A network centred on the inferior frontal cortex is critically involved in levodopa-induced dyskinesias

Abstract

Levodopa-induced dyskinesias are disabling motor complications of long-term dopamine replacement in patients with Parkinson's disease. In recent years, several alternative models have been proposed to explain the pathophysiological mechanisms underlying this hyperkinetic motor disorder. In particular, our group has shed new light on the role of the prefrontal cortex as a key site of interest, demonstrating that, among other areas, the inferior frontal cortex is particularly characterized by altered patterns of anatomical and functional changes. However, how neural activity varies depending on levodopa treatment in patients with dyskinesias and whether the reported prefrontal abnormalities may have a critical role in dyskinesias is debated. To answer these questions we performed independent functional magnetic resonance imaging and repetitive transcranial magnetic stimulation studies. In the first experiment we applied resting state functional magnetic resonance imaging on 12 patients with Parkinson's disease with levodopa-induced dyskinesias and 12 clinically matched patients without dyskinesias, before and after administration of levodopa. Functional connectivity of brain networks in the resting state was assessed in both groups. We chose the right inferior frontal cortex as the seed region given the evidence highlighting the role of this region in motor control. In a second experiment, we applied different forms of repetitive transcranial magnetic stimulation over the right inferior frontal cortex in a new group of dyskinetic patients who were taking a supramaximal dose of levodopa, to verify the clinical relevance of this area in controlling the development of hyperkinetic movements. The resting state functional imaging analysis revealed that in patients with levodopa-induced dyskinesias connectivity of the right inferior frontal cortex was decreased with the left motor cortex and increased with the right putamen when compared to patients without levodopa-induced dyskinesias. This abnormal pattern of connectivity was evident only during the ON phase of levodopa treatment and the degree of such alteration correlated with motor disability. The repetitive TMS experiments showed that a session of continuous but not intermittent or sham theta burst stimulation applied over the inferior frontal cortex was able to reduce the amount of dyskinesias induced by a supramaximal single dose of levodopa, suggesting that this area may play a key role in controlling the development of dyskinesias. Our combined resting state functional magnetic resonance and transcranial magnetic stimulation studies demonstrate that pathophysiological mechanisms underlying levodopa-induced dyskinesias may extend beyond the 'classical' basal ganglia dysfunctions model, including the modulation performed by the neural network centred on the inferior frontal cortex.

Contribution of transcranial magnetic stimulation to assessment of brain connectivity and networks

“…This method has also been applied to analyze the networks responsible for higher cerebral functions such as attention (Leitao et al, 2015), working memory (Lorenc et al, 2015), perception (Pitcher et al, 2014), learning (Steel et al, 2016), and decision making (Rahnev et al, 2016). Furthermore, recently, the application of these methods has been expanded to some patients with neurological and psychological disorders such as Parkinson’s disease (Cerasa et al, 2015), stroke (Cunningham et al, 2015), epilepsy (Makela et al, 2013), pain (Martin et al, 2013), addiction (Hanlon et al, 2015), brain injury (Guller et al, 2014), peripheral nerve injury (Li et al, 2015), depression (Li et al, 2004), and schizophrenia (Gromann et al, 2012, Guller et al, 2012). …”

Hyperkinetic disorders and loss of synaptic downscaling

“…Continuous theta burst stimulation of the cerebellum may have anti-dyskinetic effects, possibly via the modulation of cerebello-thalamocortical pathways 94 . A study combining resting state functional MRI with rTMS has shown that the inferior frontal cortex is implicated in LID and could be a potential therapeutic target 95 .…”

Transcranial Magnetic Stimulation Versus Electrical Vestibular Stimulation on Balance in Geriatrics Parkinsonian Patients

“…They concluded that TMS applied in the prefrontal cortex induces the release of endogenous dopamine in the ipsilateral caudate nucleus as observed by positron emission tomography in healthy human subjects. Cerasa and coworkers, (2015) [18], observed that repetitive TMS applied over the inferior frontal cortex reduced the amount of dyskinesia induced by a supramaximal single dose of levodopa in PD patients, suggesting that this area may play a key role in controlling the development of dyskinesia. The results of these studies show that TMS application results in partial or complete disappearance of muscular pain and L-dopa-induced dyskinesia in addition to an immediate and beneficial effect on corticostriatal interactions that play an important role in the pathophysiology of PD.…”