (PD) suffer from cognitive deficits, although there is a large variability in the severity of these impairments. Whilst the cognitive deficits are often attributed to monoaminergic changes, there is evidence that alterations in structural brain volume also play a role. The aim of our study was to gain more insight into the variability of cognitive performance amongst PD patients by examining the relation between regional gray matter (GM) volume and cognitive performance. METHODS: Linear regression analyses were performed between task performance and GM volume for six neuropsychological tasks within a group of 93 PD patients; they were additionally compared at a group level with matched healthy controls, using voxel-based morphometry. RESULTS: Our most important findings were positive correlations between GM volume and cognitive performance for (i) parahippocampal gyrus and verbal memory, (ii) medial temporal lobe and putamen and visuospatial memory, and (iii) middle temporal gyrus and frontal lobe and verbal fluency. In addition, decreased GM volume was found in the frontal, parietal and temporal cortices of PD patients compared with matched healthy controls. CONCLUSIONS: It is argued that the large variability in cognitive function across PD patients is partly mediated by GM volume differences in the implicated areas. Volume differences in these brain regions do not discriminate between patients and controls but explain cognitive variation within the patient population.

Pedunculopontine cholinergic cell loss in hallucinating Parkinson disease patients but not in dementia with Lewy bodies patients.

There is a cholinergic deficit in Parkinson disease (PD) and in dementia with Lewy bodies (DLB) that plays a role in a variety of clinical symptoms, including visual hallucinations (VH). The aim of this study was to assess cholinergic neuronal loss and PD and Alzheimer disease pathology in the pedunculopontine nucleus pars compacta (PPNc) of PD and DLB patients with VH. Postmortem brainstem tissue samples of 9 clinically diagnosed and pathologically confirmed PD patients with VH, 9 DLB patients with VH, and 9 age- and sex-matched nondemented controls were obtained from the Netherlands Brain Bank. Using a morphometric approach, we estimated the density of cholinergic neurons in the PPNc and determined the local load of α-synuclein-immunoreactive Lewy pathology, neurofibrillary tangles, and ß-amyloid plaques. Cholinergic cell density in the PPNc was significantly lower in PD compared with DLB patients with VH (-39%, p < 0.001) and controls (-41%, p < 0.001). Alpha-synuclein load was higher in PD, whereas ß-amyloid plaque pathology was more pronounced in DLB patients. The mean cell density in DLB patients was not significantly reduced compared with that in controls. These results may indicate different patterns of degeneration of cholinergic output structures in PD and DLB.

The pedunculopontine nucleus is related to visual hallucinations in Parkinson's disease: preliminary results of a voxel-based morphometry study.

Visual hallucinations (VH) are common in Parkinson's disease (PD) and lead to a poor quality of life. For a long time, dopaminergic therapy was considered to be the most important risk factor for the development of VH in PD. Recently, the cholinergic system, including the pedunculopontine nucleus (PPN), has been implicated in the pathophysiology of VH. The aim of the present study was to investigate grey matter density of the PPN region and one of its projection areas, the thalamus. Thirteen non-demented PD patients with VH were compared to 16 non-demented PD patients without VH, 13 demented PD patients (PDD) with VH and 11 patients with dementia with Lewy bodies (DLB). Isotropic 3-D T1-weighted MRI images (3T) were analysed using voxel-based morphometry (VBM) with the PPN region and thalamus as ROIs. PD and PDD patients with VH showed grey matter reductions of the PPN region and the thalamus compared to PD patients without VH. VH in PD(D) patients are associated with atrophy of the PPN region and its thalamic target area, suggesting that a cholinergic deficit may be involved in the development of VH in PD(D).

[Impulse control disorders in Parkinson's disease]. / Impulscontrolestoornissen bij de ziekte van Parkinson en de relatie tot andere stoornissen binnen het impulsieve-compulsieve spectrum.

BACKGROUND: Parkinson's disease is characterised not only by the classic triad of bradykinesia, rigidity and tremor, but also by the frequent occurrence of various non-motor symptoms such as the impulse control disorders (pathological gambling, hypersexuality, compulsive buying, binge eating, punding and dopamine dependency). AIM: To increase insight into the clinical presentation, risk factors, treatment and the underlying pathophysiological mechanisms of impulse control disorders in Parkinson's disease. METHOD: Relevant literature was reviewed. RESULTS: Impulse control disorders belong to an important group of neuropsychiatric disorders that occur at some point in 5-10% of patients with Parkinson's disease. They generally occur in conjunction with dopaminergic medication and can have a marked social, relational and/ or financial impact. CONCLUSION: Early recognition of impulse control disorders in Parkinson's disease is important and a close collaboration between the neurologist and the psychiatrist is essential in order to ensure correct diagnosis and the best possible treatment. Impulse control disorders in Parkinson's disease show considerable phenomenological overlap with other repetitive behaviours within the impulsive-compulsive spectrum of disorders to which the obsessive-compulsive disorders and addiction disorders belong. The overlap can possibly be explained by a shared pathophysiological mechanism involving an imbalance between the direct and indirect pathways of the dorsal and ventral frontal-striatal circuits.

Normal cortical excitability in Myoclonus-Dystonia--a TMS study.

OBJECTIVE: The aim of the present study is to investigate cortical excitability in patients with DYT 11 positive Myoclonus-Dystonia (M-D), using transcranial magnetic stimulation (TMS). METHODS: Silent period, motor evoked potential (MEP) recruitment curve, short interval intracortical inhibition (SICI), intracortical facilitation (ICF) and short interval intracortical facilitation (SICF), with short interstimulus intervals (ISIs) ranging from 1.2 to 3.2 ms, were studied in 15 DYT 11-positive M-D patients and their matched controls. In four patients and matched controls peripheral double pulse electrical nerve stimulation was performed. RESULTS: All TMS parameters of cortical excitability were normal compared to healthy controls. In the SICF protocol we observed more variable and polyphasic MEPs in M-D patients. Cross-covariance analysis of MEP area revealed a significant correlation difference at ISI 2.2 and 2.8 ms. This increased variability was not seen in other TMS protocols or with peripheral nerve stimulation. CONCLUSIONS: In contrast with other types of dystonia, no changes in cortical excitability were found in DYT 11 patients. Our findings suggest that M-D is both clinically and pathophysiologically a separate entity from other dystonic disorders. Polyphasic MEPs during the SICF protocol in M-D patients could reflect central neuron membrane instability. Application of the SICF protocol in other patient groups has to prove its value in movement disorders.

Myoclonus-dystonia: clinical and genetic evaluation of a large cohort.

BACKGROUND: Myoclonus-dystonia (M-D) is an autosomal dominant inherited movement disorder. Various mutations within the epsilon-sarcoglycan (SGCE) gene have been associated with M-D, but mutations are detected in only about 30% of patients. The lack of stringent clinical inclusion criteria and limitations of mutation screens by direct sequencing might explain this observation. METHODS: Eighty-six M-D index patients from the Dutch national referral centre for M-D underwent neurological examination and were classified according to previously published criteria into definite, probable and possible M-D. Sequence analysis of the SGCE gene and screening for copy number variations were performed. In addition, screening was carried out for the 3 bp deletion in exon 5 of the DYT1 gene. RESULTS: Based on clinical examination, 24 definite, 23 probable and 39 possible M-D patients were detected. Thirteen of the 86 M-D index patients carried a SGCE mutation: seven nonsense mutations, two splice site mutations, three missense mutations (two within one patient) and one multiexonic deletion. In the definite M-D group, 50% carried an SGCE mutation and one single patient in the probable group (4%). One possible M-D patient showed a 4 bp deletion in the DYT1 gene (c.934_937delAGAG). CONCLUSIONS: Mutation carriers were mainly identified in the definite M-D group. However, in half of definite M-D cases, no mutation could be identified. Copy-number variations did not play a major role in the large cohort.

Pediatric writer's cramp in myoclonus-dystonia: maternal imprinting hides positive family history.

Myoclonus-dystonia (M-D) is an autosomal dominantly inherited movement disorder with myoclonic jerks and dystonic contractions most frequently due to a mutation in the epsilon-sarcoglycan (SGCE, DYT11) gene. We describe two unrelated children with M-D (DYT11) who presented with writer's cramp. Due to maternal imprinting the family history appeared initially negative for M-D. In children with writer's cramp screening of the SGCE gene should be considered, even with a negative family history.

Pathological gambling after bilateral subthalamic nucleus stimulation in Parkinson disease.

We describe a patient with advanced Parkinson's disease who developed pathological gambling within a month after successful bilateral subthalamic nucleus (STN) stimulation. There was no history of gambling. On neuropsychological testing, slight cognitive decline was evident 1 year after surgery. Stimulation of the most dorsal contact with and without medication induced worse performances on decision making tests compared with the more ventral contact. Pathological gambling disappeared after discontinuation of pergolide and changing the stimulation parameters. Pathological gambling does not seem to be associated with decision making but appears to be related to a combination of bilateral STN stimulation and treatment with dopamine agonists.

Distal myoclonus and late onset in a large Dutch family with myoclonus-dystonia.

We report a large myoclonus-dystonia (M-D) pedigree with a two-base pair deletion in Exon 5 of the epsilon-sarcoglycan gene. Three individuals had onset after age 40 years. Distal myoclonus of the arms was present in all 20 symptomatic mutation carriers. These findings expand the known phenotype of M-D and require revision of the current diagnostic criteria. Five of 14 asymptomatic mutation carriers who inherited the mutation from their mother showed minimal axial dystonia, arguing against a maternal imprinting mechanism.

Phenotype-genotype correlation in Dutch patients with myoclonus-dystonia.

The epsilon-sarcoglycan (SGCE) gene is an important cause of myoclonus-dystonia (M-D), although the majority of cases with an M-D phenotype test negative. Seven of 31 patients with the M-D phenotype carried a mutation in the SGCE gene. Positive family history and truncal myoclonus were independent prognostic factors. Early disease onset, onset with both myoclonus and dystonia, and axial dystonia were detected significantly more often in the mutation carriers.

[Primary generalized dystonia and deep brain stimulation: a randomized, placebo-controlled, double-blind, multicentre study]. / Primaire gegeneraliseerde dystonie en diepe hersenstimulatie: een gerandomiseerd, placebogecontroleerd, dubbelblind, multicentrisch onderzoek.

Dystonia describes a group of movement disorders characterized by involuntary muscle contractions which cause twisting involuntary movements and/or abnormal postures. Primary generalized dystonia often begins in childhood and over a number of years leads to a serious and debilitating illness. The effects of medication and physiotherapy are often disappointing. In the Netherlands a randomized, placebo-controlled and double-blind study has been started to examine the effects and risks of long-term deep brain stimulation in patients with primary generalized dystonia.

Hereditary myoclonus-dystonia associated with epilepsy.

A five-generation Dutch family with inherited myoclonus-dystonia (M-D) is described. Genetic analysis revealed a novel truncating mutation within the epsilon-sarcoglycan gene (SGCE). In three of five gene carriers, epilepsy and/or EEG abnormalities were associated with the symptoms of myoclonus and dystonia. The genetic and clinical heterogeneity of M-D is extended. EEG changes and epilepsy should not be considered exclusion criteria for the clinical diagnosis of M-D.