The concepts of hope and its absence, hopelessness, are seen as crucial in palliative care for people with motor neurone disease. A primary measure in psychological research on hopelessness in people with motor neurone disease is the Beck Hopelessness Scale. This scale can be understood as being conceptually based on the philosophical standard account of hope, which understands hope as an intentional expectancy. This essay argues that this is a misconstruction of hopelessness in palliative (...) care. Rather, pre-intentional hope is essential for palliative care of people with motor neurone disease. Pre-intentional hope enables the formation of intentional hopes and is intrinsically relational. Finally, it is argued that the absence of pre-intentional hope should not be subjected to psychiatric diagnosis, for example, in the form of demoralization disorder. (shrink)

This paper focuses on the ethical dilemmas created by advanced technology that would allow patients with motor neurone disease to be sustained by artificial ventilation. The author attempts to support the patient's right to informed choice, arguing from the perspective of autonomy as a first order principle. The counter arguments of caregiver burden and financial restraints are analysed. In the UK, where active euthanasia is not legalized, the dilemma of commencing ventilation is seen to be outweighed by (...) the problems of withdrawing this treatment. The lack of accurate data and protocols that would clarify the current situation is emphasized and the conclusion takes the form of a recommendation for further research. (shrink)

Background: Parkinson’s disease is a neurodegenerative disease in which the progressive loss of dopaminergic neurons leads to initially sporadic and eventually widespread damage of the nervous system resulting in significant musculoskeletal and cognitive deterioration. Loss of motor function alongside increasing cognitive impairment is part of the natural disease progression. Gait is often considered an automatic activity; however, walking is the result of a delicate balance of multiple systems which maintain the body’s center of mass over an (...) ever-changing base of support. It is a complex motor behavior that requires components of attention and memory to prevent falls and injury. In addition, evidence points to the critical role of salient visual information to gait adaptability. There is a growing understanding that treatment for PD needs to address movement as it occurs naturally and walking needs to be practiced in more complex environments than traditional therapy has provided.MethodsIn this single-blinded randomized-controlled pilot study, an immersive treadmill training was piloted to determine feasibility and preliminary efficacy on gait and cognition in people with PD. Eighteen participants with Hoehn and Yahr stages I-III PD were randomized to either an intervention or a waitlist control group. Following baseline data collection, the intervention group trained for 30 min, three times/week for 4 weeks on a split belt treadmill combined with a first-person immersive video game targeting visuospatial skills and working memory. Assessment was repeated after 4 weeks of training for the experimental group and 1-month after baseline for the control group. Primary motor outcomes were captured with the APDM Opal sensors during 6 MWT, TUG, and TUG Cognitive. Secondary outcomes of cognition were measured with the Montreal Cognitive Assessment, Verbal Fluency and the Symbol Digit Modality Test. Within subject differences were calculated using the Wilcoxon Signed Ranked Test and between subject comparisons were analyzed using the Mann Whitney U-test.ResultsThis novel treadmill training program was well-tolerated with all participants in the intervention group completing 4 weeks of training three times a week without any adverse effects. After immersive cognitive motor training, the experimental group made clinically relevant improvements in gait speed and walking distance during the 6 MWT while members of the control group showed no change or decreased gait speed and walking distance over the 1-month trial. In addition, the experimental group demonstrated significant improvement for the TUG Cognitive and those changes were greater than the control group. The experimental group also improved scores on MoCA and SDMT cognitive outcome measures while the control group did not.ConclusionThe use of immersive gaming technology to engage specific areas of cognition related to gait is feasible in PD. The treadmill training program paired with a customized interactive video game improved walking velocity in addition to non-significant but consistent improvements in other gait measures and cognitive performance in participants with early to mid-stage PD. (shrink)

The hereditary neurodegenerative disease spinal muscular atrophy (SMA) with childhood onset is one of the most common genetic causes of infant mortality. The disease is characterized by selective loss of spinal cord motor neurons leading to muscle atrophy and is the result of mutations in the survival motor neuron (SMN) gene. The SMN protein has been implicated in diverse nuclear processes including splicing, ribosome formation and gene transcription. Even though the genetic basis of SMA is well (...) understood, it is not clear how defects in these ubiquitous processes result in motor neuron degeneration leaving other tissues unaffected. Recent evidence from animal and cell culture models of SMA points to roles for SMN in neurite outgrowth and axonal transport. Disruption of these functions might be particularly detrimental to motor neurons given their high metabolic demands and precise connectivity requirements, thus providing a possible explanation for the specificity of motor neuron susceptibility in SMA. Understanding the molecular mechanisms of SMN activity in neuronal processes may generate new targets for future therapeutic strategies. BioEssays 27:946–957, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

The mature cerebral cortex contains a staggering variety of projection neuron subtypes, and a number of complementary studies have recently begun to define their identity and embryonic origin. Among the different types of cortical projection neurons, subcerebral projection neurons, including corticospinal motor neurons (CSMN), have been extensively studied and some of the molecular controls over their differentiation have been elucidated. Here, we first provide an overview of the approaches used to purify and molecularly profile neuronal populations of the neocortex (...) and, more broadly, of the central nervous system (CNS). Next, we specifically review recent progress in understanding the genes that define and control development of the CSMN population. Finally, we briefly discuss the relevance of this work to current questions regarding the mechanisms of the establishment of projection neuron subtype identity in the neocortex and its implications to direct the differentiation of CSMN for therapeutic benefit. (shrink)

A request to admit a hospital inpatient with motor neurone disease to the hospice generated unusual unease. Significantly, withdrawal of ventilation had already been planned. The presumption that ventilation would be withdrawn after transfer presented a dilemma. Should the hospice accept the admission? If so, should the hospice staff stop the ventilation, and then when and how? Debate centred on the continuity of best interests and the logistics of withdrawing ventilation. The factors making the request contentious identified (...) competing interests within hospice admission decision making that could detrimentally impact on patient care. (shrink)

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disorder of motor neurones. Although the genetic basis of familial forms of ALS has been well explored, the molecular basis of sporadic ALS is less well understood. Recent evidence has linked sporadic ALS with the failure to edit key residues in ionotropic glutamate receptors, resulting in excessive influx of calcium ions into motor neurones which in turn triggers cell death. Here we suggest that edited AMPA glutamate (GluR2) receptor subunits serve (...) as gatekeepers for motor neurone survival. BioEssays 30:1185–1192, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

A patient with end-stage motor neurone disease was admitted for hospice care with worsening bulbar symptoms. Although he initially walked onto the ward he became very distressed and asked for sedation. After much discussion, this man was deeply sedated, and after some harrowing days, died. Was it right to provide terminal sedation? What should the threshold be for such treatment? How should our personal reservations affect how we approach the distressed patient in an end-of-life situation?

Was society’s response adequate in the cases of Mrs Pretty and Ms B?On the 11th of May, less than two weeks after losing her final legal appeal, Mrs Diane Pretty died, under sedation and in the care of a hospice. It was not the end she had pursued through the English High Court, the Court of Appeal, the House of Lords, and the European Court of Human Rights. Paralysed by motor neurone disease and unable to take her (...) own life, Mrs Pretty wanted her husband to be allowed to help her to die when they decided the time had come. But in England, assisting suicide is a crime, although suicide itself no longer is, and the English courts refused Mrs Pretty’s request to grant her husband legal immunity. In turning to the European Court of Human Rights, Mrs Pretty argued that the English courts’ refusal had violated the European Convention on Human Rights.The European court, however, judged that there had been no violation. The right to life could not be construed as conferring a “right to die”, and consequently the state could not be required to “sanction actions intended to terminate life” in order to protect Mrs Pretty from the “inhuman or degrading treatment” to which she claimed the law on assisted suicide subjected her. The right to respect for private life , moreover, had to be exercised “in accordance with the law” of the state concerned. “States were entitled to regulate through the operation of the general criminal law activities which were detrimental to the life and safety of other individuals”; and such activities were what the English law against assisting suicide was designed to prevent. Exceptions to this law could not be allowed without undermining the …. (shrink)

Lysosomal positioning is an important factor in regulating cellular responses, including autophagy. Because proteins encoded by disease‐responsible genes are involved in lysosomal trafficking, proper intracellular lysosomal trafficking is thought to be essential for cellular homeostasis. In the past few years, the mechanisms of lysosomal trafficking have been elucidated with a focus on adapter proteins linking motor proteins to lysosomes. Here, we outline recent findings on the mechanisms of lysosomal trafficking by focusing on adapter protein c‐Jun NH2‐terminal kinase‐interacting protein (...) (JIP) 4, which plays a central role in this process, and other JIP4 functions and JIP family proteins. Additionally, we discuss neuronal diseases associated with aberrance in the JIP family protein. Accumulating evidence suggests that chemical manipulation of lysosomal positioning may be a therapeutic approach for these neuronal diseases. (shrink)

Traditionally, the impairment of cognitive functions in Alzheimeŕs disease (AD) is thought to result from a reduction in neuronal and synaptic activities, and ultimately cell death. Here, we review recent in vivo evidence from mouse models and human patients indicating that, particularly in early stages of AD, neuronal circuits are hyperactive instead of hypoactive. Functional analyses at many levels, from single neurons to neuronal populations to large‐scale networks, with a variety of electrophysiological and imaging techniques have revealed two forms (...) of AD‐related hyperactivity and provided first insights into the synaptic mechanisms. The unexpected finding that hyperactivity is an early neuronal dysfunction represents a major conceptual shift in our understanding of AD that may have important implications for the development of therapeutic approaches. (shrink)

Recently it has been hypothesized that apoptotic cell death is involved in several neuropathological conditions including Parkinson's disease (PD). Initial morphological studies assessing the presence of apoptosis in Parkinsonian brain tissues yielded mixed results. Based on more recent studies in human PD brains as well in animal and cell culture models of the disease, a picture is emerging, however, that strongly suggests that many of the molecular players thought to participate in this type of neuronal cell death are (...) active in the disease. The task of researchers in the field is now to deduce how these players may be interacting with one another to bring about cell death in PD and to design effective therapies to interfere with these processes. BioEssays 23:640–646, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

BackgroundIn Parkinson's disease, the side of motor symptoms onset may influence disease progression, with a faster motor symptom progression in patients with left side lateralization. Moreover, worse neuropsychological outcomes after subthalamic nucleus deep brain stimulation have been described in patients with predominantly left-sided motor symptoms. The objective of this study was to evaluate if the body side of motor symptoms onset may predict motor outcome of bilateral STN-DBS.MethodsThis retrospective study included all consecutive PD (...) patients treated with bilateral STN-DBS at Grenoble University Hospital from 1993 to 2015. Demographic, clinical and neuroimaging data were collected before and 1 year after surgery. The predictive factors of motor outcome at one-year follow-up, measured by the percentage change in the MDS-UPDRS-III score, were evaluated through univariate and multivariate linear regression analysis.ResultsA total of 233 patients were included with one-year follow-up after surgery [143 males ; 121 right body onset; 112 left body onset; mean age at surgery, 55.31 ± 8.44 years; mean disease duration, 11.61 ± 3.87]. Multivariate linear regression analysis showed that the left side of motor symptoms onset did not predict motor outcome.ConclusionsIn this retrospective study, the body side of motor symptoms onset did not significantly influence the one-year motor outcome in a large cohort of PD patients treated with bilateral STN-DBS. (shrink)

Gemins 2–8 and Unr‐interacting protein (UNRIP) are intimate partners of the survival motor neuron (SMN) protein, which is the determining factor for the neuromuscular disorder spinal muscular atrophy (SMA). The most documented role of SMN, Gemins and UNRIP occurs within the large macromolecular SMN complex and involves the cytoplasmic assembly of spliceosomal uridine‐rich small nuclear ribonucleoproteins (UsnRNPs), a housekeeping process critical in all cells. Several reports detailing alternative functions for SMN in either motor neurons or skeletal muscles may, (...) however, hold the answer to the extreme neuromuscular tissue specificity observed in SMA. Recent discoveries indicate that collaboration between SMN and Gemins also extends to these non‐canonical functions, hence raising the possibility that mutations in Gemin genes may be the cause of unlinked neuromuscular hereditary syndromes. This review evaluates the functions of Gemins and UNRIP inside the SMN complex and discusses whether these less notorious SMN complex members are capable of acting independently of SMN. (shrink)

Spinal muscular atrophy (SMA) type 1 is a genetic neuromuscular disease in children that leads to degeneration of spinal cord motor neurons. This sometimes results in severe muscular paralysis requiring mechanical ventilation to sustain the child’s life. The onset of SMA type 1, the most severe form of the disease, is during the first year of life. These children become severely paralysed, but retain their intellectual capacity. Ethical concerns arise when mechanical ventilation becomes necessary for survival. When (...) professionals assess the resulting life for the child and family, they sometimes fear it will result in unreasonably excessive care. The aim of this article is to present an analysis of ethical arguments that could support or oppose the provision of invasive ventilation in this population. This examination is particularly relevant as France is one of the few countries performing tracheotomies and mechanical ventilation for this condition. (shrink)

Because our actions change, our responsibility is modified; because our responsibility is modified, we need to question the ethics of the action. Our action is situated right there between announcing a diagnosis, the theoretical and practical result of identification, the determining and naming of a fact and voicing the disease which is a human action where medical and technical expertise comes up against a life and its story. Amyotrophic Lateral Sclerosis (ALS), or Lou Gehrig’s disease, is a degenerative (...) disease of the motor neurons leading to paralysis. In the absence of any curative treatment, the natural course always results in death. Since 1989, progress in the management of this disease in France has been exponential, resulting in the creation of 17 expert centres throughout the country in 2003. Guidelines have been drawn up through consensus conferences and coordination meetings. For the delicate stage of the announcement, three requirements have been adopted: the quality of receptiveness of the medical practitioner and his team, their ability to listen and to adapt to the particularities of the patient in their care; their commitment with regard to legal obligations as to how and to whom to transmit information; and the need for a multidisciplined approach to be able to rapidly support the patient and his family. Questioning in the field of applied ethics has led us to examine whether having a benevolent and non-harmful attitude towards these patients, respecting their autonomy and legal rights are parameters required in this specialized practice. Through a transversal thematic analysis of the experiences of the medical practitioners at the Centres, we would like to explore a hypothesis of the remarkable epistemological progression of the neurologist in this form of care in the pure Hippocratic tradition. Through the compassionate experience of the other by these committed doctors and their teams, we will try to outline the view of anthropological phenomenology with regard to the ALS patient, their awareness of the future paralysis of the body that is being announced, their awareness of the temporality and will characteristic of the ALS patient and of his finality that they will be accompanying. (shrink)

While slowness of movement is an obligatory characteristic of Parkinson’s disease (PD), there are conditions in which patients move uncharacteristically fast, attributed to deficient motor inhibition. Here we investigate deficient inhibition in an optimal sensory-motor integration framework, using a game in which subjects used a paddle to catch a virtual ball. Display of the ball was extinguished as soon as the catching movement started, segregating the task into a sensing and acting phase. We analyzed the behavior of (...) 9 PD patients (ON medication) and 10 age-matched controls (HC). The switching times (between sensing and acting phase) were compared to the predicted optimal switching time, based on the individual estimates of sensory and motor uncertainties. The comparison showed that deviation from predicted optimal switching times were similar between groups. However, PD patients showed a weaker correlation between variability in switching time and sensory-motor uncertainty, indicating a reduced propensity to generate exploratory behavior for optimizing goal-directed movements. Analysis of the movement kinematics revealed that PD patients, compared to controls, used a lower peak velocity of the paddle and intercepted the ball with greater velocity. Adjusting the trial duration to the time for the paddle to stop moving, we found that PD patients spent a smaller proportion of the trial duration for observing the ball. Altogether, the results do not show the premature movement initiation and truncated sensory processing that we predicted to ensue from deficient inhibition in PD. (shrink)

This review discussed the effects of the impact of the Coronavirus Disease 2019 pandemic on the psychological wellbeing of people with Parkinson's disease focusing specifically on depressive symptoms, anxiety levels, sleep, and quality of life. Together with motor symptoms, psychological symptoms are common and disabling conditions in the clinical course of PD becoming a relevant topic as a result of the lockdown measure due to alter their everyday life. We searched on PubMed online electronic databases for English (...) articles published between January 2020 and 31 December 2021. Twenty-eight relevant studies were found and included in the review. Heterogeneous data emerged from the topics analyzed. Overall, data from depression studies showed significant depressive symptoms if the patient was analyzed longitudinally or vs. a control group consisting in healthy subjects, while these differences become minimal when the control group is a family member. Differently, in most of the studies reviewed there is no evidence of a statistically significant impact on anxiety disorders, nor on the quality of sleep. Conversely, PD patients showed a statistically significant negative impact of QoL compared with control groups or other neurological conditions. Although these findings must be interpreted carefully in the light of the studies' limitations, both in methodology and design, collectively our review showed that COVID-19 pandemic has had negative effects on the mental health of people with PD, due to disruption of healthcare services, loss of usual activities and supports and reduction in physical activity. (shrink)

A new class of visuomotor neuron has been recently discovered in the monkey’s premotor cortex: mirror neurons. These neurons respond both when a particular action is performed by the recorded monkey and when the same action, performed by another individual, is observed. Mirror neurons appear to form a cortical system matching observation and execution of goal-related motor actions. Experimental evidence suggests that a similar matching system also exists in humans. What might be the functional role of this matching system? (...) One possible function is to enable an organism to detect certain mental states of observed conspecifics. This function might be part of, or a precursor to, a more general mind-reading ability. Two different accounts of mind-reading have been suggested. According to “theory theory‘, mental states are represented as inferred posits of a naive theory. According to “simulation theory‘, other people’s mental states are represented by adopting their perspective: by tracking or matching their states with resonant states of one’s own. The activity of mirror neurons, and the fact that observers undergo motor facilitation in the same muscular groups as those utilized by target agents, are findings that accord well with simulation theory but would not be predicted by theory theory. (shrink)

The processing of time intervals in the sub- to supra-second range by the brain is critical for the interaction of primates with their surroundings in activities, such as foraging and hunting. For an accurate processing of time intervals by the brain, representation of physical time within neuronal circuits is necessary. I propose that time dimension of the physical surrounding is represented in the brain by different types of neuronal oscillators, generating spikes or spike bursts at regular intervals. The proposed oscillators (...) include the pacemaker neurons, tonic inputs, and synchronized excitation and inhibition of inter-connected neurons. Oscillators, which are built inside various circuits of brain, help to form modular clocks, processing time intervals or other temporal characteristics specific to functions of a circuit. Relative or absolute duration is represented within neuronal oscillators by “neural temporal unit,” defined as the interval between regularly occurring spikes or spike bursts. Oscillator output is processed to produce changes in activities of neurons, named frequency modulator neuron, wired within a separate module, represented by the rate of change in frequency, and frequency of activities, proposed to encode time intervals. Inbuilt oscillators are calibrated by (a) feedback processes, (b) input of time intervals resulting from rhythmic external sensory stimulation, and (c) synchronous effects of feedback processes and evoked sensory activity. A single active clock is proposed per circuit, which is calibrated by one or more mechanisms. Multiple calibration mechanisms, inbuilt oscillators, and the presence of modular connections prevent a complete loss of interval timing functions of the brain. (shrink)

Taking advantage of the fact that they need not replicate their DNA, terminally differentiated neurons only repair their expressed genes and largely dispense with the burden of removing damage from most of their genome. However, they may pay a heavy price for this laxity if unforeseen circumstances, such as a pathological condition like Alzheimer's disease, cause them to re‐enter the cell cycle. The lifetime accumulation of unrepaired lesions in the silent genes of neurons is likely to be significant and (...) may result in aborting the mitotic process and triggering cell death if the cells attempt to express these dormant genes and resume DNA replication. BioEssays 25:168–173, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Objective: To investigate the correlation between preoperative response to the L-dopa challenge test and efficacy of deep brain stimulation (DBS) on motor function in Parkinson’s disease (PD).Methods: We retrospectively reviewed the data of 38 patients with idiopathic PD who underwent DBS surgery with a median follow-up duration of 7 months. Twenty underwent bilateral globus pallidus interna (GPi) DBS, and 18 underwent bilateral subthalamic nucleus (STN) DBS. The Movement Disorder Society Unified Parkinson Disease Rating Scale-Motor Part (MDS (...) UPDRS-III) was assessed before surgery and at the last follow-up in different medication and stimulation conditions, respectively.Results: Pearson’s correlation analysis revealed a positive correlation between preoperative L-dopa challenge responsiveness and GPi-DBS responsiveness on the total score (R2 = 0.283, p = 0.016) but not on the non-tremor total score (R2 = 0.158, p = 0.083) of MDS UPDRS-III. Such correlation remained significant (R2′ = 0.332, p = 0.010) after controlling for age at the time of surgery as confounding factor by partial correlation analysis. The preoperative L-dopa challenge responsiveness was significantly correlated with the tremor-controlling outcome of GPi-DBS (R2 = 0.390, p = 0.003). In contrast, we found a positive correlation between preoperative L-dopa challenge responsiveness and STN-DBS responsiveness on the non-tremor total score (R2 = 0.290, p = 0.021), but not on the total score (R2 = 0.130, p = 0.141) of MDS UPDRS-III. The partial correlation analysis further demonstrated that the predictive value of preoperative L-dopa challenge responsiveness on the non-tremor motor outcome of STN-DBS was eliminated (R2′ = 0.120, p = 0.174) after controlling for age at the time of surgery as confounding factor.Interpretation: The short-term predictive value of preoperative response to the L-dopa challenge test for the motor outcome of GPi-DBS in PD was systematically described. Our findings suggest: (1) a solid therapeutic effect of GPi-DBS in treating L-dopa-responsive tremors; (2) a negative effect of age at the time of surgery on motor outcomes of STN-DBS, (3) a possible preference of STN- to GPi-DBS in L-dopa-resistant tremor control, and (4) a possible preference of GPi- to STN-DBS in elderly PD patients who have a satisfactory dopamine response. (shrink)

IntroductionDeep brain stimulation is an effective treatment for advanced Parkinson’s disease with the targeting bilateral subthalamic nucleus or globus pallidus internus. So far, detailed studies on the efficacy of unilateral STN-DBS for motor symptoms have been reported, but few studies have been conducted on unilateral GPi-DBS.Materials and MethodsSeventeen patients with Parkinson’s disease who underwent unilateral GPi-DBS were selected. We conducted comparison analyses between scores obtained 6–42 months pre- and postoperatively using the following measurement tools: the Movement Disorder (...) Society Unified Parkinson’s Disease Rating Scale part III, the Hoehn and Yahr stage, the presence/absence of dyskinesia, Mini-Mental State Examination, Frontal Assessment Battery, Geriatric Depression Scale, levodopa equivalent dose, and cerebral blood flow by single photon emission computed tomography. Patient backgrounds were compared between four cohorts with favorable and unfavorable postoperative outcome.ResultsSignificant improvement was observed postoperatively in the following: total MDS-UPDRS Part III scores during the off period, contralateral scores, ipsilateral scores, and axial scores. Similarly, the Hoehn and Yahr stages during the off period, and GDS also showed significant decrease. In contrast, LED, MMSE, and FAB remained unchanged while the number of patients who scored positive for dyskinesia decreased by 40%. Abnormal cerebral blood flow preoperatively seen in the cerebral cortex had normalized in the total score-based good responder cohort. In the ipsilateral score-based good responder cohort, cerebral blood flow increased in the contralateral frontal lobe including in the premotor cortex, contralateral to the DBS. Compared to the poor responders, postoperative good responders demonstrated significantly higher preoperative MMSE scores.DiscussionUnilateral GPi-DBS therapy was effective in improving contralateral, ipsilateral, and axial motor symptoms of patients with advanced PD; in particular, it was found to be especially beneficial in PwPD whose cognitive function was unimpaired; the treatment efficacy rivaled that of bilateral counterparts up till at least 6 months postoperatively. Finally, normalization of preoperative abnormalities in cerebral blood flow and increased cerebral blood flow in the contralateral frontal lobe indicated the beneficial potential of this therapy on ipsilateral motor symptoms. (shrink)

The ideo-motor theory of actions, which has been strongly criticized during the last century, is currently receiving new interest in both cognitive psychology and philosophy. In this paper I will describe the principal theoretical reasons of this renewed attention. More particularly, here I will propose that the functioning of the mirror neurons’ system is a very useful tool to describe how the classic concept of ideo-motor action is close to the contemporary concept of simulated action.