Subthalamic functional connectivity associated with freezing of gait dopa-response.

INTRODUCTION: Freezing of gait (FOG) is a prevalent and debilitating feature of Parkinson's Disease (PD). The subthalamic nucleus (STN) is a center for controlled locomotion and a common DBS target. The objective of this study was to identify STN circuitry associated with FOG response to dopaminergic medication. In this study, we compare BOLD functional connectivity of the subthalamic nucleus (STN) in participants with and without dopa-responsive FOG. METHODS: 55 PD participants either with FOG (n = 38) or without FOG (n = 17) were recruited. Among FOG participants 22 were dopa-responsive and 16 were dopa-unresponsive. STN whole-brain connectivity was performed using CONN toolbox. The relationship between the degree of self-reported FOG dopa-response and STN connectivity was evaluated using partial correlations corrected for age, disease duration, and levodopa equivalent daily dose. RESULTS: Right STN connectivity with the cerebellar locomotor region and the temporal/occipital cortex was greater in the dopa-responsive FOG group (voxel threshold p < 0.01, FWE corrected p < 0.05). Left STN connectivity with the occipital cortex was greater in the dopa-responsive FOG group and connectivity with the postcentral gyrus was greater in the dopa-unresponsive FOG group. Strength of connectivity to these regions correlated with l-dopa induced improvement in UPDRS Item-14 (FOG), but not UPDRS Part-III (overall motor score). DISCUSSION: We demonstrate that dopa-unresponsive FOG is associated with changes in BOLD functional connectivity between the STN and locomotor as well as sensory processing regions. This finding supports the conceptual framework that effective treatment for freezing of gait likely requires the engagement of both locomotor and sensory brain regions.

Could treatment of autonomic dysfunction in early and prodromal Parkinson's disease slow disease progression?

A recently published study by Ma et al. (Ma J, Dou K, Liu R, Liao Y, Yuan Z, Xie A. Front Aging Neurosci 14: 898149, 2022) investigated the 5-year longitudinal association between sleep disorders and depression in early and prodromal Parkinson's disease (PD). Not surprisingly, sleep disorders were associated with higher depression scores among patients with PD but, interestingly, autonomic dysfunction was revealed as a mediator between the two. This mini-review highlights these findings with an emphasis on the proposed benefit of autonomic dysfunction regulation and early intervention in prodromal PD.

Assessing combined effects of varenicline and N-acetylcysteine on reducing nicotine seeking in rats.

Nicotine addiction is a chronic relapsing brain disorder, and cigarette smoking is the leading cause of preventable death in the United States. Currently, the most effective pharmacotherapy for smoking cessation is Varenicline (VRN), which reduces both positive and negative reinforcement by nicotine. Clinically, VRN attenuates withdrawal symptoms and promotes abstinence, but >50% of smokers relapse within 3 months following a quit attempt. This may indicate that VRN fails to ameliorate components of nicotine-induced neuroplasticity that promote relapse vulnerability. Animal models reveal that glutamate dysregulation in the nucleus accumbens is associated with nicotine relapse. N-acetylcysteine (NAC) normalizes glutamate transmission and prolongs cocaine abstinence. Thus, combining VRN and NAC may promote and maintain, respectively, nicotine abstinence. In rats, we found that VRN effectively reduced nicotine self-administration and seeking in early abstinence, but not seeking later in abstinence. In contrast, NAC reduced seeking only later in abstinence. Because VRN and NAC are sometimes associated with mild adverse effects, we also evaluated a sequential approach combining subthreshold doses of VRN during self-administration and early abstinence with subthreshold doses of NAC during late abstinence. As expected, subthreshold VRN did not reduce nicotine intake. However, subthreshold VRN and NAC reduced seeking in late abstinence, suggesting a combined effect. Overall, our results suggest that combining subthreshold VRN and NAC is a viable and drug-specific approach to promote abstinence and reduce relapse while minimizing adverse effects. Our data also suggest that different components and time points in addiction engage the different neurocircuits targeted by VRN and NAC.

Paired inhibitory stimulation and gait training modulates supplemental motor area connectivity in freezing of gait.

INTRODUCTION: Freezing of gait (FOG) is a debilitating feature of Parkinson's disease (PD). Evidence suggests patients with FOG have increased cortical control of gait. The supplementary motor area (SMA) may be a key structure due to its connectivity with locomotor and cognitive networks. The objectives of this study were to determine (1) if SMA connectivity is disrupted in patients with FOG and (2) if "inhibitory" repetitive transcranial magnetic stimulation can decrease maladaptive SMA connectivity. METHODS: Two experiments were performed. In experiment 1 resting-state (T2* BOLD imaging) was compared between 38 PD freezers and 17 PD controls. In experiment 2, twenty PD patients with FOG were randomized to either 10 sessions of real or sham rTMS to the SMA (1 Hz, 110% motor threshold, 1200 pulses/session) combined with daily gait training. RESULTS: (Experiment 1) Freezers had increased connectivity between the left SMA and the vermis of the cerebellum and decreased connectivity between the SMA and the orbitofrontal cortex (pFDR-corr <0.05). (Experiment 2) 10 sessions of active TMS reduced SMA connectivity with the anterior cingulate, angular gyrus and the medial temporal cortex, whereas sham TMS did not reduce SMA connectivity. From a behavioral perspective, both groups showed nFOG-Q improvements (F(4, 25.7) = 3.87, p = 0.014). CONCLUSIONS: The SMA in freezers is hyper-connected to the cerebellum, a key locomotor region which may represent maladaptive compensation. In this preliminary study, 1 Hz rTMS reduced SMA connectivity however, this was not specific to the locomotor regions. Intervention outcomes may be improved with subject specific targeting of SMA.

Determining the optimal pulse number for theta burst induced change in cortical excitability.

Theta-burst stimulation (TBS) is a form of non-invasive neuromodulation which is delivered in an intermittent (iTBS) or continuous (cTBS) manner. Although 600 pulses is the most common dose, the goal of these experiments was to evaluate the effect of higher per-dose pulse numbers on cortical excitability. Sixty individuals were recruited for 2 experiments. In Experiment 1, participants received 600, 1200, 1800, or sham (600) iTBS (4 visits, counterbalanced, left motor cortex, 80% active threshold). In Experiment 2, participants received 600, 1200, 1800, 3600, or sham (600) cTBS (5 visits, counterbalanced). Motor evoked potentials (MEP) were measured in 10-min increments for 60 min. For iTBS, there was a significant interaction between dose and time (F = 3.8296, p = 0.01), driven by iTBS (1200) which decreased excitability for up to 50 min (t = 3.1267, p = 0.001). For cTBS, there was no overall interaction between dose and time (F = 1.1513, p = 0.33). Relative to sham, cTBS (3600) increased excitability for up to 60 min (t = 2.0880, p = 0.04). There were no other significant effects of dose relative to sham in either experiment. Secondary analyses revealed high within and between subject variability. These results suggest that iTBS (1200) and cTBS (3600) are, respectively, the most effective doses for decreasing and increasing cortical excitability.

Evaluating a novel MR-compatible foot pedal device for unipedal and bipedal motion: Test-retest reliability of evoked brain activity.

The purpose of this study was to develop and evaluate a new, open-source MR-compatible device capable of assessing unipedal and bipedal lower extremity movement with minimal head motion and high test-retest reliability. To evaluate the prototype, 20 healthy adults participated in two magnetic resonance imaging (MRI) visits, separated by 2-6 months, in which they performed a visually guided dorsiflexion/plantar flexion task with their left foot, right foot, and alternating feet. Dependent measures included: evoked blood oxygen level-dependent (BOLD) signal in the motor network, head movement associated with dorsiflexion/plantar flexion, the test-retest reliability of these measurements. Left and right unipedal movement led to a significant increase in BOLD signal compared to rest in the medial portion of the right and left primary motor cortex (respectively), and the ipsilateral cerebellum (FWE corrected, p < .001). Average head motion was 0.10 ± 0.02 mm. The test-retest reliability was high for the functional MRI data (intraclass correlation coefficients [ICCs]: >0.75) and the angular displacement of the ankle joint (ICC: 0.842). This bipedal device can robustly isolate activity in the motor network during alternating plantarflexion and dorsiflexion with minimal head movement, while providing high test-retest reliability. Ultimately, these data and open-source building instructions will provide a new, economical tool for investigators interested in evaluating brain function resulting from lower extremity movement.