There is a clear need to develop non-invasive markers of substantia nigra progression in Parkinson’s disease. We previously found elevated free-water levels in the substantia nigra for patients with Parkinson’s disease compared with controls in single-site and multi-site cohorts. Here, we test the hypotheses that free-water levels in the substantia nigra of Parkinson’s disease increase following 1 year of progression, and that baseline free-water levels in the substantia nigra predict the change in bradykinesia following 1 year. We conducted a longitudinal study in controls (n = 19) and patients with Parkinson’s disease (n = 25). Diffusion imaging and clinical data were collected at baseline and after 1 year. Free-water analyses were performed on diffusion imaging data using blinded, hand-drawn regions of interest in the posterior substantia nigra. A group effect indicated free-water values were increased in the posterior substantia nigra of patients with Parkinson’s disease compared with controls (P = 0.003) and we observed a significant group × time interaction (P < 0.05). Free-water values increased for the Parkinson's disease group after 1 year (P = 0.006), whereas control free-water values did not change. Baseline free-water values predicted the 1 year change in bradykinesia scores (r = 0.74, P < 0.001) and 1 year change in Montreal Cognitive Assessment scores (r = -0.44, P = 0.03). Free-water in the posterior substantia nigra is elevated in Parkinson's disease, increases with progression of Parkinson's disease, and predicts subsequent changes in bradykinesia and cognitive status over 1 year. These findings demonstrate that free-water provides a potential non-invasive progression marker of the substantia nigra.
Longitudinal Changes in SN 2015
Precise motor control requires the ability to scale the parameters of movement. Theta oscillations across the cortex have been associated with changes in memory, attention, and sensorimotor processing. What has proven more elusive is pinpointing the region-specific frequency band oscillations that are associated with specific parameters of movement during the acceleration and deceleration phases. We report a study using 3D analytic techniques for high density electroencephalography that examines electrocortical dynamics while participants produce upper limb movements to different distances at varying rates. During fast ballistic movements, we observed increased theta band activity in the left motor area contralateral to the moving limb during the acceleration phase of the movement, and theta power correlated with the acceleration of movement. In contrast, beta band activity scaled with the type of movement during the deceleration phase near the end of the movement and correlated with movement time. In the ipsilateral motor and somatosensory area, alpha band activity decreased with the type of movement near the end of the movement, and gamma band activity in visual cortex increased with the type of movement near the end of the movement. Our results suggest that humans use distinct lateralized cortical activity for distance and speed dependent arm movements. We provide new evidence that a temporary increase in theta band power relates to movement acceleration and is important during movement execution. Further, the theta power increase is coupled with desychronization of beta band power and alpha band power which are modulated by the task near the end of movement.
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Parkinson’s disease (PD) and the parkinsonian variant of multiple system atrophy (MSAp) are neurodegenerative disorders that can be difficult to differentiate clinically. This study provides the first characterization of the patterns of task-related functional magnetic resonance imaging (fMRI) changes across the whole brain in MSAp. We used fMRI during a precision grip force task and also performed voxel-based morphometry (VBM) on T1-weighted images in MSAp patients, PD patients, and healthy controls. All groups were matched on age, and the patient groups had comparable motor symptom durations and severities. There were three main findings. First, MSAp and PD had reduced fMRI activation in motor control areas, including the basal ganglia, thalamus, insula, primary sensorimotor and prefrontal cortices, and cerebellum compared with controls. Second, there were no activation differences among the disease groups in the basal ganglia, thalamus, insula, or primary sensorimotor cortices, but PD had more extensive activation deficits throughout the cerebrum compared with MSAp and controls. Third, VBM revealed reduced volume in the basal ganglia, middle and inferior cerebellar peduncles, pons, and throughout the cerebrum in MSAp compared with controls and PD, and additionally throughout the cerebellar cortex and vermis in MSAp compared with controls. Collectively, these results provide the first evidence that fMRI activation is abnormal in the basal ganglia, cerebellum, and cerebrum in MSAp, and that a key distinguishing feature between MSAp and PD is the extensive and widespread volume loss throughout the brain in MSAp.
Link to article: http://onlinelibrary.wiley.com/doi/10.1002/hbm.22694/abstract
Measures from diffusion magnetic resonance imaging reflect changes in the substantia nigra of Parkinson’s disease. It is the case, however, that partial volume effects from free-water can bias diffusion measurements. The bi-tensor diffusion model was introduced to quantify the contribution of free-water and eliminates its bias on estimations of tissue microstructure. Here, we test the hypothesis that free-water is elevated in the substantia nigra for Parkinson’s disease compared with controls. This hypothesis was tested between large cohorts of Parkinson’s disease and control participants in a single-site study, and validated against a multi-site study using multiple scanners. The fractional volume of free-water was increased in the posterior region of the substantia nigra in Parkinson’s disease compared with controls in both the single-site and multi-site studies. We did not observe changes in either cohort for free-water corrected fractional anisotropy or free-water corrected mean diffusivity. Our findings provide new evidence that the free-water index reflects alteration of the substantia nigra in Parkinson’s disease, and this was evidenced across both single-site and multi-site cohorts.
Link to the paper is at:
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.
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.
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.
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.
Work from our laboratory was highlighted by the Dana Foundation
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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.