What do blind people "see" with retinal prostheses? Observations and qualitative reports of epiretinal implant users.

INTRODUCTION: Retinal implants have now been approved and commercially available for certain clinical populations for over 5 years, with hundreds of individuals implanted, scores of them closely followed in research trials. Despite these numbers, however, few data are available that would help us answer basic questions regarding the nature and outcomes of artificial vision: what do recipients see when the device is turned on for the first time, and how does that change over time? METHODS: Semi-structured interviews and observations were undertaken at two sites in France and the UK with 16 recipients who had received either the Argus II or IRIS II devices. Data were collected at various time points in the process that implant recipients went through in receiving and learning to use the device, including initial evaluation, implantation, initial activation and systems fitting, re-education and finally post-education. These data were supplemented with data from interviews conducted with vision rehabilitation specialists at the clinical sites and clinical researchers at the device manufacturers (Second Sight and Pixium Vision). Observational and interview data were transcribed, coded and analyzed using an approach guided by Interpretative Phenomenological Analysis (IPA). RESULTS: Implant recipients described the perceptual experience produced by their epiretinal implants as fundamentally, qualitatively different than natural vision. All used terms that invoked electrical stimuli to describe the appearance of their percepts, yet the characteristics used to describe the percepts varied significantly between recipients. Artificial vision for these recipients was a highly specific, learned skill-set that combined particular bodily techniques, associative learning and deductive reasoning in order to build a "lexicon of flashes"-a distinct perceptual vocabulary that they then used to decompose, recompose and interpret their surroundings. The percept did not transform over time; rather, the recipient became better at interpreting the signals they received, using cognitive techniques. The process of using the device never ceased to be cognitively fatiguing, and did not come without risk or cost to the recipient. In exchange, recipients received hope and purpose through participation, as well as a new kind of sensory signal that may not have afforded practical or functional use in daily life but, for some, provided a kind of "contemplative perception" that recipients tailored to individualized activities. CONCLUSION: Attending to the qualitative reports of implant recipients regarding the experience of artificial vision provides valuable information not captured by extant clinical outcome measures.

Simulation of visual perception and learning with a retinal prosthesis.

OBJECTIVE: The nature of artificial vision with a retinal prosthesis, and the degree to which the brain can adapt to the unnatural input from such a device, are poorly understood. Therefore, the development of current and future devices may be aided by theory and simulations that help to infer and understand what prosthesis patients see. APPROACH: A biologically-informed, extensible computational framework is presented here to predict visual perception and the potential effect of learning with a subretinal prosthesis. The framework relies on optimal linear reconstruction of the stimulus from retinal responses to infer the visual information available to the patient. A simulation of the physiological optics of the eye and light responses of the major retinal neurons was used to calculate the optimal linear transformation for reconstructing natural images from retinal activity. The result was then used to reconstruct the visual stimulus during the artificial activation expected from a subretinal prosthesis in a degenerated retina, as a proxy for inferred visual perception. MAIN RESULTS: Several simple observations reveal the potential utility of such a simulation framework. The inferred perception obtained with prosthesis activation was substantially degraded compared to the inferred perception obtained with normal retinal responses, as expected given the limited resolution and lack of cell type specificity of the prosthesis. Consistent with clinical findings and the importance of cell type specificity, reconstruction using only ON cells, and not OFF cells, was substantially more accurate. Finally, when reconstruction was re-optimized for prosthesis stimulation, simulating the greatest potential for learning by the patient, the accuracy of inferred perception was much closer to that of healthy vision. SIGNIFICANCE: The reconstruction approach thus provides a more complete method for exploring the potential for treating blindness with retinal prostheses than has been available previously. It may also be useful for interpreting patient data in clinical trials, and for improving prosthesis design.

Ethical concerns regarding commercialization of deep brain stimulation for obsessive compulsive disorder.

The United States Food and Drug Administration's recent approval of the commercial use of Deep Brain Stimulation (DBS) as a treatment for Obsessive Compulsive Disorder (OCD) will be discussed within the context of the existing USA regulatory framework. The purpose will be to illustrate the current lack of regulation and oversight of the DBS market, which has resulted in the violation of basic ethical norms. The discussion will focus on: 1) the lack of available evidence on procedural safety and efficacy, 2) the numerous conflicts of interest held by research investigators, and 3) the ambiguity of both aforementioned categories due to an inherent lack of transparency in the research. It is argued that in order to address these issues, ethical analyses of DBS for psychiatric disorders must include the role of the industry forces that have become the primary impetus for this research. As such, DBS for OCD serves as an important case example in studies of neurotechnology and innovative surgery.

Increased number of heterotopic Purkinje cells in essential tremor.

OBJECTIVE: Recent postmortem studies reveal degenerative changes, including Purkinje cell (PC) loss, in most brains from individuals with essential tremor (ET). Heterotopic PCs (HPCs) (ie, PC bodies displaced into the molecular layer) may be found in neurodegenerative diseases with PC loss. HPCs have been observed in ET but no quantitative case control analysis has been performed. METHODS: HPCs were counted in 35 ET brains and 32 control brains (including 21 non-diseased controls and 11 diseased controls with progressive supranuclear palsy (PSP)) using a standard 20 × 25 mm cerebellar cortical section stained with a modified Bielscholwsky method. RESULTS: The median number of HPCs per section was three times higher in 35 ET cases (median 3, mean ± SD 3.8 ± 3.6, range 0-14) versus 32 controls (median 1, mean ± SD 1.6 ± 1.7, range 0-5) (p = 0.007). The number of HPCs was similarly low in the 21 non-diseased controls and 12 PSP brains (median 1 in each group) (p = 0.04 and p = 0.01 compared with ET). In ET, the number of HPCs was inversely related to the number of PCs (Spearman's rho -0.36, p = 0.038) (ie, cases with more HPCs had fewer PCs). CONCLUSION: PC heterotopia, which occurs in cerebellar degenerative disorders, is also a feature of ET. These findings further contribute to our understanding of the postmortem changes in this common neurological disease.

"Hairy baskets" associated with degenerative Purkinje cell changes in essential tremor.

Essential tremor (ET) is one of the most common neurologic diseases. Increased numbers of torpedoes and Purkinje cell (PC) loss have been documented in the brains of patients with ET. We recently observed a dense and tangled appearance ("hairiness") of the basket cell axonal plexuses that surround PC soma in Bielschowsky preparations of cerebellar cortex in ET brains. Here, we assessed basket cell "hairiness" in 37 ET (32 cerebellar ET; 5 Lewy body variant ET), 21 nondisease control, and 48 disease control brains using a semiquantitative scale. In 8 cerebellar ET cases (25%), there were high basket scores (rating = 3), whereas no Lewy body variant ET, 1 nondisease control (4.8%), and 2 diseased controls (4.2%) had high basket scores (p = 0.001). The hairy basket scores correlated with numbers of torpedoes (p < 0.001) and inversely with numbers of PCs (p = 0.06). Axonal plexus density obtained by image analysis of basket cell processes traced from digitized images was higher in ET than in nondiseased control cases (p = 0.016). Closely spaced sites of synaptic contact between basket cell processes and PCs were identified by electron microscopy in ET cases. These data indicate that structural changes are not restricted to PCs in ET, and that other neurons within their functional network may be involved in its pathogenesis.

Sexual and relationship satisfaction among persons with young-onset Parkinson's disease.

INTRODUCTION: Parkinson's disease (PD) presents unique personal and social challenges, particularly for those with onset before the age of 50 years. AIM: The aim of this article is to evaluate sexual and non-sexual aspects of relationship satisfaction among persons with young-onset PD and their partners. MAIN OUTCOME MEASURES: The main outcome measures were Index of Sexual Satisfaction (ISS) and Golombok-Rust Inventory of Marital State (GRIMS). METHODS: Persons with PD (PWP) and partners who attended the 2005 National Parkinson Foundation Young Onset Network Conference were asked to complete a survey. Each survey included demographics, a clinical history questionnaire, the Beck Depression Inventory (BDI), ISS, and GRIMS. RESULTS: Sixty PWP (63% men, 85% in a relationship) responded to the survey. Median age was 50 years (range 29-62), with a median age at symptom onset of 43 years (range 17-55). ISS scores indicated clinically significant sexual dissatisfaction in 37%. Relationship dissatisfaction measured by the GRIMS was scored as "poor" or worse in 57%. Depressive symptomatology was severe in 19% and mild in 33%. Sexual dissatisfaction (ISS) correlated with relationship dissatisfaction (GRIMS) (correlation coefficient [CC] = 0.58, P < 0.001). Relationship dissatisfaction (GRIMS) correlated with depressive symptomatology (BDI) (CC = 0.38, P = 0.007). No correlations were found with any demographic or disease characteristics. Thirty-two couples (both the PWP and their partner) completed the surveys. Sexual and relationship dissatisfaction among PWP paralleled that of their partner (ISS: CC = 0.48, P = 0.005; GRIMS: CC = 0.61, P < 0.001). Depressive symptomatology of the PWP correlated with their partners' relationship dissatisfaction (CC = 0.46, P = 0.010). CONCLUSIONS: In this study, sexual and relationship dissatisfaction were prevalent among young-onset PD patients. PD patients were similar to their partners in their level of sexual and relationship dissatisfaction. The degree of dissatisfaction did not correlate with demographics or self-reported disease characteristics. Self-reported depressive symptomatology among PD patients was adversely associated with both their and their partner's relationship satisfaction. Wiel

Assessing cognition in Parkinson disease: use of the cognitive linguistic quick test.

OBJECTIVE: To evaluate the Cognitive Linguistic Quick Test (CLQT) as a cognitive screening tool in Parkinson disease (PD). METHODS: A total of 93 patients with PD were evaluated with the Mini-Mental State Examination (MMSE) and the CLQT. The CLQT provides separate ratings for 5 cognitive domains. Descriptive statistics, correlations between the tests, and diagnostic value for dementia were analyzed. RESULTS: Cognitive Linguistic Quick Test correlated well with MMSE. Diagnostic values for dementia were similar for the 2 instruments. Unlike the MMSE, the CLQT also provided domain-specific information on cognitive deficits. Cognitive domains were differentially affected between and within the demented and nondemented patient groups with PD: memory was the weakest domain in the demented group and attention in the nondemented. CONCLUSIONS: The CLQT is a valuable instrument in assessing cognitive dysfunction in PD. The CLQT is superior to the MMSE as it also provides cognitive domain-specific information.

Torpedoes in Parkinson's disease, Alzheimer's disease, essential tremor, and control brains.

Purkinje cell axonal swellings ("torpedoes"), described in several cerebellar disorders as well as essential tremor (ET), have not been quantified in common neurodegenerative conditions. The aim of this study was to quantify torpedoes Parkinson's disease (PD) and Alzheimer's disease (AD) compared with ET and control brains. Brains included 40 ET cases (34 cerebellar ET, 6 Lewy body variant of ET) and age-matched comparison brains (21 AD, 14 PD/diffuse Lewy body disease, 25 controls). Torpedoes were counted in 20 x 25 mm cerebellar cortical sections stained with Luxol Fast Blue/Hematoxylin and Eosin. The median number of torpedoes in cerebellar ET (12) was 12x higher than that of controls (1) and nearly 2.5x higher than in AD (5) or PD/DLBD (5) (all P < or = 0.005). Furthermore, in a logistic regression model that adjusted for age and Alzheimer's-type changes, each torpedo more than doubled the odds of having cerebellar ET (Odds ratio(cerebellar ET vs. control) = 2.57, P = 0.006), indicating that the association between increased torpedoes and cerebellar ET was independent of these Alzheimer's-type changes. Although torpedoes are increased in AD and PD, as well as cerebellar ET, the magnitude of increase in cerebellar ET is greater, and cannot be accounted for by concomitant AD or PD pathology.

Older onset essential tremor: More rapid progression and more degenerative pathology.

There are few data on rate of progression in essential tremor (ET). To quantify the rate of tremor progression in a cross-sectional sample of 348 ET cases in an epidemiological study; characterize the relationship between age of tremor onset and rate of tremor progression in that sample; and characterize the relationship between age of tremor onset, rate of tremor progression, and severity of underlying brain changes in 9 cases from a brain repository. Rate of tremor progression was defined as tremor severity / duration. The degeneration index = number of torpedoes per section / Purkinje cell linear density. In the epidemiological study, older age of tremor onset was associated with faster rate of tremor progression (P < 0.001). In the brain repository, older age of tremor onset was associated with higher degeneration index (P = 0.037), and higher degeneration index was associated with faster rate of tremor progression (P = 0.018). In a large clinical sample, older age of onset was associated with more rapid tremor progression. In a brain bank, older age of onset was associated with more degenerative pathology in the cerebellum. As in several neurodegenerative disorders, in older onset cases, it is possible that the disease advances more rapidly.

Structural study of Purkinje cell axonal torpedoes in essential tremor.

Essential tremor (ET) is one of the most common neurological diseases. A basic understanding of its neuropathology is now emerging. Aside from Purkinje cell loss, a prominent finding is an abundance of torpedoes (rounded swellings of Purkinje cell axons). Such swellings often result from the mis-accumulation of cell constituents. Identifying the basic nature of these accumulations is an important step in understanding the underlying disease process. Torpedoes, only recently identified in ET, have not yet been characterized ultrastructurally. Light and electron microscopy were used to characterize the structural constituents of torpedoes in ET. Formalin-fixed cerebellar cortical tissue from four prospectively collected ET brains was sectioned and immunostained with a monoclonal phosphorylated neurofilament antibody (SMI-31, Covance, Emeryville, CA). Using additional sections from three ET brains, torpedoes were assessed using electron microscopy. Immunoreactivity for phosphorylated neurofilament protein revealed clear labeling of torpedoes in each case. Torpedoes were strongly immunoreactive; in many instances, two or more torpedoes were noted in close proximity to one another. On electron microscopy, torpedoes were packed with randomly arranged 10-12nm neurofilaments. Mitochondria and smooth endoplasmic reticulum were abundant as well, particularly at the periphery of the torpedo. We demonstrated that the torpedoes in ET represent the mis-accumulation of disorganized neurofilaments and other organelles. It is not known where in the pathogenic cascade these accumulations occur (i.e., whether these accumulations are the primary event or a secondary/downstream event) and this deserves further study.

Falls and injuries resulting from falls among patients with Parkinson's disease and other parkinsonian syndromes.

We sought to ascertain frequency, type, risk factors of falling, and resulting injuries among parkinsonian patients. A survey was mailed to all patients treated at our center between 1/1/2000 and 4/30/2002 (N = 1,417). Information was collected on falls within the past 2 years, related injuries, and use of health care services. A total of 1,131 responses (response rate, 79.8%) were received. After the exclusion of nonparkinsonian disorders, statistics for the remaining group (n = 1,092) and predictive statistics for those diagnosed before 1/1/2000 (n = 1,013) were calculated. Outcomes included falls, fractures, injuries, surgery, and related use of health care services. Explanatory variables included sex, age, age at diagnosis, disease duration, atypical parkinsonism, and dementia. Most patients (55.9%) were men; 12.2% had atypical parkinsonism; 12.5% had dementia; median age was 74.7 years; median disease duration was 7 years; 55.9% had at least one fall in the past 2 years; 65.0% of them sustained an injury; 33.0% sustained a fracture; 75.5% of injuries required health care services; 40.6% of fractures required surgery. Older age, atypical parkinsonism, longer disease duration, and dementia were risk factors for falling; female sex and older age were predictors of fractures. Need for health care services after an injury was higher among older patients. Further prospective studies will be necessary to elucidate the specific prognostic outcomes of injuries due to falls among parkinsonian patients, and the impact of these injuries on disease progression and quality of life.