Subthalamic nucleus and motor cortex connectivity impaired in Parkinson’s disease

Kurani et al. 2014 Neurobiology of Aging

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Previous research has indicated increased functional connectivity between subthalamic nucleus (STN) and sensorimotor cortex in off-medication Parkinson’s disease (PD) compared with control subjects. It is not clear if the increase in functional connectivity between STN and sensorimotor cortex occurs in de novo PD, which is before patients begin dopamine therapy. Resting-state functional magnetic resonance imaging was carried out in 20 de novo (drug naïve) patients with PD (Hoehn and Yahr stage: I-II), 19 patients with moderate PD (Hoehn and Yahr stage: II-III), and 19 healthy controls. The functional connectivity analysis in de novo and moderate PD patients focused on the connectivity of the more affected STN and the sensorimotor cortex. Using resting-state functional connectivity analysis, we provide new evidence that people with de novo PD and off-medicated moderate PD have increased functional connectivity between the more affected STN and different regions within the sensorimotor cortex. The overlapping sensorimotor cortex found in both de novo and moderate PD had functional connectivity values that correlated positively with the Unified Parkinson’s Disease Rating Scale part III. This key finding suggests that changes in functional connectivity between STN and sensorimotor cortex occur early in the disease following diagnosis and before dopamine therapy.

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Essential tremor pathophysiology linked to cortex and cerebellum

Neely et al. (2014) Cerebral Cortex

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It is well-established that during goal-directed motor tasks, patients with essential tremor have increased oscillations in the 0–3 and 3–8 Hz bands. It remains unclear if these increased oscillations relate to activity in specific brain regions. This study used task-based functional magnetic resonance imaging to compare the brain activity associated with oscillations in grip force output between patients with essential tremor, patients with Parkinson’s disease who had clinically evident tremor, and healthy controls. The findings demonstrate that patients with essential tremor have increased brain activity in the motor cortex and supplementary motor area compared with controls, and this activity correlated positively with 3–8 Hz force oscillations. Brain activity in cerebellar lobules I–V was reduced in essential tremor compared with controls and correlated negatively with 0–3 Hz force oscillations. Widespread differences in brain activity were observed between essential tremor and Parkinson’s disease. Using functional connectivity analyses during the task evidenced reduced cerebellar-cortical functional connectivity in patients with essential tremor compared with controls and Parkinson’s disease. This study provides new evidence that in essential tremor 3–8 Hz force oscillations relate to hyperactivity in motor cortex, 0–3 Hz force oscillations relate to the hypoactivity in the cerebellum, and cerebellar-cortical functional connectivity is impaired.

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New article published in PLoS ONE: Dose-response effect of isometric force production on the perception of pain

PLoS One. 2014 Feb 4;9(2):e88105. doi: 10.1371/journal.pone.0088105. eCollection 2014.
Dose-response effect of isometric force production on the perception of pain.
Misra G, Paris TA, Archer DB, Coombes SA.

Isometric contractions can influence the way that we perceive pain, but conclusions on the dose-response effect of force amplitude on pain perception are limited because previous studies have not held the duration of force contractions constant while varying force amplitude. To address this issue we designed an experiment that allowed us to accurately guide the amplitude of an isometric pinch grip force contraction on a trial-by-trial basis, while a thermal pain eliciting stimulus was simultaneously delivered for the same duration to the non-contracting hand. Our results show that an increase in the amplitude of force produced by one hand corresponded with a decrease in pain perception in the opposite hand. Our observations provide novel evidence that the centralized inhibitory response that underlies analgesia is sensitive to and enhanced by stronger isometric contractions.

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New article published in Cerebral Cortex: Motor control and pain processing in midcingulate cortex

Misra and Coombes

Human neuroimaging and virus-tracing studies in monkey predict that motor control and pain processes should overlap in anterior midcingulate cortex (aMCC), but there is currently no direct evidence that this is the case. We used a novel functional magnetic resonance imaging paradigm to examine brain activity while subjects performed a motor control task, experienced a pain-eliciting stimulus on their hand, and performed the motor control task while also experiencing the pain-eliciting stimulus. Our experiment produced 3 novel results. First, group-level analyses showed that when separate trials of motor control and pain processing were performed, overlapping functional activity was found in the same regions of aMCC, supplementary motor area (SMA), anterior insula, and putamen. Secondly, increased activity was found in the aMCC and SMA when motor control and pain processing occurred simultaneously. Thirdly, individual-level analyses showed that 93% of subjects engaged the same region of aMCC during separate trials of motor control and pain processing irrespective of differences in the sulcal/gyral morphology of the cingulate cortex across individuals. These observations provide direct evidence in humans that the same region of aMCC is engaged for motor control and pain processing.

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Dana Foundation Highlights Biomarkers for Parkinson’s Disease

Work from our laboratory was highlighted by the Dana Foundation

Read more about the article by Carl Sherman:

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Review describes evidence for dopamine overdose hypothesis

Movement Disorders
Dopamine overdose hypothesis: Evidence and clinical implications.
Vaillancourt DE, Schonfeld D, Kwak Y, Bohnen NI, Seidler R.

About a half a century has passed since dopamine was identified as a neurotransmitter, and it has been several decades since it was established that people with Parkinson’s disease receive motor symptom relief from oral levodopa. Despite the evidence that levodopa can reduce motor symptoms, there has been a developing body of literature that dopaminergic therapy can improve cognitive functions in some patients but make them worse in others. Over the past two decades, several laboratories have shown that dopaminergic medications can impair the action of intact neural structures and impair the behaviors associated with these structures. In this review, we consider the evidence that has accumulated in the areas of reversal learning, motor sequence learning, and other cognitive tasks. The purported inverted-U shaped relationship between dopamine levels and performance is complex and includes many contributory factors. The regional striatal topography of nigrostriatal denervation is a critical factor, as supported by multimodal neuroimaging studies. A patient’s individual genotype will determine the relative baseline position on this inverted-U curve. Dopaminergic pharmacotherapy and individual gene polymorphisms can affect the mesolimbic and prefrontal cortical dopaminergic functions in a comparable, inverted-U dose-response relationship. Depending on these factors, a patient can respond positively or negatively to levodopa when performing reversal learning and motor sequence learning tasks. These tasks may continue to be relevant as our society moves to increased technological demands of a digital world that requires newly learned motor sequences and adaptive behaviors to manage daily life activities.

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New article shows that acute exercise reduces pain perception

Effects of a Force Production Task and a Working Memory Task on Pain Perception

Tiffany A. Paris, Gaurav Misra, Derek B. Archer, Stephen A. Coombes

The goal in the current study was to examine the analgesic effects of a pinch grip-force production task and a working memory task when pain-eliciting thermal stimulation was delivered simultaneously to the left or right hand during task performance. Control conditions for visual distraction and thermal stimulation were included, and force performance measures and working memory performance measures were collected and analyzed. Our experiments revealed 3 novel findings. First, we showed that accurate isometric force contractions elicit an analgesic effect when pain-eliciting thermal stimulation was delivered during task performance. Second, the magnitude of the analgesic effect was not different when the pain-eliciting stimulus was delivered to the left or right hand during the force task or the working memory task. Third, we found no correlation between analgesia scores during the force task and the working memory task. Our findings have clinical implications for rehabilitation settings because they suggest that acute force production by one limb influences pain perception that is simultaneously experienced in another limb. From a theoretical perspective, we interpret our findings on force and memory driven analgesia in the context of a centralized pain inhibitory response.

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Review: Diffusion MRI, DTI, and Movement Disorders

Curr Neurol Neurosci Rep. 2013 Nov;13(11):400. doi: 10.1007/s11910-013-0400-1.

The evolving role of diffusion magnetic resonance imaging in movement disorders.
Hess CW, Ofori E, Akbar U, Okun MS, Vaillancourt DE.

Significant advances have allowed diffusion magnetic resonance imaging (MRI) to evolve into a powerful tool in the field of movement disorders that can be used to study disease states and connectivity between brain regions. Diffusion MRI is a promising potential biomarker for Parkinson’s disease and other forms of parkinsonism, and may allow the distinction of different forms of parkinsonism. Techniques such as tractography have contributed to our current thinking regarding the pathophysiology of dystonia and possible mechanisms of penetrance. Diffusion MRI measures could potentially assist in monitoring disease progression in Huntington’s disease, and in uncovering the nature of the processes and structures involved the development of essential tremor. The ability to represent structural connectivity in vivo also makes diffusion MRI an ideal adjunctive tool for the surgical treatment of movement disorders. We review recent studies using diffusion MRI in movement disorders research and present the current state of the science as well as future directions.

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REM sleep problems linked with freezing of gait in Parkinson’s disease

Neurology. 2013 Aug 14. [Epub ahead of print]
Increased REM sleep without atonia in Parkinson disease with freezing of gait.
Videnovic A, Marlin C, Alibiglou L, Planetta PJ, Vaillancourt DE, Mackinnon CD.

The objective of this cross-sectional study was to test the hypothesis that patients with Parkinson disease (PD) and freezing of gait (PD+FOG) would demonstrate sleep disturbances comparable to those seen in patients with REM sleep behavior disorder (RBD) and these changes would be significantly different from those in PD patients without FOG (PD-FOG) and age-matched controls.
We conducted overnight polysomnography studies in 4 groups of subjects: RBD, PD-FOG, PD+FOG, and controls. Tonic and phasic muscle activity during REM sleep were quantified using EMG recordings from the chin, compared among study groups, and correlated with disease metrics.
There were no significant differences in measures of disease severity, duration, or dopaminergic medications between the PD+FOG and PD-FOG groups. Tonic muscle activity was increased significantly (p < 0.007) in the RBD and PD+FOG groups compared to the PD-FOG and control groups. There was no significant difference in tonic EMG between the PD+FOG and RBD group (p = 0.364), or in tonic or phasic EMG between the PD-FOG and control group (p = 0.107). Phasic muscle activity was significantly increased in the RBD group compared to all other groups (p = 0.029) and between the PD+FOG and control group (p = 0.001), but not between the PD+FOG and PD-FOG groups (p = 0.059). CONCLUSIONS: These findings provide evidence that increased muscle activity during REM sleep is a comorbid feature of patients with PD who exhibit FOG as a motor manifestation of their disease.

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New article published on Parkinson’s disease, atypical parkinsonism, and essential tremor

Mov Disord. 2013 May 14. doi: 10.1002/mds.25491. [Epub ahead of print]
Diffusion tensor imaging of Parkinson’s disease, atypical parkinsonism, and essential tremor.
Prodoehl J, Li H, Planetta PJ, Goetz CG, Shannon KM, Tangonan R, Comella CL, Simuni T, Zhou XJ, Leurgans S, Corcos DM, Vaillancourt DE.

Diffusion tensor imaging could be useful in characterizing movement disorders because it noninvasively examines multiple brain regions simultaneously. We report a multitarget imaging approach focused on the basal ganglia and cerebellum in Parkinson’s disease, parkinsonian variant of multiple system atrophy, progressive supranuclear palsy, and essential tremor and in healthy controls. Seventy-two subjects were studied with a diffusion tensor imaging protocol at 3 Tesla. Receiver operating characteristic analysis was performed to directly compare groups. Sensitivity and specificity values were quantified for control versus movement disorder (92% sensitivity, 88% specificity), control versus parkinsonism (93% sensitivity, 91% specificity), Parkinson’s disease versus atypical parkinsonism (90% sensitivity, 100% specificity), Parkinson’s disease versus multiple system atrophy (94% sensitivity, 100% specificity), Parkinson’s disease versus progressive supranuclear palsy (87% sensitivity, 100% specificity), multiple system atrophy versus progressive supranuclear palsy (90% sensitivity, 100% specificity), and Parkinson’s disease versus essential tremor (92% sensitivity, 87% specificity). The brain targets varied for each comparison, but the substantia nigra, putamen, caudate, and middle cerebellar peduncle were the most frequently selected brain regions across classifications. These results indicate that using diffusion tensor imaging of the basal ganglia and cerebellum accurately classifies subjects diagnosed with Parkinson’s disease, atypical parkinsonism, and essential tremor and clearly distinguishes them from control subjects. © 2013 Movement Disorder Society.

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