Conor Fearon

DESPRIT - histogram based blind source separation of more sources than sensors using subspace methods

A blind source separation (BSS) technique is presented which combines the subspace processing and associated DOA capability of ESPRIT with the weighted histogram of DUET. The method allows for a weakened version of the disjoint signal assumption of DUET and can be seen as a natural extension of DUET to more than two mixtures. Instead of only allowing at most one source be active at any time-frequency point, up to M-1 sources can be active where M is the number of anechoic mixtures. The combination of these techniques creates a DUET-ESPRIT (DESPRIT) blind source separation algorithm which can demix an arbitrary number of sources N, even when N > M

Towards a hardware realization of time-frequency source separation of speech

This paper presents preliminary work on a hardware implementation of a source separation algorithm employing time-frequency masking methods. DUET (degenerate unmixing estimation technique) has previously been shown to achieve excellent source separation in real time in software. The current work is a move towards a hardware realization of DUET that allows integration of the algorithm into consumer devices. Initial stages involve investigating the performance of DUET when implemented in fixed-point arithmetic and a consideration of algorithmic changes to make DUET more amenable to implementation on a DSP processor. Performance is compared for floating-point and fixed-point implementations. A weighted K-means clustering algorithm is presented as an alternative to gradient descent methods for peak tracking and demonstrated to achieve excellent performance without adversely affecting computational load. Preliminary performance figures are given for an implementation on a TMS320VC5510 DSK.

The impact of dual tasking on cognitive performance in a Parkinson's disease cohort with and without freezing of gait: An EEG and behavioral based approach

Freezing of gait (FOG) is a common disabling gait disorder in late stage Parkinsons disease (PD), which can lead to falls and loss of independence. To date, the mechanisms causing FOG are still unknown and no treatment has proven to be effective. In this study, sixteen PD participants with and without clinically confirmed FOG symptoms were recruited, referred to as FOG+ and FOG-, respectively. All participants navigated through a customized virtual reality (VR) corridor by stepping in place (SIP) on a force plate while electroencephalography (EEG) data was recorded. The VR environment was combined with a cognitive, visual two-stimulus oddball response task, which was repeated while seated to allow for comparisons to the SIP condition. The VR environment proved to be a reliable tool to elicit FOG like symptoms in a clinical test environment. EEG recordings were compared between conditions (seated/SIP) within groups and behavioral performance was compared between groups and conditions for qualitative differences. In the seated condition FOG+ participants showed similar behavioral performance to FOG- participants, however, in the SIP condition the FOG+ group showed significantly decreased performance with longer reaction times and more target misses. Analysis of the EEG data revealed consistent visual responses to the stimuli, but an absence of the P3b component in stimulus-locked brain responses for FOG+ participants and both conditions. However, if data is response-locked, the P3b component is clearly visible for both conditions, supporting the theory that components related to decision making and motor preparation are present, but with variable delays.

Audiovisual Processing is Abnormal in Parkinson’s Disease and Correlates with Freezing of Gait and Disease Duration

BACKGROUND Sensory and perceptual disturbances progress with disease duration in Parkinsons disease (PD) and probably contribute to motor deficits such as bradykinesia and gait disturbances, including freezing of gait (FOG). Simple reaction time tests are ideal to explore sensory processing, as they require little cognitive processing. Multisensory integration is the ability of the brain to integrate sensory information from multiple modalities into a single coherent percept, which is crucial for complex motor tasks such as gait. OBJECTIVES The aims of this study were to: 1. Assess differences in unisensory (auditory and visual) and multisensory processing speed in people with PD and age-matched healthy controls. 2. Compare relative differences in unisensory processing in people with PD with disease duration and freezing of gait status taking into account the motor delays, which are invariably present in PD. 3. Compare relative differences in multisensory (audiovisual) processing between the PD cohort and age-matched controls. METHODS 39 people with PD (23 with FOG) and 17 age-matched healthy controls performed a reaction time task in response to unisensory (auditory-alone, visual-alone) and multisensory (audiovisual) stimuli. RESULTS The PD group were significantly slower than controls for all conditions compared with healthy controls but auditory reaction times were significantly faster than visual for the PD group only. These relative unisensory differences are correlated with disease duration and divide the PD group by FOG status, but these factors are co-dependent. Although multisensory facilitation occurs in PD, it is significantly less enhanced than in healthy controls. CONCLUSION There are significant unisensory and multisensory processing abnormalities in PD. The relative differences in unisensory processing are specific to PD progression, providing a link between these sensory abnormalities and a motor feature of PD. Sensory disturbances have previously been postulated to be central to FOG but this is the first study to predict audiovisual processing abnormalities using FOG status. The multisensory processing abnormalities are independent of disease duration and FOG status and may be a potential biomarker for the disease.

New Perception of Mitochondrial Regulatory Pathway in Parkinsonism - Ubiquitin, PINK1, and Parkin.

Mutations in PARK2, a gene encoding cytosolic E3 ubiquitin ligase parkin cause autosomal recessive Parkinsonism similar to mutations in the less prevalent PINK1 (PTEN induced putative kinase 1). Parkin and PINK 1 (Ser/Thr kinase) eliminate damaged mitochondria through mitophagy and mutations cause accumulation of impaired mitochondria and reactive oxygen species (1). PINK1, when activated by depolarization of the mitochondrial membrane potential, leads to phosphorylation and activation of E3 parkin ligase [Okatsu (2)]. PINK1 acts upstream to parkin accelerating latent E3 parkin activity and increasing accumulation of parkin on depolarized mitochondria in Drosophila. Presumably, PINK1-dependent phosphorylation of parkin at Ser65 accelerates E3 parkin activity. However, the substrate for PINK 1 phosphorylation of parkin has remained elusive. Koyano et al. (1) demonstrated that PINK1 phosphorylates ubiquitin, which subsequently activates parkin on damaged mitochondria. PINK1-dependent parkin activation proceeds in two phases: phosphorylation of ubiquitin-like (UBL) domain of parkin at Ser 65, followed by phosphorylation at Ser 65 of ubiquitin itself. While UBL domain is known for keeping parkin inactivated, phosphorylation of Ser 65 activates parkin partially (3). Autoubiquitination is not promoted by non-phosphorylated ubiquitin. Kane et al. (4) and Kazlauskaite et al. (3) also confirmed phosphorylated ubiquitin as a parkin activator. These studies shed light on two further PINK1/parkin metabolism issues: (1) why does a phosphorylation-deficient mutation of parkin inhibit formation of a ubiquitin-ester (an intermediate product in the parkin activation pathway), (2) why does a phosphomimetic parkin mutant still require PINK1 for activation. Koyano et al. used phosphate affinity (phos-tag) PAGE assay to identify a slower-migrating ubiquitin band, phosphorylated by PINK1 on damaged mitochondria (i.e., pre-treated a protonophore). Mass spectrometry analysis identified Ser 65 as the ubiquitin phosphorylation site. A yeast system was used to confirm that phosphorylated ubiquitin at Ser 65 is a parkin activator. Thus, ubiquitin acts not only as a substrate for phosphorylation but also activates parkin itself. Koyano et al. proposed that parkin is fully activated by repression of the catalytic cysteine by RING0 domain unlocked by phosphorylated ubiquitin and UBL domain. Parkinson’s disease is an incurable neurodegenerative condition. Defects in mitochondrial regulation have been implicated as one of the key elements in the etiology of parkinsonism. PINK 1 and parkin act as neuroprotective agents by maintaining mitochondrial homeostasis. Decreased antioxidant effect may be seen in other serious disorders, such as tumors where parkin expression is frequently diminished (5). Mechanism of interaction between these two proteins has been unclear. Koyano et al. used a yeast system to aid demonstration of the important role of phosphorylated ubiquitin acting as a long-searched for mediator between PINK1 and parkin. The above results may lead to novel therapeutic options for Parkinson’s disease. Cornelissen et al. (6) proposed a treatment strategy based upon inhibition of ubiquitin-specific protease 15 (USP15), a deubiquitinating enzyme (DUB) counteracting Parkin-mediated autophagy, while Kazlauskaite et al. (3) suggested development of a parkin activator in the form of ubiquitin-like agent. PINK1 driven phosphorylation of ubiquitin has important implications in understanding the underlying pathophysiological mechanisms of parkinsonism and to develop new treatment strategies for an incurable movement disorder.

Failure of Sequential Pallidal and Motor Thalamus DBS for Rapid-Onset Dystonia-Parkinsonism (DYT12)

Rapid-onset dystonia-parkinsonism (DYT12) is an autosomal dominant combined dystonia associated with mutations of the ATP1A3 gene. Onset is precipitated abruptly by physical/psychological stressors. Dystonia displays a rostrocaudal distribution with prominent orofacial and upper limb involvement, with symptoms remaining refractory to dopaminomimetic or GABA-mimetic agents. It is also the preeminent movement disorder in DYT12, with little parkinsonism, including bradykinesia (possibly reflecting dystonic slowing without decrement). We describe the response to sequential deep brain stimulation (DBS) of the globus pallidus internus (GPI) and, subsequently, the thalamic zona incerta and nucleus ventralis oralis posterior (VOP) in a patient from the Irish DYT12, which was described in detail by Pittock and colleagues. The 8-year-old patient, while playing in a playground, fell to the ground after hanging upside-down. After several minutes she began to whisper. Over the next fortnight, her speech deteriorated, and she subsequently became anarthric. She developed significant upper limb dystonia and dystonic posturing of the left foot. Slow rapidly alternating movements and facial dystonia were noted. MRI brain, neurometabolic bloods, and CSF were normal. Genetic analysis identified a C1838T point mutation in exon 14 of the ATP1A3 gene, co-segregating with disease phenotype in the family. There was no response to pharmacotherapy with levodopa, benzodiazepines, or acetazolamide. Bilateral GPI DBS was performed. Postoperatively, serial assessments identified objective deterioration in communication and feeding; verbal communication was eventually lost and she developed jaw opening dystonia. With optimization of her DBS parameters, she had fluctuating improvement of left arm function. Paradoxically, despite worsening oromandibular dystonia, it was easier to bring food to her mouth. Over time, it became apparent that DBS adjustments to improve orofacial symptoms were consistently coupled with deterioration in upper limb dystonia. Having failed to optimize GPI stimulation, she had further surgery to target the nucleus ventralis oralis posterior (VOP; a pallidal receiving area) and zona incerta (ZI). The previous pallidal system was removed. Postoperative imaging confirmed satisfactory lead placement (Fig. 1). After initial stimulation, she noticed increased difficulty swallowing, which improved with down-titration. There has been little improvement in either the orofacial or upper limb dystonia (Video S1). DYT12 remains a formidable disorder to treat and lack of response to medical therapy makes DBS appealing as a therapeutic option, however evidence is limited. Given the favorable outcomes seen in other primary dystonias, including DYT1 or similarly combined dystonias, including Lubag, it is disappointing that DBS of GPI or motor thalamus (VOP and ZI) has not resulted in significant improvements in this patient. One previous report of DBS in genetically confirmed DYT12 (GPI satisfactorily targeted) showed a reduction in dystonia severity of “borderline” clinical significance. Previous reports of pallidal +/STN-DBS in non-genetically defined, rapid-onset dystonic, and parkinsonian syndromes did not demonstrate benefit. We describe the second case of GPI DBS and the first case of VOP/ZI DBS in DYT12. There was no significant

Motor preparation rather than decision-making differentiates Parkinson’s disease patients with and without freezing of gait

OBJECTIVE Freezing of gait (FOG) is a brief, episodic phenomenon affecting over half of people with Parkinsons disease (PD) and leads to significant morbidity. The pathophysiology of FOG remains poorly understood but is associated with deficits in cognitive function and motor preparation. METHOD We studied 20 people with PD (10 with FOG, 10 without FOG) and performed a timed response target detection task while electroencephalographic data were acquired. We analysed the data to detect and examine cortical markers of cognitive decision making (P3b or centroparietal positivity, CPP) and motor readiness potential. We analysed current source density (CSD) to increase spatial resolution and allow identification of distinct signals. RESULTS There was no difference in the P3b/CPP response between people with PD with and without FOG, suggesting equivalent cognitive processing with respect to decision-making. However, the FOG group had significant difference with an earlier onset and larger amplitude of the lateralized readiness potential. Furthermore, the amplitude of the lateralised readiness potential correlated strongly with total Frontal Assessment Battery score. CONCLUSIONS The difference in lateralized readiness potentials may reflect excessive recruitment of lateral premotor areas to compensate for dysfunction of the supplementary motor area and resultant loss of automatic motor control. This early, excessive recruitment of frontal networks occurs in spite of equivalent motor scores and reaction times between groups. SIGNIFICANCE The saturation of frontal processing mechanisms could help explain deficits in attentional set-shifting, dual-tasking and response inhibition which are frequently reported in FOG.

Superficial siderosis and dural ectasia A case report

A 61-year-old woman with known neurofibromatosis type 1 (NF1) presented with lower back pain, urinary retention, impaired hearing, and tinnitus. Her lower limb deep tendon reflexes were brisk bilaterally with extensor plantar responses. MRI showed extensive dural ectasia, as well as hemosiderin deposition characteristic of superficial siderosis (figures 1 and 2). CSF analysis showed elevated erythrocyte counts, protein, and ferritin. Dural ectasia and meningocele formation are recognized complications of NF1.1 In this case, friable vessels at the site of the ectatic dura are the likely source of chronic bleeding into the CSF,2 resulting in diffuse superficial siderosis.

Distal myasthenia gravis presenting as isolated distal myopathy.

association with other malignancies or with nivolumab. We present a case of a patient with SCLC who developed drug-induced MG shortly after induction with nivolumab and ipilimumab. A 70-year-old man with a 1-year history of stage 4 SCLC refractory to first-line cisplatin/etoposide chemotherapy and radiation presented with ptosis and diplopia 16 days after starting treatment with ipilimumab and nivolumab (NCT01928394). After developing symptoms, the agents were discontinued. MG was suspected, and repetitive nerve stimulation (RNS) demonstrated a decremental response (17%) to 3-HZ stimulation of the abductor digiti minimi. No facilitation was present to suggest Lambert–Eaton myasthenic syndrome (LEMS). Acetylcholine receptor binding antibodies were positive (1.64 nmol/L), as were modulating and striational antibodies. P/Q-type calciumchannel antibodies were absent. There was no thymoma on computed tomography imaging. He started prednisone 1 mg/kg (90 mg/day) at onset, followed by 3 sessions of plasmapheresis with improvement. He was discharged 7 days later on prednisone 90 mg/day, but was readmitted 1 day later with dyspnea and generalized weakness. He required intubation and did not improve despite a switch to intravenous methylprednisolone starting at 80 mg, and 3 additional sessions of plasmapheresis followed by 200 g (0.5 g/kg) of intravenous immunoglobulin. He had repeat RNS 9 days after his initial study, which showed a 25% decrement without post-exercise facilitation. His subsequent hospital course was complicated by complete heart block requiring pacemaker placement, sepsis, and bleeding duodenal ulcers. Medical care was withdrawn in concert with family’s wishes on hospital day 22. Ipilimumab and nivolumab monotherapy are established treatments for melanoma, and they are used in clinical trials for the treatment of other malignancies. Ipilimumab has been associated with druginduced MG and other autoimmune neurologic conditions (e.g., transverse myelitis), and the reported severity of ipilimumab-associated MG has ranged from mild fatigue to death. Given the rapid progression to respiratory failure, our patient highlights the potential risk of severe myasthenic crisis associated with ipilimumab. The severity may be explained by overstimulation of the patient’s immune system in response to his chemotherapeutic regimen and his coexisting SCLC. The exact mechanism of MG induction is unclear, but it is suspected to be due to cytotoxic T-lymphocyte activation. The possible role of nivolumab in causation is unclear. Neurologists should recognize ipilimumab and similar treatments as potential causes of MG. Development of MG symptoms during ipililmumab administration should result in prompt drug cessation and initiation of therapy directed at preventing myasthenic crisis.

The effects of immunologic brainstem encephalopathy on cognitive function following awakening from a progressive autoimmune coma

We describe a unique patient who experienced a progressive autoimmune coma from age 14 to 17. The patient awoke after treatment with immunosuppressant medication. Although alertness, verbalization, and mobilization markedly improved, the patient reported persistent cognitive difficulties. Neuropsychological assessment from age 21 showed impairments in selective attention, distractibility, and memory. Conversely, higher-order executive functions were preserved. Electrophysiological analysis also identified abnormal neural signatures of selective attention. Eighteen months after the neuropsychological assessment, voxel-based morphometry revealed reduced white matter in the medulla compared to controls. The findings are discussed in terms of the impact of brainstem encephalopathy on cognitive mechanisms.