ABSTRACT
Interactions between dorsal premotor cortex (PMd) and primary motor cortex (M1) and interhemispheric inhibition (IHI) between M1 are impaired in Parkinson's disease (PD). We used dual-site transcranial magnetic stimulation to compare effects of first-time levodopa application with chronic dopaminergic therapy on these interactions in PD. Twelve untreated PD patients were studied before and after their first-ever intake of levodopa. The effects of chronic dopaminergic medication were evaluated in 11 patients who had received regular dopaminergic medication for approximately 3 years. Nine of these patients were also measured after overnight withdrawal of medication. For IHI, conditioning stimuli (CS) were applied to left M1 followed by test stimuli (TS) over right M1 and vice versa in separate blocks at interstimulus intervals (ISI) of 6-10 ms. Next, CS were applied to left PMd at subthreshold intensity followed by TS over left M1 at ISIs of 4 and 6 ms. Results were compared to 17 age- and gender-matched controls. In de novo PD patients, levodopa reduced left-to-right IHI, but did not alter PMd-M1 connectivity. In contrast, inhibitory PMd-M1 connectivity was present in early disease patients under chronic dopaminergic stimulation, but not in de novo PD patients at low stimulus intensities at an ISI of 4 ms. First-time exposure to levodopa exerts different effects on cortico-cortical pathways than chronic dopaminergic stimulation in PD, suggesting a change in the responsiveness of cortico-cortical circuits during the course of PD.
Subject(s)
Antiparkinson Agents/pharmacology , Levodopa/pharmacology , Motor Cortex/drug effects , Nerve Net/drug effects , Parkinson Disease/drug therapy , Adult , Aged , Antiparkinson Agents/therapeutic use , Evoked Potentials, Motor/drug effects , Evoked Potentials, Motor/physiology , Female , Humans , Levodopa/therapeutic use , Male , Middle Aged , Motor Cortex/physiopathology , Nerve Net/physiopathology , Neural Pathways/drug effects , Neural Pathways/physiopathology , Parkinson Disease/physiopathology , Transcranial Magnetic StimulationABSTRACT
OBJECTIVE: To describe excitability of motor pathways in Kufor-Rakeb syndrome (PARK9), an autosomal recessive nigro-striatal-pallidal-pyramidal neurodegeneration caused by a mutation in the ATP13A2 gene, using transcranial magnetic stimulation (TMS). METHODS: Five members of a Chilean family with an ATP13A2 mutation (one affected mutation carrier (MC) with a compound heterozygous mutation, 4 asymptomatic MC with a single heterozygous mutation) and 11 healthy subjects without mutations were studied. We measured motor evoked potentials (MEP), the contralateral silent period (cSP), short interval intracortical inhibition (SICI), intracortical facilitation (ICF), short latency afferent inhibition (SAI) as markers of intracortical intrahemispheric inhibition/facilitation and the ipsilateral silent period (iSP) and paired-pulse interhemispheric inhibition (IHI) to probe interhemispheric motor interactions. RESULTS: CSP duration was increased in the symptomatic ATP13A2 MC. The iSP measurements revealed increased interhemispheric inhibition in both the compound heterozygous and the heterozygous MC. CONCLUSION: A compound heterozygous mutation in the ATP13A2 gene is associated with increased intracortical inhibition. In addition, some aspects of interhemispheric inhibition are increased in the presence of a single ATP13A2 mutation.
Subject(s)
Efferent Pathways/physiopathology , Evoked Potentials, Motor/genetics , Mutation/genetics , Parkinsonian Disorders , Proton-Translocating ATPases/genetics , Transcranial Magnetic Stimulation , Aged , Analysis of Variance , Chile , Electromyography , Family Health , Female , Functional Laterality/genetics , Humans , Male , Middle Aged , Muscle, Skeletal/physiopathology , Neural Inhibition/genetics , Parkinsonian Disorders/genetics , Parkinsonian Disorders/pathology , Parkinsonian Disorders/physiopathology , Reaction Time/geneticsABSTRACT
Although Parkinson's disease (PD) has traditionally been considered to be a non-genetic disorder, recent progress in the neurogenetics of PD provided converging evidence that genetic factors play a relevant role in the etiology of PD. The strongest case for a genetic contribution to PD was made by the discovery of mutations in single genes that can cause autosomal dominant (alpha-synuclein (SNCA)) and leucine rich repeat kinase 2 (LRRK2) gene) or recessive (Parkin, PTEN-induced putative kinase 1 (PINK1), DJ-1, and ATP13A2 gene) forms of PD. Here, we review how structural and functional neuroimaging of individuals carrying a mutation in one of the PD genes has offered a unique avenue of research into the pathogenesis of PD. In symptomatic mutation carriers (i.e. those with overt disease), brain mapping can help to link the molecular pathogenesis of PD more directly with functional and structural changes in the intact human brain. In addition, neuroimaging of presymptomatic (i.e. non-manifesting) mutation carriers has emerged as a valuable tool to identify mechanisms of adaptive motor reorganization at the preclinical stage that may prevent or delay clinical manifestation. In addition to mutations causing monogenic forms of PD, common polymorphisms in genes that influence mono-aminergic signaling or synaptic plasticity may have modifying effects on distinct aspects of PD. We also discuss how functional and structural neuroimaging can be used to better characterize these genotype-phenotype correlations.
