-
Cell Reports. Medicine Jun 2024Levodopa-induced dyskinesia (LID) is an intractable motor complication arising in Parkinson's disease with the progression of disease and chronic treatment of levodopa....
Levodopa-induced dyskinesia (LID) is an intractable motor complication arising in Parkinson's disease with the progression of disease and chronic treatment of levodopa. However, the specific cell assemblies mediating dyskinesia have not been fully elucidated. Here, we utilize the activity-dependent tool to identify three brain regions (globus pallidus external segment [GPe], parafascicular thalamic nucleus, and subthalamic nucleus) that specifically contain dyskinesia-activated ensembles. An intensity-dependent hyperactivity in the dyskinesia-activated subpopulation in GPe (GPe) is observed during dyskinesia. Optogenetic inhibition of GPe significantly ameliorates LID, whereas reactivation of GPe evokes dyskinetic behavior in the levodopa-off state. Simultaneous chemogenetic reactivation of GPe and another previously reported ensemble in striatum fully reproduces the dyskinesia induced by high-dose levodopa. Finally, we characterize GPe as a subset of prototypic neurons in GPe. These findings provide theoretical foundations for precision medication and modulation of LID in the future.
Topics: Levodopa; Globus Pallidus; Dyskinesia, Drug-Induced; Animals; Neurons; Male; Optogenetics; Mice; Parkinson Disease; Humans; Subthalamic Nucleus
PubMed: 38759649
DOI: 10.1016/j.xcrm.2024.101566 -
Medicine May 2024This study aims to investigate the effect of amantadine use on neurological outcomes and mortality in patients with severe traumatic brain injury (TBI) (Glasgow coma... (Observational Study)
Observational Study
This study aims to investigate the effect of amantadine use on neurological outcomes and mortality in patients with severe traumatic brain injury (TBI) (Glasgow coma score [GCS] between 3 and 8) who have been followed up on mechanical ventilators in the intensive care unit (ICU). Data from the hospital's electronic records were retrospectively searched. Patients over 18 years of age, with severe brain trauma (GCS between 3-8), who were treated with endotracheal intubation and invasive mechanical ventilation at admission to the ICU, and who were treated with Amantadine hydrochloride at least once in the first week of follow-up were included in the study. To evaluate the patients' neurological outcomes, the GCS and FOUR scores were used. GCS and FOUR scores were recorded on the 1st, 3rd, and 7th days of the first week. In addition, the score difference between the 1st and 7th day was calculated for both scores. The patients were divided into 2 groups: those receiving amantadine treatment (Group A, n = 44) and the control group (Group C, n = 47). The median age of all patients was 39 (18-81) (P = .425). When Group A and Group C were compared, no statistically significant results were found between the 1st, 3rd, and 7th day GCS values (P = .474, P = .483, and P = 329, respectively). However, the difference in GCS values between day 1 and day 7 (∆ GCS 7-1) was statistically significant (P = .012). Similarly, when Group A and Group C were compared, no statistically significant results were found between the 1st, 3rd, and 7th day FOUR score values (P = .948, P = .471, and P = .057, respectively). However, the FOUR score values between day 1 and day 7 (∆ FOUR score 7-1) were statistically significant (P = .004). There was no statistically significant difference among the groups in terms of ICU length of stay, duration of non-ICU hospital stay, and length of hospital stay (P = .222, P = .175, and P = .067, respectively). Amantadine hydrochloride may help improve neurological outcomes in patients with severe TBI. However, further research is needed to investigate this topic.
Topics: Humans; Amantadine; Respiration, Artificial; Male; Female; Middle Aged; Adult; Retrospective Studies; Intensive Care Units; Aged; Glasgow Coma Scale; Adolescent; Aged, 80 and over; Brain Injuries, Traumatic; Young Adult; Treatment Outcome; Craniocerebral Trauma
PubMed: 38758901
DOI: 10.1097/MD.0000000000038172 -
Neurobiology of Disease Jul 2024Parkinson's disease (PD) is characterized by the disruption of repetitive, concurrent and sequential motor actions due to compromised timing-functions principally...
Parkinson's disease (PD) is characterized by the disruption of repetitive, concurrent and sequential motor actions due to compromised timing-functions principally located in cortex-basal ganglia (BG) circuits. Increasing evidence suggests that motor impairments in untreated PD patients are linked to an excessive synchronization of cortex-BG activity at beta frequencies (13-30 Hz). Levodopa and subthalamic nucleus deep brain stimulation (STN-DBS) suppress pathological beta-band reverberation and improve the motor symptoms in PD. Yet a dynamic tuning of beta oscillations in BG-cortical loops is fundamental for movement-timing and synchronization, and the impact of PD therapies on sensorimotor functions relying on neural transmission in the beta frequency-range remains controversial. Here, we set out to determine the differential effects of network neuromodulation through dopaminergic medication (ON and OFF levodopa) and STN-DBS (ON-DBS, OFF-DBS) on tapping synchronization and accompanying cortical activities. To this end, we conducted a rhythmic finger-tapping study with high-density EEG-recordings in 12 PD patients before and after surgery for STN-DBS and in 12 healthy controls. STN-DBS significantly ameliorated tapping parameters as frequency, amplitude and synchrony to the given auditory rhythms. Aberrant neurophysiologic signatures of sensorimotor feedback in the beta-range were found in PD patients: their neural modulation was weaker, temporally sluggish and less distributed over the right cortex in comparison to controls. Levodopa and STN-DBS boosted the dynamics of beta-band modulation over the right hemisphere, hinting to an improved timing of movements relying on tactile feedback. The strength of the post-event beta rebound over the supplementary motor area correlated significantly with the tapping asynchrony in patients, thus indexing the sensorimotor match between the external auditory pacing signals and the performed taps. PD patients showed an excessive interhemispheric coherence in the beta-frequency range during the finger-tapping task, while under DBS-ON the cortico-cortical connectivity in the beta-band was normalized. Ultimately, therapeutic DBS significantly ameliorated the auditory-motor coupling of PD patients, enhancing the electrophysiological processing of sensorimotor feedback-information related to beta-band activity, and thus allowing a more precise cued-tapping performance.
Topics: Humans; Parkinson Disease; Male; Female; Middle Aged; Deep Brain Stimulation; Aged; Beta Rhythm; Motor Cortex; Cortical Synchronization; Levodopa; Fingers; Subthalamic Nucleus; Antiparkinson Agents; Electroencephalography
PubMed: 38740349
DOI: 10.1016/j.nbd.2024.106529 -
Tremor and Other Hyperkinetic Movements... 2024Opsoclonus is a rare disorder characterized by conjugate multidirectional, horizontal, vertical, and torsional saccadic oscillations, without intersaccadic interval,...
BACKGROUND
Opsoclonus is a rare disorder characterized by conjugate multidirectional, horizontal, vertical, and torsional saccadic oscillations, without intersaccadic interval, resulting from dysfunction within complex neuronal pathways in the brainstem and cerebellum. While most cases of opsoclonus are associated with autoimmune or paraneoplastic disorders, infectious agents, trauma, or remain idiopathic, opsoclonus can also be caused by medications affecting neurotransmission. This review was prompted by a case of opsoclonus occurring in a patient with Multiple System Atrophy, where amantadine, an NMDA-receptor antagonist, appeared to induce opsoclonus.
METHODS
Case report of a single patient and systematized review of toxic/drug-induced opsoclonus, selecting articles based on predefined criteria and assessing the quality of included studies.
RESULTS
The review included 30 articles encompassing 158 cases of toxic/drug-induced opsoclonus. 74% of cases were attributed to bark scorpion poisoning, followed by 9% of cases associated with chlordecone intoxication. The remaining cases were due to various toxics/drugs, highlighting the involvement of various neurotransmitters, including acetylcholine, glutamate, GABA, dopamine, glycine, and sodium channels, in the development of opsoclonus.
CONCLUSION
Toxic/drug-induced opsoclonus is very rare. The diversity of toxics/drugs impacting different neurotransmitter systems makes it challenging to define a unifying mechanism, given the intricate neuronal pathways underlying eye movement physiology and opsoclonus pathophysiology.
Topics: Humans; Male; Amantadine; Multiple System Atrophy; Ocular Motility Disorders; Aged
PubMed: 38737300
DOI: 10.5334/tohm.832 -
BMC Psychiatry May 2024Restless arms syndrome (RAS) is the most common variant of restless legs syndrome (RLS), which is easy to be ignored in clinical practice due to the lack of specific...
BACKGROUND
Restless arms syndrome (RAS) is the most common variant of restless legs syndrome (RLS), which is easy to be ignored in clinical practice due to the lack of specific diagnostic criteria. When effective therapeutic agents induced RAS and symptoms persisted after briefly observation, clinicians will face the challenge of weighing efficacy against side effects.
CASE PRESENTATION
A 67-year-old woman was admitted to a geriatric psychiatric ward with depression. Upon admission, the escitalopram dose was reduced from 15 mg to 10 mg per day, and the duloxetine dose was increased from 60 mg to 80 mg per day. The next night before bedtime, she developed itching and creeping sensations deep inside bilateral shoulders and arms, with the urge to move, worsening at rest, and alleviation after hammering. The symptoms persisted when escitalopram was discontinued. A history of RLS was confirmed. Treatment with 40 mg of duloxetine and 0.125 mg of pramipexole significantly improved depression, and the paresthesia disappeared, with no recurrence occurring 6 months after discharge.
DISCUSSION AND CONCLUSIONS
This case suggests that psychiatrists should pay attention to RLS variants when increasing doses of duloxetine. Long-term improvement can be achieved through dosage reduction combined with dopaminergic drugs instead of immediate discontinuation.
Topics: Aged; Female; Humans; Antidepressive Agents; Duloxetine Hydrochloride; Phenotype; Pramipexole; Restless Legs Syndrome; Serotonin and Noradrenaline Reuptake Inhibitors
PubMed: 38730422
DOI: 10.1186/s12888-024-05763-7 -
Journal of Parkinson's Disease 2024Gait issues, including reduced speed, stride length and freezing of gait (FoG), are disabling in advanced phases of Parkinson's disease (PD), and their treatment is...
BACKGROUND
Gait issues, including reduced speed, stride length and freezing of gait (FoG), are disabling in advanced phases of Parkinson's disease (PD), and their treatment is challenging. Levodopa/carbidopa intestinal gel (LCIG) can improve these symptoms in PD patients with suboptimal control of motor fluctuations, but it is unclear if continuous dopaminergic stimulation can further improve gait issues, independently from reducing Off-time.
OBJECTIVE
To analyze before (T0) and after 3 (T1) and 6 (T2) months of LCIG initiation: a) the objective improvement of gait and balance; b) the improvement of FoG severity; c) the improvement of motor complications and their correlation with changes in gait parameters and FoG severity.
METHODS
This prospective, longitudinal 6-months study analyzed quantitative gait parameters using wearable inertial sensors, FoG with the New Freezing of Gait Questionnaire (NFoG-Q), and motor complications, as per the MDS-UPDRS part IV scores.
RESULTS
Gait speed and stride length increased and duration of Timed up and Go and of sit-to-stand transition was significantly reduced comparing T0 with T2, but not between T0-T1. NFoG-Q score decreased significantly from 19.3±4.6 (T0) to 11.8±7.9 (T1) and 8.4±7.6 (T2) (T1-T0 p = 0.018; T2-T0 p < 0.001). Improvement of MDS-UPDRS-IV (T0-T2, p = 0.002, T0-T1 p = 0.024) was not correlated with improvement of gait parameters and NFoG-Q from T0 to T2. LEDD did not change significantly after LCIG initiation.
CONCLUSION
Continuous dopaminergic stimulation provided by LCIG infusion progressively ameliorates gait and alleviates FoG in PD patients over time, independently from improvement of motor fluctuations and without increase of daily dosage of dopaminergic therapy.
Topics: Humans; Levodopa; Parkinson Disease; Male; Aged; Female; Middle Aged; Gait Disorders, Neurologic; Longitudinal Studies; Gels; Carbidopa; Prospective Studies; Drug Combinations; Antiparkinson Agents
PubMed: 38728203
DOI: 10.3233/JPD-240003 -
Clinical and Translational Science May 2024Apomorphine, used to treat OFF episodes in patients with Parkinson's disease (PD), is typically administered via subcutaneous injections. Administration of an oromucosal...
Apomorphine, used to treat OFF episodes in patients with Parkinson's disease (PD), is typically administered via subcutaneous injections. Administration of an oromucosal solution could offer a non-invasive and user-friendly alternative. This two-part clinical study evaluated the safety, tolerability, pharmacokinetics (PK), and dose proportionality of a novel apomorphine hydrochloride oromucosal solution, as well as its relative bioavailability to subcutaneous apomorphine injection and apomorphine sublingual film. In part A of the study, 12 patients with PD received 2 mg oromucosal apomorphine (4% weight/volume) and 2 mg subcutaneous apomorphine in a randomized order, followed by 4 and 8 mg oromucosal apomorphine. In part B of the study, 13 patients with PD received 7 mg oromucosal apomorphine (7% weight/volume) and 30 mg sublingual apomorphine in a randomized order, followed by 14 mg oromucosal apomorphine. Washout between dose administrations in both study parts was at least 2 days. Safety, tolerability, and PK were assessed pre- and post-dose. Both study parts showed that oromucosal apomorphine was generally well-tolerated. Observed side effects were typical for apomorphine administration and included asymptomatic orthostatic hypotension, yawning, fatigue, and somnolence. Oromucosal apomorphine exposure increased with dose, although less than dose proportional. The mean (SD) maximum exposure reached with 14 mg oromucosal apomorphine was 753.0 (298.6) ng*min/mL (area under the plasma concentration-time curve from zero to infinity) and 8.0 (3.3) ng/mL (maximum plasma concentration). This was comparable to exposure reached after 2 mg subcutaneous apomorphine and approximately half of the exposure observed with 30 mg sublingual apomorphine. In summary, clinically relevant plasma concentrations could be reached in PD patients without tolerability issues.
Topics: Aged; Female; Humans; Male; Middle Aged; Administration, Oral; Administration, Sublingual; Antiparkinson Agents; Apomorphine; Biological Availability; Cross-Over Studies; Dose-Response Relationship, Drug; Injections, Subcutaneous; Parkinson Disease; Adult; Aged, 80 and over
PubMed: 38712716
DOI: 10.1111/cts.13796 -
Brain and Behavior May 2024Sequential working memory is the ability to maintain and manipulate sequential information at a second time scale. Patients with progressive supranuclear palsy (PSP) or...
PURPOSE
Sequential working memory is the ability to maintain and manipulate sequential information at a second time scale. Patients with progressive supranuclear palsy (PSP) or Parkinson's disease (PD) perform poorly in tests that require the flexible arrangement of thoughts or actions. This study investigated whether sequential working memory is differently impaired in patients with PSP versus PD.
METHOD
Twenty-nine patients with PSP Richardson's syndrome (PSP-RS), 36 patients with PD, and 36 healthy controls (HC) completed 3 well-established neuropsychological tests, including digit span forward (DST-F), digit span backward (DST-B), and adaptive digit ordering tests (DOT-A). The DST-F required maintaining digit sequences, and the DST-B and DOT-A required maintaining and manipulating digit sequences.
FINDING
The PSP-RS group scored lower than the PD and HC groups in the DST-B and DOT-A but not in the DST-F, indicating that the ability to manipulate sequences was impaired, but the maintenance ability was preserved in PSP-RS patients. Moreover, in PSP-RS, the DST-B score negatively correlated with the severity of motor symptoms. The actual levodopa dose positively correlated with the DST-B ordering cost (DST-F score vs. DST-B score). The PSP patients who took a greater dose of levodopa tended to have higher DST-B ordering cost. There was no effect of levodopa on DST-B or DOT-A in PD.
CONCLUSION
These results suggested that the ability to manipulate sequence was already reduced in patients with PSP-RS and was worse than in patients with PD.
Topics: Humans; Supranuclear Palsy, Progressive; Male; Female; Aged; Parkinson Disease; Middle Aged; Memory, Short-Term; Neuropsychological Tests; Levodopa
PubMed: 38702898
DOI: 10.1002/brb3.3527 -
Clinical Neurology and Neurosurgery Jun 2024Pyruvate dehydrogenase complex (PDC) deficiency is a genetic mitochondrial disease mostly associated with severe lactic acidosis, rapid progression of neurological...
Pyruvate dehydrogenase complex (PDC) deficiency is a genetic mitochondrial disease mostly associated with severe lactic acidosis, rapid progression of neurological symptoms and death during childhood. We present a 33-year-old male with PDC deficiency caused by a Val262Leu mutation in PDHA1gene. He demonstrated generalized dystonia affecting trunk and upper extremities and paraparesis as the most significant features, with onset of symptoms at age 8. Brain MRI showed bilaterally increased signal within the globus pallidus, typical of Leigh syndrome. A periodic lactate increase in serum and cerebrospinal fluid was detected. We describe a case of pyruvate dehydrogenase deficiency being diagnosed only 25 years after the onset of symptoms and highlight PDHC deficiency as a possible cause of treatable dystonia in childhood, which may respond well to thiamine and levodopa treatment.
Topics: Humans; Male; Adult; Pyruvate Dehydrogenase Complex Deficiency Disease; Pyruvate Dehydrogenase (Lipoamide); Dystonia; Levodopa; Dystonic Disorders; Magnetic Resonance Imaging; Mutation
PubMed: 38701546
DOI: 10.1016/j.clineuro.2024.108307 -
Movement Disorders Clinical Practice Jun 2024Blood pressure control in Parkinson's disease (PD) under subthalamic deep brain stimulation (STN-DBS) is influenced by several intertwined aspects, including autonomic...
BACKGROUND
Blood pressure control in Parkinson's disease (PD) under subthalamic deep brain stimulation (STN-DBS) is influenced by several intertwined aspects, including autonomic failure and levodopa treatment.
OBJECTIVE
To evaluate the effect of chronic STN-DBS, levodopa, and their combination on cardiovascular autonomic functions in PD.
METHODS
We performed cardiovascular reflex tests (CRTs) before and 6-months after STN-DBS surgery in 20 PD patients (pre-DBS vs. post-DBS). CRTs were executed without and with medication (med-OFF vs. med-ON).
RESULTS
CRT results and occurrence of neurogenic orthostatic hypotension (OH) did not differ between pre- and post-DBS studies in med-OFF condition. After levodopa intake, the BP decrease during HUTT was significantly greater compared to med-OFF, both at pre-DBS and post-DBS evaluation. Levodopa-induced OH was documented in 25% and 5% of patients in pre-DBS/med-ON and post-DBS/med-ON study.
CONCLUSION
Chronic stimulation did not influence cardiovascular responses, while levodopa exerts a relevant hypotensive effect. The proportion of patients presenting levodopa-induced OH decreases after STN-DBS surgery.
Topics: Humans; Parkinson Disease; Deep Brain Stimulation; Male; Female; Middle Aged; Aged; Levodopa; Autonomic Nervous System; Antiparkinson Agents; Blood Pressure; Subthalamic Nucleus; Hypotension, Orthostatic
PubMed: 38698586
DOI: 10.1002/mdc3.14060