Neurophysiological Predictors of Response to Medication in Parkinson's Disease

Background: Although dopaminergic medication has been the foundation of Parkinson's disease (PD) therapy for decades, sensitive and specific therapeutic response biomarkers that allow for better treatment optimization are lacking. Objective: We tested whether the features of Transcranial Magnetic Stimulation-based neurophysiological measures taken off-medication are associated with dopaminergic medication-induced clinical effects. Method: Motor cortex excitability [short-latency intracortical inhibition (SICI), intracortical facilitation (ICF), short-latency afferent inhibition (SAI), and input-output (IO) curve], and plasticity [paired associative stimulation (PAS) protocol] neurophysiological measures were examined in 23 PD patients off-medication. Clinical features were quantified by the motor section of the Unified Parkinson's Disease Scale (total score and lateralized total, bradykinesia, and rigidity sub-scores), and the differences between measures off-medication and on-medication (following the usual morning dose), were determined. Total daily dopaminergic medication dose (expressed as levodopa equivalent daily dose-LEDD), was also determined. Results: SICI significantly correlated with changes in lateralized UPDRS motor and bradykinesia sub-scores, suggesting that patients with stronger basal intracortical inhibition benefit more from dopaminergic treatment than patients with weaker intracortical inhibition. Also, ICF significantly negatively correlated with LEDD, suggesting that patients with stronger intracortical facilitation require less dopaminergic medication to achieve optimal therapeutic benefit. Both associations were independent of disease severity and duration. Conclusions: The results suggest variability of (patho) physiological phenotypes related to intracortical inhibitory and facilitatory mechanisms determining clinical response to dopaminergic medication in PD. Measures of intracortical excitability may help predict patients' response to dopaminergic therapy, thus potentially providing a background for developing personalized therapy in PD

Effect of transcranial magnetic stimulation on clinical and electrophysiological parameters in Parkinson's disease patients

REZIME Cilj rada. Cilj ovog rada je analiza promena ekscitabilnosti i kortikalnog plasticiteta kod pacijenata obolelih od Parkinsonove bolesti (PB) uslovljenih primenom facilitatornog PAS 25 protokola u zavisnosti od primenjene terapije. Materijal i metode. Pregledano je 30 pacijenta obolelih od PB, i to po 10 pacijenata sa novonastalom PB, 10 pacijenata sa DKPB, bez i sa terapijom i po 10 pacijenata sa Ldopa indukovanim diskinezijama, bez i sa terapijom. Kontrolnu grupu je činilo 10 zdravih ispitanika koji su upareni sa pacijentima po starosti i polu. Plasticitet i stepen ekscitabilnosti je ispitivan na više zahvaćenoj strani u u regionu za šaku motornog korteksa primenom uparene asocijativne stimulacije, kao modela transkranijalne magnetne stimulacije (TMS). Rezultati. Sve grupe pacijenata su, u odnosu na KG, pokazale postojanje deficita LTP – sličnog plasticiteta. Manji nagib krive regrutacije na višim intenzitetima TMS stimulacije je bio prisutan u svim grupama, kratka intrakortikalna inhibicija je bila manja u grupi pacijenata sa novonastom PB i grupi sa diskinezijama, dok je kratka aferentna inhibicija bila oštećena na početku bolesti. LTP plasticitet koji je narušen i na početku bolesti, ostaje oslabljen nezavisno od primenjene terapije. Zaključak. Redukovana ekscitabilnost uslovljena PAS protokolom može biti fiziološki marker prisustva patoloških promena kod PB. Takođe, dugotrajno lečenje ne menja bitno patofiziološke procese koji su u osnovi ove bolesti.Objective. Analyze changes of cortical excitability and plasticity in patients with Parkinson's disease (PD) according to the applied therapy using PAS 25 protocol. Methods. We examined 30 patients with PD: 10 patients with drug naive PD, 10 patients who had been on dopaminergic medication without any complications and side effect (“off” and “on” state) and 10 patients with L-dopa induced dyskinesia (LID) (“off” and “on” state). The control group (CG) consisted of 10 healthy subjects who were matched to the patients by age and sex. Plasticity and excitability of the hand primary motor cortex of the more affected side were evaluated using transcranial magnetic stimulation (TMS) techniques. Results. All patient groups had deficits LTP – like plasticity in comparison to controls: diminished slope of input-output curves at higher TMS intensities, impaired shortinterval intracortical inhibition (SICI) in de novo PD group and group with dyskinesias and decreased facilitatory sensory-motor plasticity (as measured by paired associative stimulation [PAS] protocol). LTP plasticity that has been damaged at the beginning of the disease, remains disrupted independently of medical treatment. Conclusions. There is little interaction between plasticity and excitability features of motor cortex in PD. Reduced response to facilitatory PAS protocol, reduced SICI, and reduced slope of the input - output curve at higher TMS pulse intensities, seem to be physiological markers for the presence of the pathological disease process in PD. Long term treatment does not seem to change the underlying physiology of the disease

Social Cognition in Patients With Cerebellar Neurodegenerative Disorders

ObjectiveCerebellar neurodegenerative disorders (CDs) are a heterogeneous group of disorders. It is known that the cerebellum plays a role not only in motor, but also in cognitive and social cognitive functions. The aim of this study was to investigate social cognition in patients with different CDs.Materials and MethodsSocial cognition was examined in 34 patients, 12 with spinocerebellar ataxia type 1 (SCA1), 6 with spinocerebellar ataxia type 2 (SCA2), and 16 with idiopathic late onset cerebellar ataxia (ILOCA). All patients were clinically evaluated using the Scale for the Rating and Assessment of Ataxia. In addition, 34 age, sex, and education-matched healthy control (HC) subjects were similarly analyzed. Social cognition was studied using two tests: the Faux Pas Recognition Test and the Reading the Mind in the Eyes Test (RMET). An appropriate array of neuropsychological tests was used to assess the global cognitive status as well as the frontal functions and mood.ResultsCD patients achieved significantly worse results on both tests of social cognition compared to the HCs. The SCA1 + 2 group achieved the poorest results on the Faux Pas Recognition Test and exhibited poor performance on all cognitive tests, but was only significantly worse compared to the ILOCA group on the Free and Cued Selective Reminding Test (FCSRT) – recognition. The patients in the SCA1 + 2 and ILOCA groups obtained similar scores on RMET. In the SCA1 + 2 group the findings significantly correlated with clinical parameters of disease severity and duration and executive functions (EFs), and with mood and executive functions in the ILOCA group. In the SCA group EFs appeared as the only significant predictor of RMET achievement. The Boston Naming Test (BTN) was a significant predictor of the CD patients’ achievement on RMET, while the BTN, the Trail Making Test Part A and FCSRT – Delayed free recall predicted their performance on the Faux Pas Recognition Test.ConclusionPatients with CD have social cognitive impairments as demonstrated by the Faux Pas Test and the RMET test results. The SCA1 and 2 patients exhibited a more pronounced impairment compared with the ILOCA patients. The independent cognitive predictors of social cognition impairment were EFs and language

Changes in cortical excitability during paired associative stimulation in Parkinson's disease patients and healthy subjects

Paired associative stimulation (PAS) combines repetitive peripheral nerve stimulation with motor cortex (M1) transcranial magnetic stimulation (TMS), to induce plastic-like changes of cortical excitability. While much attention has been dedicated to post-PAS effects little is known about processes during PAS. We compared the time-course of changes in M1 excitability during standard facilitatory PAS intervention among patients with Parkinsons disease (PD), known to have diminished post-PAS response, and healthy subjects. Compared to baseline pre-PAS MEPs, conditioned MEPs during PAS decreased significantly in both groups. The decrease was significantly larger in healthy subjects than in PD patients, regardless whether patients were drug-naive or not. Although post-PAS excitability increase was also larger in healthy subjects than in PD patients, there was no significant correlation between the two phenomena, i.e. the extent of MEP decrease during PAS and the extent of the post-PAS excitability increase. The results highlight an apparent physiological paradox that repetitive application of an inhibitory stimulation pattern leads to subsequent prolonged facilitation, thus broadening the understanding of the phenomenology of PAS response. Results also suggest that in PD cortical circuits involved in conveying inhibition during PAS, are impaired at the clinical onset of the disease and are not influenced by subsequent PD treatment

The effect of benfothiamine in the therapy of diabetic polyneuropathy

Introduction. Diabetic polyneuropathy (DPN) is one of the most common diabetic complications, which can result in a significant functional impairment and reduction of the quality of life in affected individuals. It occurs due to alterations in different biochemical mechanisms which require the presence of thiamine, which is why this vitamin is used in the therapy of DPN. Due to the low bioavailability of the hydrosolubile forms of thiamine, its liposolubile preparations (benfotiamine) are preferentially used. Objective. The aim of this study was to determine the efficacy of benfotiamine in combination with vitamin B6 in the therapy of DPN. Methods. The study group comprised of 22 patients with DPN who were treated with the combination of benfotiamine and vitamin B6 during 45 days. The effect of the therapy was evaluated by the analysis of different clinical, laboratory and electrophysiological parameters before and after conducted treatment. Results. After the treatment period, a statistically highly significant reduction of pain (p<0.01) was noted with the reduction of pain score on visual analogue scale in 86.4% of patients. A significant reduction of subjective complaints was also noted, with decreased modified total symptom score in 95.5% of patients (p<0.01). The presence of alodynia was reported at the beginning of the study in 77.3%, and after the benfotiamine therapy only in 22.7% of patients, while hyperpathy was initially present in 90.9%, and after treatment in 31.8% of patients (p<0,01). Neurophysiological parameters of polyneuropathy also significantly improved, with the improvement of the compound muscle action potential amplitude in 68.2% (p<0.01) and motor conduction velocity of the peroneal nerve in 45.5% of patients (p<0.01). The improvement of the sensory nerve action potential amplitude (p<0.01) and sensory conduction velocity (p=0.05) of the sural nerve was found in 45.5% of patients. After the treatment period, there was a highly statistically significant lowering of the glycosylated haemoglobin (p<0.01), with improved findings in 63.6% of patients. After completed study treatment protocol 86.4% of patients rated their overall condition as improved. Conclusion. Our results showed that the conducted treatment resulted in significant subjective and objective improvement of the disease signs symptoms, which confirmed that benfotiamine was good starting choice for the treatment of diabetic polyneuropathy

Impairment of cortical inhibition in writer's cramp as revealed by changes in electromyographic silent period after transcranial magnetic stimulation

Changes in silent period (SP) duration following transcranial magnetic stimulation (TMS) set at 20% above the motor threshold were studied in six subjects suffering from writer's cramp, while performing dystonic movement and during voluntary isometric contraction of the muscles mostly involved in the dystonic movement. Dependency of SP duration on the intensity of preceding muscle contraction was compared on both affected and healthy side. In all subjects SP duration during dystonic contraction was shorter than during voluntary contraction of the similar strength performed with the same hand. Also, in five subjects, SP duration during dystonic contraction was shorter than during voluntary contraction of the similar strength performed with the healthy hand. In addition, the SP duration on the affected side was negatively associated with the intensity of the preceding contraction (i.e. the stronger contraction the shorter SP), while on the healthy side it was not the case. It is concluded that central inhibitory mechanisms are abnormal in writer's cramp

Chronic inflammatory demyelinating polyradiculoneuropathy: Diagnostic problems in clinical practice in Serbia

Making diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is challenging since it can mimic a multitude of disorders, and is misdiagnosed in at least 50% of cases. We sought to determine the frequency of CIDP misdiagnosis in clinical practice in Serbia, to uncover CIDP mimics, and to identify factors that may aid in CIDP diagnosis. Our longitudinal retrospective cohort study included 86 eligible adult patients referred to the Neurology Clinic, University Clinical Centre of Serbia, with a diagnosis of CIDP. We also included 15 patients referred to us with different diagnoses that ended up having CIDP as their final diagnosis. Exactly half of patients referred as CIDP failed to meet the established diagnostic criteria (non-CIDP) and were given an alternative diagnosis at the first hospitalization. At the 1-year follow-up, the diagnosis was further revised in four subjects. Confirmed CIDP patients usually had their initial diagnosis based on the nerve conduction studies (NCS), a typical presentation with symmetrical involvement of all four limbs, as well as higher frequencies of elevated protein levels and albuminocytologic dissociation in the cerebrospinal fluid (CSF). CIDP patients also responded better to immune therapy. We found that 52% of the patients initially referred to our Clinic as CIDP were given other diagnoses after a 1-year follow-up. Out of all CIDP cases, 27% had been unrecognized prior to referral to our Center. Utilization of clear and objective indicators - conclusive NCS, improvement on therapy, and elevated CSF proteins may provide greater certainty in diagnosing CIDP

History of exposure to dopaminergic medication does not affect motor cortex plasticity and excitability in Parkinson's disease

Objective: Little is known whether and how chronic exposure to dopaminergic treatment alters physiological mechanisms in Parkinson's disease (PD). Methods: Two clinically similar groups of PD patients, one consisting of drug-naive patients and another of patients already on chronic dopaminergic medication (when off medication), were compared to each other and to a control group. Plasticity and excitability of the hand primary motor cortex of the more affected side were evaluated using transcranial magnetic stimulation (TMS) techniques. Results: There was little difference between two patient groups, and both groups showed similar differences in comparison to controls: decreased facilitatory sensory-motor plasticity (as measured by paired associative stimulation [PAS] protocol), impaired short-interval intracortical inhibition (SICI), and diminished slope of input-output curves at higher TMS intensities. The exception was that 30 min after PAS, intracortical facilitation (ICF) was significantly reduced in drug-naive patients, whereas it changed much less in other two groups. Conclusions: Chronic exposure to dopaminergic drugs does not affect substantially the features of motor cortex excitability and plasticity in PD. There is little interaction between plasticity and excitability features of motor cortex in PD. Significance: Reduced response to facilitatory PAS protocol, reduced SICI, and reduced slope of the input-output curve at higher TMS pulse intensities, seem to be physiological markers for the presence of the pathological disease process in PD. Long term treatment does not seem to change the underlying physiology of the disease