Synaptic activity protects against AD and FTD-like pathology via autophagic-lysosomal degradation.

Changes in synaptic excitability and reduced brain metabolism are among the earliest detectable alterations associated with the development of Alzheimer's disease (AD). Stimulation of synaptic activity has been shown to be protective in models of AD beta-amyloidosis. Remarkably, deep brain stimulation (DBS) provides beneficial effects in AD patients, and represents an important therapeutic approach against AD and other forms of dementia. While several studies have explored the effect of synaptic activation on beta-amyloid, little is known about Tau protein. In this study, we investigated the effect of synaptic stimulation on Tau pathology and synapses in in vivo and in vitro models of AD and frontotemporal dementia (FTD). We found that chronic DBS or chemically induced synaptic stimulation reduced accumulation of pathological forms of Tau and protected synapses, while chronic inhibition of synaptic activity worsened Tau pathology and caused detrimental effects on pre- and post-synaptic markers, suggesting that synapses are affected. Interestingly, degradation via the proteasomal system was not involved in the reduction of pathological Tau during stimulation. In contrast, chronic synaptic activation promoted clearance of Tau oligomers by autophagosomes and lysosomes. Chronic inhibition of synaptic activity resulted in opposite outcomes, with build-up of Tau oligomers in enlarged auto-lysosomes. Our data indicate that synaptic activity counteracts the negative effects of Tau in AD and FTD by acting on autophagy, providing a rationale for therapeutic use of DBS and synaptic stimulation in tauopathies.

Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy.

This article reviews and summarizes 200 years of Parkinson's disease. It comprises a relevant history of Dr. James Parkinson's himself and what he described accurately and what he missed from today's perspective. Parkinson's disease today is understood as a multietiological condition with uncertain etiopathogenesis. Many advances have occurred regarding pathophysiology and symptomatic treatments, but critically important issues are still pending resolution. Among the latter, the need to modify disease progression is undoubtedly a priority. In sum, this multiple-author article, prepared to commemorate the bicentenary of the shaking palsy, provides a historical state-of-the-art account of what has been achieved, the current situation, and how to progress toward resolving Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society.

Lack of depotentiation at basal ganglia output neurons in PD patients with levodopa-induced dyskinesia.

Parkinson's disease (PD), characterized by the loss of dopaminergic nigrostriatal projections, is a debilitating neurodegenerative disease which produces bradykinesia, rigidity, tremor and postural instability. The dopamine precursor levodopa (L-Dopa) is the most effective treatment for the amelioration of PD signs and symptoms, but long-term administration can lead to disabling motor fluctuations and L-Dopa-induced dyskinesias. In animal models of PD, a form of plasticity called depotentiation, or the reversal of previous potentiation, is selectively lost after the development of dyskinetic movements following L-Dopa treatment. We investigated whether low frequency stimulation (LFS) in the globus pallidus internus (GPi) and substantia nigra pars reticulata (SNr) could induce depotentiation at synapses that had already undergone high frequency stimulation (HFS)-induced potentiation. To do so, we measured the field potentials (fEPs) evoked by stimulation from a nearby microelectrode in 28 patients undergoing implantation of deep brain stimulating (DBS) electrodes in the subthalamic nucleus (STN) or GPi. We found that GPi and SNr synapses in patients with less severe dyskinesia underwent greater depotentiation following LFS than in patients with more severe dyskinesia. This demonstration of impaired depotentiation in basal ganglia output nuclei in PD patients with dyskinesia is an important validation of animal models of levodopa-induced dyskinesia. The ability of a synapse to reverse previous potentiation may be crucial to the normal function of the BG, perhaps by preventing saturation of the storage capacity required in motor learning and optimal motor function. Loss of this ability at the output nuclei may underlie, or contribute to the cellular basis of dyskinetic movements.

Adaptive Deep Brain Stimulation in Parkinson's Disease: A Delphi Consensus Study.

Importance: If history teaches, as cardiac pacing moved from fixed-rate to on-demand delivery in in 80s of the last century, there are high probabilities that closed-loop and adaptive approaches will become, in the next decade, the natural evolution of conventional Deep Brain Stimulation (cDBS). However, while devices for aDBS are already available for clinical use, few data on their clinical application and technological limitations are available so far. In such scenario, gathering the opinion and expertise of leading investigators worldwide would boost and guide practice and research, thus grounding the clinical development of aDBS. Observations: We identified clinical and academically experienced DBS clinicians (n=21) to discuss the challenges related to aDBS. A 5-point Likert scale questionnaire along with a Delphi method was employed. 42 questions were submitted to the panel, half of them being related to technical aspects while the other half to clinical aspects of aDBS. Experts agreed that aDBS will become clinical practice in 10 years. In the present scenario, although the panel agreed that aDBS applications require skilled clinicians and that algorithms need to be further optimized to manage complex PD symptoms, consensus was reached on aDBS safety and its ability to provide a faster and more stable treatment response than cDBS, also for tremor-dominant Parkinson's disease patients and for those with motor fluctuations and dyskinesias. Conclusions and Relevance: Despite the need of further research, the panel concluded that aDBS is safe, promises to be maximally effective in PD patients with motor fluctuation and dyskinesias and therefore will enter into the clinical practice in the next years, with further research focused on algorithms and markers for complex symptoms.

Physical therapy in patients with Parkinson's disease treated with Deep Brain Stimulation: a Delphi panel study.

Although deep brain stimulation of the subthalamic nucleus (STN-DBS) induces motor benefits in people with Parkinson's disease (PwPD), the size and duration of the effects of STN-DBS on motor axial (e.g., postural instability, trunk posture alterations) and gait impairments (e.g., freezing of gait - FOG) are still ambiguous. Physical therapy (PT) effectively complements pharmacological treatment to improve postural stability, gait performance, and other dopamine-resistant symptoms (e.g. festination, hesitation, axial motor dysfunctions, and FOG) in PwPD who are non-surgically treated. Despite the potential for positive adjuvant effects of PT following STN-DBS surgery, there is a paucity of science available on the topic. In such a scenario, gathering the opinion and expertise of leading investigators worldwide was pursued to study motor rehabilitation in PwPD following STN-DBS. After summarizing the few available findings through a systematic review, we identified clinical and academically experienced DBS clinicians (n=21) to discuss the challenges related to PT following STN-DBS. A 5-point Likert scale questionnaire was used and based on the results of the systematic review along with a Delphi method. Thirty-nine questions were submitted to the panel - half related to general considerations on PT following STN-DBS, half related to PT treatments. Despite the low-to-moderate quality, the few available rehabilitative studies suggested that PT could improve dynamic and static balance, gait performance and posture. Similarly, panellists strongly agreed that PT might help in improving motor symptoms and quality of life, and it may be possibly prescribed to maximize the effects of the stimulation. The experts agreed that physical therapists could be part of the multidisciplinary team taking care of the patients. Also, they agreed on prescribing of conventional PT, but not massage or manual therapy. Our results will inform the rehabilitation and the DBS community to engage, publish and deepen this area of research. Such efforts may spark guidelines for PT following STN-DBS.

Reduced paired pulse depression in the basal ganglia of dystonia patients.

Decreased inhibition and aberrant plasticity are key features in the pathophysiology of dystonia. Impaired short interval cortical inhibition and resultant increased excitability have been described for various forms of dystonia using paired pulse methods with transcranial magnetic stimulation of motor cortex. It is hypothesized that, in addition to cortical abnormalities, impairments in basal ganglia function may lead to dystonia but a deficit of inhibition within the basal ganglia has not been demonstrated to date. To examine the possibility that impaired inhibition and synaptic plasticity within the basal ganglia play a role in dystonia, the present study used a pair of microelectrodes to test paired pulse inhibition in the globus pallidus interna (GPi) and substantia nigra pars reticulata (SNr) of dystonia and PD patients undergoing implantation of deep brain stimulating (DBS) electrodes. We found that there was less paired pulse depression of local field evoked potentials in the basal ganglia output nuclei of dystonia patients compared with Parkinson's disease patients on dopaminergic medication. Paired pulse depression could be restored following focal high frequency stimulation (HFS). These findings suggest that abnormalities exist in synaptic function of striatopallidal and/or striatonigral terminals in dystonia patients and that these abnormalities may contribute to the pathophysiology of dystonia, either independent of, or in addition to the increased excitability and plasticity observed in cortical areas in dystonia patients. These findings also suggest that HFS is capable of enhancing striatopallidal and striatonigral GABA release in basal ganglia output nuclei, indicating a possible mechanism for the therapeutic benefits of DBS in the GPi of dystonia patients.

[Functional evaluation in patient with critical SARS-CoV-2 disease: Cohort study in a third level hospital rehabilitation unit]. / Evaluación funcional tras SARS-CoV-2 crítico. Estudio de cohortes de la unidad de rehabilitación en un hospital de tercer nivel.

INTRODUCTION: SARS-COV-2 pneumonia is a highly contagious respiratory disease that causes respiratory, physical and psychological dysfunctions. We present the results of patient assessment when they were discharged from the ICU. MATERIAL AND METHOD: Cohort study of patients affected by SARS-COV-2 pneumonia admitted to the intensive care unit from 01/10/2020 to 31/07/2021. We collect sociodemographic data, personal history, ICU and hospital stay, Barthel, FAC and mMRC (pre-admission/initial assessment/discharge), development of osteomuscular and/or neurological pathology and need for rehabilitation treatment. RESULTS: A total of 341 patients were evaluated, of which 224 met criteria. The average age was 63 years (68.75% men). Mean ICU/hospital stay were 27/44 days. They were assessed by physiatry, after that, we provide a guide developed by physiatry, solving doubts about the disease and setting exercises of intensity and progressive difficulty, to be carried out during the admission and at home. Neurological pathology was present at 42.86% patients, of whom a 83.33% were peripheral nervous system disease. The total of the sample needed respiratory physiotherapy and a 72.32% motor physiotherapy. CONCLUSIONS: In our study, a high number of patients have needed rehabilitation treatment in order to get functional recovery, highlighting the development of post-COVID neurological pathology. SARS-COV-2 generates other complications, not only respiratory, subsidiary to be assessed and treated by rehabilitation services for a comprehensive recovery that minimizes sequelae.

Oscillatory network markers of subcallosal cingulate deep brain stimulation for depression.

Identifying functional biomarkers related to treatment success can aid in expediting therapy optimization, as well as contribute to a better understanding of the neural mechanisms of the treatment-resistant depression (TRD) and subcallosal cingulate deep brain stimulation (SCC-DBS). Magnetoencephalography data were obtained from 16 individuals with SCC-DBS for TRD and 25 healthy subjects. The first objective of the study was to identify region-specific oscillatory modulations that both (i) discriminate individuals with TRD (with SCC-DBS OFF) from healthy controls, and (ii) discriminate TRD treatment responders from non-responders (with SCC-DBS ON). The second objective of this work was to further explore the effects of stimulation intensity and frequency on oscillatory activity in the identified brain regions of interest. Oscillatory power analyses led to the identification of brain regions that differentiated responders from non-responders based on modulations of increased alpha (8-12 Hz) and decreased gamma (32-116 Hz) power within nodes of the default mode, central executive, and somatomotor networks, Broca's area, and lingual gyrus. Within these nodes, it was also found that low stimulation frequency had stronger effects on oscillatory modulation than increased stimulation intensity. The identified functional network biomarkers implicate modulation of TRD-related activity in brain regions involved in emotional control/processing, motor control, and the interaction between speech, vision, and memory, which have all been implicated in depression. These electrophysiological biomarkers have the potential to be used as functional proxies for therapy optimization. Additional stimulation parameter analyses revealed that oscillatory modulations can be strengthened by increasing stimulation intensity or reducing frequency, which may represent potential avenues of direction in non-responders.

A psychiatric primer for the functional neurosurgeon.

There is increasing attention in the neurosurgical literature towards surgery, specifically deep brain stimulation (DBS), for psychiatric indications. Several positive trials have spurred intense investigation and research in this area, owing to rapid advances in the neurosciences. As a result, the scope of neurosurgical practice is evolving to now include disorders that weren't traditionally in the purview of the average functional neurosurgeon. Further, functional neurosurgeons are now being charged with taking care of patients as part of a multi-disciplinary group that includes psychologists and psychiatrists. As DBS for psychiatry continues to evolve, and as further indications are explored, it is incumbent on neurosurgeons who treat these disorders to familiarize themselves with current standards of diagnosis and treatment. Just as the movement disorder surgeon should be familiar with the biology, physiology, diagnosis and treatment of Parkinson's disease, so they should become familiar with similar aspects of commonly referred psychiatric conditions. Specifically, much of the interest in the DBS literature currently surrounds major depression, obsessive-compulsive disorder and Tourette's syndrome. Here, we review the epidemiology, diagnostic criteria, hypothesized neurocircuitry and current treatments, both medical and surgical of each of these conditions to serve as a centralized, introductory primer for the practicing functional neurosurgeon.

Deep brain stimulation effects on memory.

As the population of many countries ages, disorders of cognition and memory-such as Alzheimer's Disease (AD) and dementia associated with Parkinson's Disease-will become a major societal burden. At present, few effective medical therapies against these conditions are available. Deep brain stimulation (DBS) may be a potential therapeutic option, because it can directly target and modulate the activity of structures implicated in circuits subserving memory function. In this article, we review the scientific literature to address some of the mechanisms by which DBS may impact memory and cognition. We then summarize the results of recent clinical experience with DBS in AD and Parkinsonian dementia.

Globus pallidus stimulation activates the cortical motor system during alleviation of parkinsonian symptoms.

Studies of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in monkeys suggest that excessive inhibitory outflow from the internal segment of the globus pallidus (GPi) suppresses the motor thalamus, which reduces activation of the cerebral cortex motor system, resulting in the slowness and poverty of movement of Parkinson's disease (PD). This hypothesis is supported by reports of high rates of spontaneous neuronal discharges and hypermetabolism in GPi (ref. 4-7) and impaired activation of the supplementary motor area (SMA) and dorsolateral prefrontal regions in PD patients. Furthermore, lesion or chronic high-frequency electrical (likely inactivating) stimulation of GPi (ref. 10-14) is associated with marked improvements in akinesia and rigidity, and the impaired activation of SMA is reversed when the akinesia is treated with dopamine agonists. To test whether improvement in motor function with pallidal surgery can be attributed to increased activity in premotor cortical regions, we assessed the changes in regional cerebral blood flow (rCBF) and parkinsonian symptoms during disruption of GPi activity with high-frequency stimulation delivered through implanted brain electrodes. Positron emission tomography (PET) revealed an increase in rCBF in ipsilateral premotor cortical areas during GPi stimulation, which improved rigidity and bradykinesia. These results suggest that disrupting the excessive inhibitory output of the basal ganglia reverses parkinsonism, via a thalamic relay, by activation of brain areas involved in the initiation of movement.

Does conventional early life academic excellence predict later life scientific discovery? An assessment of the lives of great medical innovators.

BACKGROUND: Perhaps, as never before, we need innovators. With our growing population numbers, and with increasing pressures on our education systems, are we in danger of becoming more rigid and formulaic and increasingly inhibiting innovation? When young can we predict who will become the great innovators? For example, in medicine, who will change clinical practice? AIMS: We therefore determined to assess whether the current academic excellence approach to medical school entrance would have captured previous great innovators in medicine, assuming that they should all have well fulfilled current entrance requirements. METHODS: The authors assembled a list of 100 great medical innovators which was then approved, rejected or added to by a jury of 12 MD fellows of the Royal Society of Canada. Two reviewers, who had taken both the past and present Medical College Admission Test as part of North American medical school entrance requirements, independently assessed each innovator's early life educational history in order to predict the innovator's likely success at medical school entry, assuming excellence in all entrance requirements. RESULTS: Thirty-one percent of the great medical innovators possessed no medical degree and 24% would likely be denied entry to medical school by today's standards (e.g. had a history of poor performance, failure, dropout or expulsion) with only 24% being guaranteed entry. Even if excellence in only one topic was required, the figure would only rise to 41% certain of medical school entry. CONCLUSION: These data show that today's medical school entry standards would have barred many great innovators and raise questions about whether we are losing medical innovators as a consequence. Our findings have important implications for promoting flexibility and innovation for medical education, and for promoting an environment for innovation in general.

Levodopa enhances synaptic plasticity in the substantia nigra pars reticulata of Parkinson's disease patients.

Parkinson's disease, caused by the loss of dopaminergic nigrostriatal projections, is a debilitating neurodegenerative disease characterized by bradykinesia, rigidity, tremor and postural instability. The dopamine precursor levodopa (L-dopa) is the most effective treatment for the amelioration of Parkinson's disease signs and symptoms, but long-term administration can lead to disabling motor fluctuations and L-dopa -induced dyskinesias (LIDs). Studies in rat striatal slices have shown dopamine to be an essential component of activity-dependent synaptic plasticity at the input to the basal ganglia, but dopamine is also released from ventrally projecting dendrites of the substantia nigra pars compacta (SNc) on the substantia nigra pars reticulata (SNr), a major output structure of the basal ganglia. We characterized synaptic plasticity in the SNr using field potentials evoked with a nearby microelectrode (fEPs), in 18 Parkinson's disease patients undergoing implantation of deep brain stimulating (DBS) electrodes in the subthalamic nucleus (STN). High frequency stimulation (HFS--four trains of 2 s at 100 Hz) in the SNr failed to induce a lasting change in test fEPs (1 Hz) amplitudes in patients OFF medication (decayed to baseline by 160 s). Following oral L-dopa administration, HFS induced a potentiation of the fEP amplitudes (+29.3% of baseline at 160 s following a plateau). Our findings suggest that extrastriatal dopamine modulates activity-dependent synaptic plasticity at basal ganglia output neurons. Dopamine medication state clearly impacts fEP amplitude, and the lasting nature of the increase is reminiscent of LTP-like changes, indicating that aberrant synaptic plasticity may play a role in the pathophysiology of Parkinson's disease.

Pallidal stimulation in cervical dystonia: clinical implications of acute changes in stimulation parameters.

BACKGROUND AND PURPOSE: Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is successful in dystonia, but the role of each electrical parameters of stimulation is unclear. We studied the clinical effects of acute changes of different parameters of GPi-DBS in cervical dystonia (CD). METHODS: Eight CD patients with bilateral GPi-DBS at 28.6 +/- 19.2 (mean +/- SD) months after surgery were recruited. Mean improvement in the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) severity score was 54.5% compared to before surgery. Ten settings, including a combination of a wide range of pulse widths (PWs), low and high frequencies and voltage, were administered in a randomized double blinded fashion. Clinical benefit was assessed by two raters using the TWSTRS and by the patients using an analogue rating scale. RESULTS: The TWSTRS severity scores were reduced by 56.7% with stimulation at the best settings. Improvement was significantly associated with high frequency (> or = 60 Hz) and high voltage. Stimulation at 130 Hz showed the best clinical improvement. Increasing PWs (from 60 to 450 micros) did not result in a significant improvement. CONCLUSION: Frequency and amplitude appear to be the most important factors in the acute anti-dystonic effects in GPi-DBS patients with CD.

Anatomical connectivity of the subgenual cingulate region targeted with deep brain stimulation for treatment-resistant depression.

Chronic deep brain stimulation (DBS) of subgenual cingulate white matter results in dramatic remission of symptoms in some previously treatment-resistant depression patients. The effects of stimulation may be mediated locally or via corticocortical or corticosubcortical connections. We use tractography to define the likely connectivity of cingulate regions stimulated in DBS-responsive patients using diffusion imaging data acquired in healthy control subjects. We defined 2 distinct regions within anterior cingulate cortex based on anatomical connectivity: a pregenual region strongly connected to medial prefrontal and anterior midcingulate cortex and a subgenual region with strongest connections to nucleus accumbens, amygdala, hypothalamus, and orbitofrontal cortex. The location of electrode contact points from 9 patients successfully treated with DBS lies within this subgenual region. The anatomical connectivity of the subgenual cingulate region targeted with DBS for depression supports the hypothesis that treatment efficacy is mediated via effects on a distributed network of frontal, limbic, and visceromotor brain regions. At present, targeting of DBS for depression is based on landmarks visible in conventional magnetic resonance imaging. Preoperatively acquired diffusion imaging for connectivity-based cortical mapping could improve neurosurgical targeting. We hypothesize that the subgenual region with greatest connectivity across the distributed network described here may prove most effective.

Control of a neuroprosthesis for grasping using off-line classification of electrocorticographic signals: case study.

STUDY DESIGN: Proof of concept study to control a neuroprosthesis for grasping using identification of arm movements from ECoG signals. OBJECTIVE: To test the feasibility of using electrocorticographic (ECoG) signals as a control method for a neuroprosthesis for grasping. SETTING: Acute care hospital, Toronto Western Hospital and spinal cord injury (SCI) rehabilitation centre, Toronto Rehabilitation Institute, Lyndhurst Centre. Both hospitals are located in Toronto, Canada. METHODS: Two subjects participated in this study. The first subject had subdural electrodes implanted on the motor cortex for the treatment of essential tremor (ET). ECoG signals were recorded while the subject performed specific arm movements. The second subject had a complete SCI at C6 level (ASIA B score) and was fitted with a neuroprosthesis, capable of identifying arm movements from ECoG signals off-line, for grasping. To operate the neuroprosthesis, subject 2 issued a command that would trigger the release of a randomly selected ECoG signal recorded from subject 1, associated with a particular arm movement. The neuroprosthesis identified which arm movement was performed at the time of recording and used that information to trigger the stimulation sequence. A correct ECoG classification resulted in the neuroprosthesis producing the correct hand function (that is grasp and release). RESULTS: The neuroprosthesis classified ECoG signals correctly delivering the correct stimulation strategy with 94.5% accuracy. CONCLUSIONS: The feasibility of using ECoG signals as a control strategy for a neuroprosthesis for grasping was shown.

Expression of the growth-associated protein GAP-43 in adult rat retinal ganglion cells following axon injury.

We have studied the expression of the growth-associated protein GAP-43 after injury to the axons of adult rat retinal ganglion cells (CNS neurons that do not normally regenerate injured axons). Both the biosynthetic labeling of GAP-43 and the GAP-43 immunoreactivity of the retina increased after axotomy, but only when the injury was within 3 mm of the eye. These results suggest the following conclusions: First, axon injury is sufficient to alter GAP-43 expression in CNS neurons, even in the absence of regeneration. Second, mechanisms that regulate GAP-43 expression are sensitive to the length of uninterrupted axon remaining after injury. Finally, the conditions that favor increased GAP-43 are similar to those that favor regrowth of injured CNS axons into grafts of peripheral nerve, suggesting that GAP-43 induction is accompanied by an increased potential of injured CNS neurons to regenerate.

Deep brain stimulation and chemical neuromodulation: current use and perspectives for the future.

During the last decade there has been a marked increase in the applications of deep brain stimulation for the treatment of neurological and psychiatric disorders. In addition, the last years were marked by the first studies using the intraparenchymal administration of drugs into the brain. There have been improvements in outcome and an increase in the number of surgical candidates and conditions to be treated. This will act as a driving force to improve the technology applied to design and manufacture new devices.

[Total brain T2-hyperintense lesion-volume and the axonal damage in the normal-appearing white matter of brainstem in early lapsing-remitting multiple sclerosis]. / Relación entre el volumen lesional cerebral total en resonancia magnética secuencia T2 y el daño neuroaxonal en la sustancia blanca aparentemente normal del tronco del encéfalo en la esclerosis múltiple remitente-recurrente.

AIM: To evaluate the relationship between the total brain T2-hyperintense lesion volume (TBT2LV) and the axonal damage in the normal-appearing white matter of brainstem measured by 1H-MRS in a group of early relapsing-remitting multiple sclerosis patients. SUBJECTS AND METHODS: 40 relapsing-remitting multiple sclerosis patients and ten sex- and age-matched healthy subjects were prospectively studied for two years. T2-weighted MR and 1H-MRS imaging were acquired at time of recruitment and at year two. The TBT2LV was calculated with a semiautomatic program; N-acetylaspartate (NAA), creatine (Cr) and choline (Cho) resonances areas were integrated with jMRUI program and the ratios were calculated for four volume elements that represented the brainstem. RESULTS: At basal study we obtained an axonal loss (as a decrement of NAA/ Cho ratio) in the group of patients compared with controls (p = 0.017); this axonal loss increased at the second year of the follow-up for patients (NAA/Cho decrease, p = 0.004, and NAA/Cr decrease, p = 0.002) meanwhile control subjects had no significant metabolic changes. Higher lesion load was correlated with a poor clinical outcome, being the correlation between the basal TBT2LV and the Expanded Disability Status Scale at second year (r = 0.299; p = 0.05). Besides, axonal loss was not homogeneous for all multiple sclerosis patients, being stronger in the subgroup of patients with high basal TBT2LV (p = 0.043; ANOVA). CONCLUSION: Our data suggest that axonal damage is early in multiple sclerosis and higher in patients high basal TBT2LV, suggesting a possible relationship between these two phenomena.

New developments in understanding the etiology of Parkinson's disease and in its treatment.

Important recent advances have been made in understanding the etiology and pathogenesis of Parkinson's disease, as well as in developing novel treatments. Two newly identified genes, alpha-synuclein and parkin, have been linked to parkinsonism. In addition, disturbances to the normal basal ganglia circuits in Parkinson's patients are being described at both anatomical and physiological levels. These developments provide a strong scientific basis for novel medical and surgical strategies to treat the profound motor disturbances in patients with Parkinson's disease.