Mwiza Ushe

Unilateral Subthalamic Nucleus Stimulation Has a Measurable Ipsilateral Effect on Rigidity And Bradykinesia in Parkinson Disease

BACKGROUND Bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor function in Parkinson disease (PD). However, little is known about the quantitative effects on motor behavior of unilateral STN DBS. METHODS In 52 PD subjects with STN DBS, we quantified in a double-blinded manner rigidity (n=42), bradykinesia (n=38), and gait speed (n=45). Subjects were tested in four DBS conditions: both on, left on, right on and both off. A force transducer was used to measure rigidity across the elbow, and gyroscopes were used to measure angular velocity of hand rotations for bradykinesia. About half of the subjects were rated using the Unified Parkinson Disease Rating Scale (part III) motor scores for arm rigidity and repetitive hand rotation simultaneously during the kinematic measurements. Subjects were timed walking 25 feet. RESULTS All subjects had significant improvement with bilateral STN DBS. Contralateral, ipsilateral and bilateral stimulation significantly reduced rigidity and bradykinesia. Bilateral stimulation improved rigidity more than unilateral stimulation of either side, but there was no significant difference between ipsilateral and contralateral stimulation. Although bilateral stimulation also increased hand rotation velocity more than unilateral stimulation of either side, contralateral stimulation increased hand rotation significantly more than ipsilateral stimulation. All stimulation conditions improved walking time but bilateral stimulation provided the greatest improvement. CONCLUSIONS Unilateral STN DBS decreased rigidity and bradykinesia contralaterally as well ipsilaterally. As expected, bilateral DBS improved gait more than unilateral DBS.

Effect of stimulation frequency on tremor suppression in essential tremor

We sought to determine the effect of deep brain stimulation (DBS) frequency on tremor suppression in essential tremor (ET) patients with deep brain stimulators implanted in the ventral intermediate nucleus (VIM) of the thalamus. A uniaxial accelerometer was used to measure tremor in the right upper extremity of subjects with a diagnosis of ET who had DBS electrodes implanted in the left VIM. The root‐mean‐square acceleration was used as the index of tremor magnitude and normalized to the OFF DBS condition. There was a highly significant inverse sigmoidal relationship between stimulation frequency and normalized tremor acceleration (X2/DoF = 0.42, r2 = 0.997). Tremor acceleration had a nearly linear response to stimulation frequencies between 45 and 100 Hz with little additional benefit above 100 Hz. These findings have two important implications. Clinically, frequency of thalamic stimulation is an important variable for optimal tremor control with maximal benefit achieved with 100 to 130 Hz in most patients. Second, thalamic DBS provides tremor benefit in a graded manner and is not an all‐or‐nothing phenomenon.

Functional anatomy of subthalamic nucleus stimulation in Parkinson disease

We developed a novel method to map behavioral effects of deep brain stimulation (DBS) across a 3‐dimensional brain region and to assign statistical significance after stringent type I error correction. This method was applied to behavioral changes in Parkinson disease (PD) induced by subthalamic nucleus (STN) DBS to determine whether these responses depended on anatomical location of DBS.

Cerebral blood flow responses to dorsal and ventral STN DBS correlate with gait and balance responses in Parkinson's disease.

OBJECTIVES The effects of subthalamic nucleus (STN) deep brain stimulation (DBS) on gait and balance vary and the underlying mechanisms remain unclear. DBS location may alter motor benefit due to anatomical heterogeneity in STN. The purposes of this study were to (1) compare the effects of DBS of dorsal (D-STN) versus ventral (V-STN) regions on gait, balance and regional cerebral blood flow (rCBF) and (2) examine the relationships between changes in rCBF and changes in gait and balance induced by D-STN or V-STN DBS. METHODS We used a validated atlas registration to locate and stimulate through electrode contacts in D-STN and V-STN regions of 37 people with Parkinsons disease. In a within-subjects, double-blind and counterbalanced design controlled for DBS settings, we measured PET rCBF responses in a priori regions of interest and quantified gait and balance during DBS Off, unilateral D-STN DBS and unilateral V-STN DBS. RESULTS DBS of either site increased stride length without producing significant group-level changes in gait velocity, cadence or balance. Both sites increased rCBF in subcortical regions and produced variable changes in cortical and cerebellar regions. DBS-induced changes in gait velocity are related to premotor cortex rCBF changes during V-STN DBS (r=-0.40, p=0.03) and to rCBF changes in the cerebellum anterior lobe during D-STN DBS (r=-0.43, p=0.02). CONCLUSIONS DBS-induced changes in gait corresponded to rCBF responses in selected cortical and cerebellar regions. These relationships differed during D-STN versus V-STN DBS, suggesting DBS acts through distinct neuronal pathways dependent on DBS location.

Postural tremor suppression is dependent on thalamic stimulation frequency

Deep brain stimulation (DBS) of the ventral intermediate nucleus (VIM) reduces tremor in people with essential tremor (ET), yet the dependence of tremor suppression on stimulation frequency remains unclear. To address this issue, we tested tremor suppression for three 15‐second measurements during a variety of stimulation frequencies in 11 ET patients treated with VIM DBS. Stimulation frequencies at or above 100 Hz produced maximal benefit; higher frequencies provided no additional benefit. If this short‐term measure predicts long‐term response in routine activities at home, then this stimulation frequency setting will prolong battery half‐life compared to higher frequency settings. These findings suggest that ET patients treated with VIM DBS may receive adequate benefit from stimulation frequencies about 100 Hz and this setting compared to commonly used higher settings will prolong battery life of surgically implanted pulse generators.

Oromandibular and lingual dystonia associated with spinocerebellar ataxia type 8.

The spinocerebellar ataxias (SCAs) are a group of genetically heterogeneous neurodegenerative diseases characterized by limb ataxia with impaired balance, gait and eye movements. Either identified genetic mutations or suspected loci define the specific spinocerebellar ataxia (36 and counting) and each may have additional neurological features including cognitive impairment, seizure or pyramidal signs1. Spinocerebellar ataxia type 8 (SCA8) is a dominantly inherited mutation of chromosome 13q21 with a CTG•CAG expansion that is transcribed in both directions causing mutations in both ATXN8 and ATXN8OS (coding for Ataxin-8 and a noncoding sequence respectively). Spinocerebellar ataxia type 8 is an adult onset ataxia characterized by scanning dysarthria, gait and limb ataxia, hyperreflexia and variable eye movement abnormalities2. We describe here a patient with prominent oromandibular and lingual dystonia due to spinocerebellar ataxia type 8; these features have not been previously associated with spinocerebellar ataxia type 8. Oromandibular dystonia (OMD) often associated with lingual dystonia is a focal dystonia of either involuntary jaw opening or closure. Oromandibular dystonia especially with the presence of lingual dystonia can lead to dysarthria as well as chewing and swallowing problems. Patients with oromandibular dystonia may have a sensory trick such that placing an item in the mouth like a straw may reduce the involuntary movements thereby improving articulation, chewing or swallowing. Oromandibular dystonia can be a primary focal dystonia or secondary to disorders such as Wilson’s disease, neuroacathocytosis, Huntington disease or brainstem and basal ganglia lesions3. A 66 year old woman with a twenty year history of gait instability and 18 year history of dysarthria was referred to the Movement Disorders Clinic after four years of markedly worsening speech. Examination revealed dysarthria with excessive jaw opening accompanied by tongue protrusions while speaking. Jaw opening and speech improved by placing a dowel rod in her mouth. She also had wide based unstable gait, limb ataxia, hyperreflexia and ocular overshoot with sustained horizontal nystagmus and fine upbeat nystagmus on upgaze. She was much more affected by the oromandibular dystonia than the ataxia (Video). Strength and cognitive function were normal. There was no family history of similar illness or other movement disorders. Investigations including CSF, autoimmune serologies, blood smear and vitamins B12 and E were normal. Brain MRI revealed prominent atrophy of the cerebellar vermis and hemispheres without any other lesion (Figure 1). Genetic testing demonstrated a mutation of ATXN8 with 106 CTG repeats on the abnormal allele and 24 on the normal allele (normal <50). Botulinum toxin A therapy to the bilateral lateral pterygoids, digastric and genioglossus muscles at low doses impaired swallowing while providing minimal benefit for the oromandibular dystonia and lingual dystonia. Figure 1 Axial T2-weighted image (A) and sagittal T1-weighted image (B) demonstrating cerebellar atrophy. The current vignette represents the first report of OMD and lingual dystonia in the context of spinocerebellar ataxia type 8. The prevalence of all dominantly inherited SCAs is 1 per 100,000 2. spinocerebellar ataxia type 8 is a rare disorder accounting for 2 – 5% for all autosomal dominant forms of inherited ataxia, with a prevalence of 2 – 5 per 107, while the prevalence of OMD is between 1 and 2.8 per 100,000 4,5. The probability of these rare diseases occurring together as independent events by chance in a randomly selected person is 2 – 14 per 1012, however the probability of an individual with spinocerebellar ataxia type 8 also having oromandibular dystonia would be between 1 – 2.8 per 100,000. The development of dystonia in ataxic syndromes with cerebellar degeneration may reflect either direct involvement of basal ganglia-cerebello-thalamo-cortical circuits, dysfunction of those of circuits due to functional connectivity with cerebellar circuits or direct involvement of cerebellar circuits if that may contribute to dystonia. Recent anatomical tract tracing studies have demonstrated the presence of disynaptic projections between the dentate nucleus of the cerebellum and the striatum and between the subthalamic nucleus and the cerebellar cortex6. In addition positron emission tomographic studies of hereditary dystonia patients have demonstrated striatal and cerebellar functional abnormalities7. Abnormalities in cerebello-thalamo-cortical connectivity may even differentiate disease phenotypes from manifesting carriers in hereditary dystonia7. Furthermore, neuropathologic examinations of SCA8 reveal not only cerebellar degeneration with Purkinje cell loss, and loss of pigmented neurons from the substantia nigra pars compacta and loss of inferior olivary neurons8. Cerebellar atrophy has also been demonstrated in multiple families with an inherited dystonia phenotype with minimal cerebellar ataxia9. Other forms of spinocerebellar ataxias including SCA3, SCA14 and SCA17 have cerebellar pathology and may include dystonic manifestations1,10. Examination of additional patients with spinocerebellar ataxia type 8 mutations will determine how commonly dystonia occurs in this disorder. Further, functional imaging in these patients may help to define the underlying connection between ataxic syndromes with cerebellar degeneration and dystonia. We propose that the ATXN8/ATXN8OS mutations may be implicated in the development of focal dystonia with oromandibular and lingual involvement. The presence of oromandibular dystonia and lingual dystonia in our patient expands the clinical phenotype of spinocerebellar ataxia type 8.

Sex, drugs and Parkinson’s disease

Dopaminergic therapy to relieve motor manifestations of idiopathic Parkinson’s disease may inadvertently cause inappropriate hypersexuality (Vilas et al., 2012). Impulse control disorders that include gambling, eating and hypersexuality seem to occur more commonly with dopamine receptor agonist therapy than l-DOPA and can lead to substantial morbidity with social, psychological and legal consequences (Vilas et al., 2012). The unregulated nature of direct dopamine receptor activation may provide potential clues to the underlying mechanisms. However, the pathophysiological basis for these behaviours remains unknown. Interestingly, dopaminergic pathways also play a key role in brain networks involved in the reward system, and pathological responses in this system may underlie addiction (Volkow et al., 2012). Similarities between addictive behaviour and drug-induced hypersexuality in Parkinson’s disease suggest that they may share common pathological brain mechanisms. Thus investigations of brain regions and networks related to dopaminergic-induced hypersexuality in Parkinson’s disease could shed light on these potentially common underlying mechanisms and provide clues for rationale treatment. The study by Politis et al. (2013) in this issue of Brain takes an important step in this direction. Impulse control disorders including pathological gambling and eating, compulsive shopping and hypersexuality, as well as the dopamine dysregulation syndrome have been described in the context of dopaminergic therapy for Parkinson’s disease (Vilas et al., 2012). Similarly, dopaminergic neurotransmission has been linked to …

7T MRI subthalamic nucleus atlas for use with 3T MRI

Abstract. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) reduces motor symptoms in most patients with Parkinson disease (PD), yet may produce untoward effects. Investigation of DBS effects requires accurate localization of the STN, which can be difficult to identify on magnetic resonance images collected with clinically available 3T scanners. The goal of this study is to develop a high-quality STN atlas that can be applied to standard 3T images. We created a high-definition STN atlas derived from seven older participants imaged at 7T. This atlas was nonlinearly registered to a standard template representing 56 patients with PD imaged at 3T. This process required development of methodology for nonlinear multimodal image registration. We demonstrate mm-scale STN localization accuracy by comparison of our 3T atlas with a publicly available 7T atlas. We also demonstrate less agreement with an earlier histological atlas. STN localization error in the 56 patients imaged at 3T was less than 1 mm on average. Our methodology enables accurate STN localization in individuals imaged at 3T. The STN atlas and underlying 3T average template in MNI space are freely available to the research community. The image registration methodology developed in the course of this work may be generally applicable to other datasets.

Mapping movement, mood, motivation and mentation in the subthalamic nucleus

The anatomical connections of the subthalamic nucleus (STN) have driven hypotheses about its functional anatomy, including the hypothesis that the precise anatomical location of STN deep brain stimulation (DBS) contributes to the variability of motor and non-motor responses across patients with Parkinsons disease (PD). We previously tested the hypothesis using a three-dimensional (3D) statistical method to interpret the acute effects of unilateral DBS at each patients clinically optimized DBS settings and active contact. Here, we report a similar analysis from a new study in which DBS parameters were standardized and DBS locations were chosen blind to clinical response. In 74 individuals with PD and STN DBS, STN contacts were selected near the dorsal and ventral borders of the STN contralateral to the more affected side of the body. Participants were tested off PD medications in each of three unilateral DBS conditions (ventral STN DBS, dorsal STN DBS and DBS off) for acute effects on mood, apathy, working memory, response inhibition and motor function. Voltage, frequency and pulse width were standardized, and participants and raters were blind to condition. In a categorical analysis, both dorsal and ventral STN DBS improved mean motor function without affecting cognitive measures. Ventral STN DBS induced greater improvement in rigidity and anxiety than dorsal STN DBS. In the 3D analysis, contact location was significant for body hypokinesia, rigidity and resting tremor, with the greatest improvement occurring with DBS in dorsal STN and zona incerta. The 3D results provide new, direct functional evidence for the anatomically derived model of STN, in which motor function is best represented in dorsal STN. However, our data suggest that functional segregation between motor and non-motor areas of the STN is limited, because locations that induced improvements in motor function and mood overlapped substantially.