Freezing of gait (FOG) in Parkinson's disease patients-the contribution of Garcin and Melaragno.

Raymond Garcin, professor of neurology in Paris, France, and his Brazilian assistant, Professor Roberto Melaragno described in 1948 the phenomenon defined as "bégaiement de la mise en route du mouvement" in patients with Parkinson's disease. This was one of the first descriptions of freezing of gait (FOG) in the world.

Commentary: Dealing with the Aftermath.

In 2006, our team reported our experience in the use of bilateral high-frequency stimulation of the subthalamic nucleus (STN) in patients with severe levodopa-responsive forms of Parkinson's disease (PD). 1 The aim was to better understand and manage the difficulties experienced by patients who undergo neurosurgery, and by their families.

Goal-directed and habitual control in the basal ganglia: implications for Parkinson's disease.

Progressive loss of the ascending dopaminergic projection in the basal ganglia is a fundamental pathological feature of Parkinson's disease. Studies in animals and humans have identified spatially segregated functional territories in the basal ganglia for the control of goal-directed and habitual actions. In patients with Parkinson's disease the loss of dopamine is predominantly in the posterior putamen, a region of the basal ganglia associated with the control of habitual behaviour. These patients may therefore be forced into a progressive reliance on the goal-directed mode of action control that is mediated by comparatively preserved processing in the rostromedial striatum. Thus, many of their behavioural difficulties may reflect a loss of normal automatic control owing to distorting output signals from habitual control circuits, which impede the expression of goal-directed action.

Tourette syndrome deep brain stimulation: a review and updated recommendations.

Deep brain stimulation (DBS) may improve disabling tics in severely affected medication and behaviorally resistant Tourette syndrome (TS). Here we review all reported cases of TS DBS and provide updated recommendations for selection, assessment, and management of potential TS DBS cases based on the literature and implantation experience. Candidates should have a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM V) diagnosis of TS with severe motor and vocal tics, which despite exhaustive medical and behavioral treatment trials result in significant impairment. Deep brain stimulation should be offered to patients only by experienced DBS centers after evaluation by a multidisciplinary team. Rigorous preoperative and postoperative outcome measures of tics and associated comorbidities should be used. Tics and comorbid neuropsychiatric conditions should be optimally treated per current expert standards, and tics should be the major cause of disability. Psychogenic tics, embellishment, and malingering should be recognized and addressed. We have removed the previously suggested 25-year-old age limit, with the specification that a multidisciplinary team approach for screening is employed. A local ethics committee or institutional review board should be consulted for consideration of cases involving persons younger than 18 years of age, as well as in cases with urgent indications. Tourette syndrome patients represent a unique and complex population, and studies reveal a higher risk for post-DBS complications. Successes and failures have been reported for multiple brain targets; however, the optimal surgical approach remains unknown. Tourette syndrome DBS, though still evolving, is a promising approach for a subset of medication refractory and severely affected patients.

Correction: Association of Rare Genetic Variants in Opioid Receptors with Tourette Syndrome.

[This corrects the article DOI: 10.5334/tohm.464.].

Does unilateral basal ganglia activity functionally influence the contralateral side? What we can learn from STN stimulation in patients with Parkinson's disease.

In humans, the control of voluntary movement, in which the corticobasal ganglia (BG) circuitry participates, is mainly lateralized. However, several studies have suggested that both the contralateral and ipsilateral BG systems are implicated during unilateral movement. Bilateral improvement of motor signs in patients with Parkinson's disease (PD) has been reported with unilateral lesion or high-frequency stimulation (HFS) of the internal part of the globus pallidus or the subthalamic nucleus (STN-HFS). To decipher the mechanisms of production of ipsilateral movements induced by the modulation of unilateral BG circuitry activity, we recorded left STN neuronal activity during right STN-HFS in PD patients operated for bilateral deep brain stimulation. Left STN single cells were recorded in the operating room during right STN-HFS while patients experienced, or did not experience, right stimulation-induced dyskinesias. Most of the left-side STN neurons (64%) associated with the presence of right dyskinesias were inhibited, with a significant decrease in burst and intraburst frequencies. In contrast, left STN neurons not associated with right dyskinesias were mainly activated (48%), with a predominant increase 4-5 ms after the stimulation pulse and a decrease in oscillatory activity. This suggests that unilateral neuronal STN modulation is associated with changes in the activity of the contralateral STN. The fact that one side of the BG system can influence the functioning of the other could explain the occurrence of bilateral dyskinesias and motor improvement observed in PD patients during unilateral STN-HFS, as a result of a bilateral disruption of the pathological activity in the corticosubcortical circuitry.

The COMT Val158Met polymorphism affects the response to entacapone in Parkinson's disease: a randomized crossover clinical trial.

OBJECTIVE: In Parkinson disease (PD), the selective C-O-methyltransferase (COMT) inhibitor entacapone prolongs the effect of levodopa on motor symptoms (ON time) by increasing its bioavailability. The COMT Val158Met polymorphism is equally distributed in PD patients and modulates COMT activity, which can be high (Val/Val, COMT(HH) ), intermediate (Val/Met, COMT(HL) ), or low (Met/Met, COMT(LL) ). The objective of this study was to determine the response to entacapone in COMT(HH) and COMT(LL) PD patients. METHODS: Thirty-three PD patients, homozygous for the COMT alleles COMT(HH) (n = 17) and COMT(LL) (n = 16), were randomized in a double-blind crossover trial consisting of 2 successive acute levodopa challenges associated with 200mg entacapone or placebo. The primary endpoint was the gain in the best ON time. Secondary endpoints were levodopa pharmacokinetics and COMT activity in red blood cells. RESULTS: The gain in the best ON time was higher in COMT(HH) than in COMT(LL) patients (39 ± 10 vs 9 ± 9 minutes, p = 0.04, interaction between treatment and genotype). Area under the concentration over time curve of levodopa increased more after entacapone in COMT(HH) than in COMT(LL) patients (+62 ± 6% vs +34 ± 8%, p = 0.01). COMT inhibition by entacapone was higher in COMT(HH) than in COMT(LL) patients (-0.54 ± 0.07 vs -0.31 ± 0.06 pmol/min/mg protein, p = 0.02). INTERPRETATION: The COMT(HH) genotype in PD patients enhances the effect of entacapone on the pharmacodynamics and pharmacokinetics of levodopa. The response to entacapone after repeated administrations and in heterozygous patients remains to be determined.

Judith Balkányi-Lepintre (1912-1982): first woman neurosurgeon, first woman war neurosurgeon, and first woman pediatric neurosurgeon in France.

Recently, a series of historical reports portrayed the first women neurosurgeons in various countries. One such woman, a pioneer on many levels, remained unrecognized: Judith Balkányi-Lepintre. She was the first woman neurosurgeon in France, the first woman war neurosurgeon for the French Army, and the first woman pediatric neurosurgeon in France. Born in 1912 to a Hungarian Jewish family, she graduated with honors from medical school in Budapest in 1935, then moved to Paris where she started neurosurgical training in 1937 at L'Hôpital de la Pitié under the mentorship of Clovis Vincent, the founder of French neurosurgery. Shortly after marrying a French colleague in 1940, she had to escape the Geheime Staatspolizei (Gestapo) in Paris and ended up in Algeria, where she joined the French Army of De Gaulle. As a neurosurgeon, she participated in the campaigns of Italy and France between 1943 and 1945. After the war, she returned to work at La Pitié Hospital. In 1947, she defended her doctoral thesis, "Treatment of cranio-cerebral wounds by projectiles and their early complications." Soon thereafter, she joined Europe's first dedicated children's hospital, Hôpital Necker-Enfants Malades in Paris, and contributed to the establishment of pediatric neurosurgery in France. She remained clinically and academically active at Necker until her death in 1982 but was never promoted.

Subthalamic nucleus stimulation in severe obsessive-compulsive disorder.

BACKGROUND: Severe, refractory obsessive-compulsive disorder (OCD) is a disabling condition. Stimulation of the subthalamic nucleus, a procedure that is already validated for the treatment of movement disorders, has been proposed as a therapeutic option. METHODS: In this 10-month, crossover, double-blind, multicenter study assessing the efficacy and safety of stimulation of the subthalamic nucleus, we randomly assigned eight patients with highly refractory OCD to undergo active stimulation of the subthalamic nucleus followed by sham stimulation and eight to undergo sham stimulation followed by active stimulation. The primary outcome measure was the severity of OCD, as assessed by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), at the end of two 3-month periods. General psychopathologic findings, functioning, and tolerance were assessed with the use of standardized psychiatric scales, the Global Assessment of Functioning (GAF) scale, and neuropsychological tests. RESULTS: After active stimulation of the subthalamic nucleus, the Y-BOCS score (on a scale from 0 to 40, with lower scores indicating less severe symptoms) was significantly lower than the score after sham stimulation (mean [+/-SD], 19+/-8 vs. 28+/-7; P=0.01), and the GAF score (on a scale from 1 to 90, with higher scores indicating higher levels of functioning) was significantly higher (56+/-14 vs. 43+/-8, P=0.005). The ratings of neuropsychological measures, depression, and anxiety were not modified by stimulation. There were 15 serious adverse events overall, including 1 intracerebral hemorrhage and 2 infections; there were also 23 nonserious adverse events. CONCLUSIONS: These preliminary findings suggest that stimulation of the subthalamic nucleus may reduce the symptoms of severe forms of OCD but is associated with a substantial risk of serious adverse events. (ClinicalTrials.gov number, NCT00169377.)

Cognitive impairment in patients with multiple system atrophy and progressive supranuclear palsy.

This article reports the severity and profile of neuropsychological impairment on a prevalent cohort of patients with a clinical diagnosis of either multiple system atrophy (n=372) or progressive supranuclear palsy (n=311) from the Neuroprotection and Natural History in Parkinson Plus Syndromes cohort. The Dementia Rating Scale and Frontal Assessment Battery were used to assess global cognition and executive dysfunction. For the Dementia Rating Scale impairment was observed in approximately 57% of the progressive supranuclear palsy group and 20% of the multiple system atrophy group. In the former, impairment in a single cognitive domain was observed in 40%, with the same number showing impairment in multiple domains, while in the latter the figures were 28.6 and 13.5%, respectively. On the Frontal Assessment Battery, impairment was observed in 62.0% of patients with progressive supranuclear palsy and 31.8% of those with multiple system atrophy. Although the progressive supranuclear palsy group performed worse overall, the cognitive profiles of the two groups on the Dementia Rating Scale subscales were identical, with the main impairment of the Initiation and Perseveration subscale. The impaired patients in the two groups were largely indistinguishable, qualitatively and quantitatively. Impairment was associated with greater age and clinical disability in both groups and was evident even in the early stages (22% in multiple system atrophy and 50% in progressive supranuclear palsy). Where a pathological diagnosis was available, the original clinical diagnosis was confirmed in the majority of cases, including those with significant cognitive impairment. The rate of impairment in those with a confirmed pathological diagnosis was comparable to that of the sample as a whole. These results demonstrate, in the largest prospectively recruited cohort of patients with progressive supranuclear palsy and multiple system atrophy studied to date, the existence of a cognitive profile similar to that previously reported in idiopathic Parkinson's disease. The results indicate a high level of cognitive impairment associated with progressive supranuclear palsy, but also point to comparable dysfunction in a substantial proportion of the patients with multiple system atrophy. Significant cognitive impairment appears consistent with a diagnosis of multiple system atrophy, even early in the disease, with important implications for diagnosis, research and management.

Orodispersible sublingual piribedil to abort OFF episodes: a single dose placebo-controlled, randomized, double-blind, cross-over study.

S90049, a novel sublingual formulation of the non-ergoline D(2)-D(3) agonist piribedil, has a pharmacokinetic profile promising to provide rapid relief on motor signs in Parkinson's disease (PD). We assessed the efficacy and safety of S90049 in aborting OFF episodes responding to subcutaneous apomorphine in PD patients with motor fluctuations. This was a single-dose double-blind double-placebo 3 x 3 cross-over study. Optimal tested doses were determined during a previous open-label titration phase (S90049 median dose: 60 mg, apomorphine: 5 mg). Primary endpoint was the maximal change versus baseline in UPDRS motor score (Delta UPDRS III) assessed after drug administration following an overnight withdrawal of antiparkinsonian medications. Thirty patients (age: 60 +/- 8 years, PD duration: 12 +/- 6 years, UPDRS III OFF: 37 +/- 15) participated. S90049 was superior to placebo on Delta UPDRS III (-13 +/- 12 versus -7 +/- 9 respectively; estimated difference -5.2, 95% Confidence Interval (CI)[-10.4;0.05], P = 0.05). This was also true for secondary outcomes: number of patients switching from OFF to ON (17 on S90049 vs. 8 on placebo, P = 0.03), time to turn ON (P = 0.013) and duration of the ON phase (P = 0.03). In the 17 patients who switched ON on S90049, Delta UPDRS III was similar on S90049 (-21.2 +/- 10.1) and apomorphine (-23.6 +/- 14.1) (estimated difference: 4.0 95% CI [-2.9;10.9]). S90049 was well tolerated: no serious or unexpected adverse event occurred. A single dose of up to 60 mg of S90049 given sublingually was superior to placebo in improving UPDRS III and aborting a practical OFF in patients with advanced PD. Testing greater doses might improve response rate.

Long-term results of a multicenter study on subthalamic and pallidal stimulation in Parkinson's disease.

We report the 5 to 6 year follow-up of a multicenter study of bilateral subthalamic nucleus (STN) and globus pallidus internus (GPi) deep brain stimulation (DBS) in advanced Parkinson's disease (PD) patients. Thirty-five STN patients and 16 GPi patients were assessed at 5 to 6 years after DBS surgery. Primary outcome measure was the stimulation effect on the motor Unified Parkinson's Disease Rating Scale (UPDRS) assessed with a prospective cross-over double-blind assessment without medications (stimulation was randomly switched on or off). Secondary outcomes were motor UPDRS changes with unblinded assessments in off- and on-medication states with and without stimulation, activities of daily living (ADL), anti-PD medications, and dyskinesias. In double-blind assessment, both STN and GPi DBS were significantly effective in improving the motor UPDRS scores (STN, P < 0.0001, 45.4%; GPi, P = 0.008, 20.0%) compared with off-stimulation, regardless of the sequence of stimulation. In open assessment, both STN- and GPi-DBS significantly improved the off-medication motor UPDRS when compared with before surgery (STN, P < 0.001, 50.5%; GPi, P = 0.002, 35.6%). Dyskinesias and ADL were significantly improved in both groups. Anti-PD medications were significantly reduced only in the STN group. Adverse events were more frequent in the STN group. These results confirm the long-term efficacy of STN and GPi DBS in advanced PD. Although the surgical targets were not randomized, there was a trend to a better outcome of motor signs in the STN-DBS patients and fewer adverse events in the GPi-DBS group.

Riluzole treatment, survival and diagnostic criteria in Parkinson plus disorders: the NNIPPS study.

Parkinson plus diseases, comprising mainly progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) are rare neurodegenerative conditions. We designed a double-blind randomized placebo-controlled trial of riluzole as a potential disease-modifying agent in Parkinson plus disorders (NNIPPS: Neuroprotection and Natural History in Parkinson Plus Syndromes). We analysed the accuracy of our clinical diagnostic criteria, and studied prognostic factors for survival. Patients with an akinetic-rigid syndrome diagnosed as having PSP or MSA according to modified consensus diagnostic criteria were considered for inclusion. The psychometric validity (convergent and predictive) of the NNIPPS diagnostic criteria were tested prospectively by clinical and pathological assessments. The study was powered to detect a 40% decrease in relative risk of death within PSP or MSA strata. Patients were randomized to riluzole or matched placebo daily and followed up to 36 months. The primary endpoint was survival. Secondary efficacy outcomes were rates of disease progression assessed by functional measures. A total of 767 patients were randomized and 760 qualified for the Intent to Treat (ITT) analysis, stratified at entry as PSP (362 patients) or MSA (398 patients). Median follow-up was 1095 days (range 249-1095). During the study, 342 patients died and 112 brains were examined for pathology. NNIPPS diagnostic criteria showed for both PSP and MSA excellent convergent validity with the investigators' assessment of diagnostic probability (point-biserial correlation: MSA r(pb) = 0.93, P < 0.0001; PSP, r(pb) = 0.95, P < 0.0001), and excellent predictive validity against histopathology [sensitivity and specificity (95% CI) for PSP 0.95 (0.88-0.98) and 0.84 (0.77-0.87); and for MSA 0.96 (0.88-0.99) and 0.91 (0.86-0.93)]. There was no evidence of a drug effect on survival in the PSP or MSA strata (3 year Kaplan-Meier estimates PSP-riluzole: 0.51, PSP-placebo: 0.50; MSA-riluzole: 0.53, MSA-placebo: 0.58; P = 0.66 and P = 0.48 by the log-rank test, respectively), or in the population as a whole (P = 0.42, by the stratified-log-rank test). Likewise, rate of progression was similar in both treatment groups. There were no unexpected adverse effects of riluzole, and no significant safety concerns. Riluzole did not have a significant effect on survival or rate of functional deterioration in PSP or MSA, although the study reached over 80% power to detect the hypothesized drug effect within strata. The NNIPPS diagnostic criteria were consistent and valid. They can be used to distinguish between PSP and MSA with high accuracy, and should facilitate research into these conditions relatively early in their evolution.

How can drug discovery for psychiatric disorders be improved?

Psychiatric disorders such as depression, anxiety and schizophrenia are leading causes of disability worldwide, and have a huge societal impact. However, despite the clear need for better therapies, and major advances in the understanding of the molecular basis of these disorders in recent years, efforts to discover and develop new drugs for neuropsychiatric disorders, particularly those that might revolutionize disease treatment, have been relatively unsuccessful. A multidisciplinary approach will be crucial in addressing this problem, and in the first Advances in Neuroscience for Medical Innovation symposium, experts in multiple areas of neuroscience considered key questions in the field, in particular those related to the importance of neuronal plasticity. The discussions were used as a basis to propose steps that can be taken to improve the effectiveness of drug discovery for psychiatric disorders.

Amyloid-ß in Alzheimer's Disease: A Study of Citation Practices of the Amyloid Cascade Hypothesis Between 1992 and 2019.

The amyloid cascade hypothesis (ACH) has dominated contemporary biomedical research into Alzheimer's disease (AD) since the 1990 s but still lacks definitive confirmation by successful clinical trials of anti-amyloid medicines in human AD. In this uncertain period regarding the centrality of amyloid-ß (Aß) in AD pathophysiology, and with the community apparently divided about the ACH's validity, we used citation practices as a proxy for measuring how researchers have invested their belief in the hypothesis between 1992 and 2019. We sampled 445 articles citing Hardy & Higgins (1992, "HH92") and classified the polarity of their HH92 citation according to Greenberg (2009)'s citation taxonomy of positive, neutral, and negative citations, and then tested four hypotheses. We identified two major attitudes towards HH92: a majority (62%) of neutral attitudes with consistent properties across the time period, and a positive attitude (35%), tending to cite HH92 earlier on within the bibliography as time went by, tending to take HH92 as an established authority. Despite the majority of neutral HH92 citations, there was a positive majority of attitudes toward different versions of the ACH and anti-amyloid therapeutic strategies (65%), suggesting that the ACH has been dominant and has undergone significant refinement since 1992. Finally, of those 110 original articles within the sample also testing the ACH empirically, an overwhelming majority (89%) returned a pro-ACH test result, suggesting that the ACH's central claim is reproducible. Further studies will quantify the extent to which results from different methods within such original studies convergence to provide a robust conclusion vis-à-vis Aß's pathogenicity in AD.

Bilateral pallidal deep brain stimulation for the treatment of patients with dystonia-choreoathetosis cerebral palsy: a prospective pilot study.

BACKGROUND: Cerebral palsy (CP) with dystonia-choreoathetosis is a common cause of disability in children and in adults, and responds poorly to medical treatment. Bilateral pallidal deep brain stimulation (BP-DBS) of the globus pallidus internus (GPi) is an effective treatment for primary dystonia, but the effect of this reversible surgical procedure on dystonia-choreoathetosis CP, which is a subtype of secondary dystonia, is unknown. Our aim was to test the effectiveness of BP-DBS in adults with dystonia-choreoathetosis CP. METHODS: We did a multicentre prospective pilot study of BP-DBS in 13 adults with dystonia-choreoathetosis CP who had no cognitive impairment, little spasticity, and only slight abnormalities of the basal ganglia on MRI. The primary endpoint was change in the severity of dystonia-choreoathetosis after 1 year of neurostimulation, as assessed with the Burke-Fahn-Marsden dystonia rating scale. The accuracy of surgical targeting to the GPi was assessed masked to the results of neurostimulation. Analysis was by intention to treat. FINDINGS: The mean Burke-Fahn-Marsden dystonia rating scale movement score improved from 44.2 (SD 21.1) before surgery to 34.7 (21.9) at 1 year post-operatively (p=0.009; mean improvement 24.4 [21.1]%, 95% CI 11.6-37.1). Functional disability, pain, and mental health-related quality of life were significantly improved. There was no worsening of cognition or mood. Adverse events were related to stimulation (arrest of the stimulator in one patient, and an adjustment to the current intensity in four patients). The optimum therapeutic target was the posterolateroventral region of the GPi. Little improvement was seen when the neurostimulation diffused to adjacent structures (mainly to the globus pallidus externus [GPe]). INTERPRETATION: Bilateral pallidal neurostimulation could be an effective treatment option for patients with dystonia-choreoathetosis CP. However, given the heterogeneity of motor outcomes and the small sample size, results should be interpreted with caution. The optimum placement of the leads seemed to be a crucial, but not exclusive, factor that could affect a good outcome. FUNDING: National PHRC; Cerebral Palsy Foundation: Fondation Motrice/APETREIMC; French INSERM Dystonia National Network; Medtronic.