Essential tremor (ET) is characterized by bilateral upper limb postural and/or kinetic tremor, but also cognitive deficits. Tremor in ET, as well as aspects of cognitive deficits associated with ET, ...have been suggested to be linked to dysfunction in the cerebello-thalamo-cerebral circuit. In ET patients with disabling and medically intractable motor symptoms, Deep Brain Stimulation (DBS) is effective in reducing tremor. DBS in the caudal Zona incerta (cZi) has been shown to modulate the activity of the sensorimotor cerebello-cerebral circuit during motor tasks. Whether the activity in the cerebello-cerebral circuit is modulated by DBS during tasks involving working memory is unknown. The present study therefore aimed to investigate the possible effects of cZi DBS on working-memory processing in ET patients by means of task-based blood oxygen level-dependent (BOLD) fMRI.
Thirteen ET patients completed a working-memory task during DBS OFF and ON conditions. The task involved three conditions: maintenance, manipulation, and control. Behaviorally, there was no significant effect from DBS on accuracy, but a marginally significant Task x DBS interaction was detected for response times (RTs). However, post hoc comparisons for each condition failed to reach statistical significance. FMRI analyses revealed that DBS did not alter BOLD signal in regions of interest (lateral prefrontal cortex, parietal cortex, and the cerebellum), or in a complementary whole-brain analysis.
The present study indicates that DBS in the cZi in patients with ET has at most marginal effects on working memory, which is consistent with the results of pre- and post-DBS neuropsychological assessment showing minimal cognitive effects of surgery.
Background. Deep brain stimulation of the subthalamic nucleus (STN-DBS) has been shown to be generally safe from a cognitive perspective, with consistent evidence that the major impact of STN-DBS in ...Parkinson’s disease (PD) is on verbal fluency. Objective. The aim of this study was first to identify the influence of acute manipulation of STN-DBS in PD on the number and time pattern of word generation on different verbal fluency (VF) tasks, phonemic, switching, and cued switching, and second to determine whether cueing improved VF and if cueing effects interacted with STN-DBS effects. Methods. Parallel versions of these three verbal fluency tasks were completed by 31 patients with Parkinson’s disease who had had bilateral DBS of the STN, twice, with DBS On and Off, with the order counterbalanced across patients. Results. There was no effect of acute STN-DBS on the total number of words generated during verbal fluency. As expected, the number of words generated significantly declined over the six 10-second intervals of the verbal fluency tasks, but this time pattern of word generation was not altered by STN-DBS. External cueing significantly increased the number of words generated relative to an uncued switching verbal fluency task, but the cueing effect on VF was not altered by STN-DBS. Conclusion. In conclusion, (i) acute STN-DBS manipulation did not alter either verbal fluency performance or the time pattern of word generation and (ii) external cueing significantly improved verbal fluency performance both with STN-DBS On and Off.
In the long-term, with progression of the illness, Parkinson's disease dementia affects up to 90% of patients with Parkinson's disease. With increasing life expectancy in western countries, ...Parkinson's disease dementia is set to become even more prevalent in the future. However, current treatments only give modest symptomatic benefit at best. New treatments are slow in development because unlike the pathological processes underlying the motor deficits of Parkinson's disease, the neural mechanisms underlying the dementing process and its associated cognitive deficits are still poorly understood. Recent insights from neuroscience research have begun to unravel the heterogeneous involvement of several distinct neural networks underlying the cognitive deficits in Parkinson's disease dementia, and their modulation by both dopaminergic and non-dopaminergic transmitter systems in the brain. In this review we collate emerging evidence regarding these distinct brain networks to give a novel perspective on the pathological mechanisms underlying Parkinson's disease dementia, and discuss how this may offer new therapeutic opportunities.
Background. Motivational improvement of movement speed in Parkinson’s disease (PD) is observed in life-threatening situations and has been empirically demonstrated in experimental studies using ...reaction time paradigms. Objectives. To address two clinically relevant questions: first, if in PD, motivational modulation through provision of monetary incentive on a sorting task that approximates performance on everyday life tasks affects movement speed. Second, how this effect is compared between PD patients treated with medication or subthalamic deep brain stimulation. Methods. We used the Card Arranging Reward Responsivity Objective Test that shares component processes with everyday life tasks to compare reward responsivity of movement speed in 10 PD patients with STN-DBS, 10 nonoperated medicated PD patients, both OFF and ON their usual medications/stimulation, and 11 age-matched healthy controls. Results. Despite longer disease duration and more severe motor symptoms, STN-DBS PD patients with the stimulator turned ON showed greater improvement of movement speed with the prospect of monetary incentive compared to both medicated PD patients and healthy participants. Discussion. The effect of monetary incentive on movement speed in PD patients is more pronounced with STN-DBS than dopaminergic medications, suggesting that motivational modulation of movement speed may be enhanced as a direct consequence of STN stimulation.
Dementia with Lewy bodies (DLB) is the second most common form of dementia. Current symptomatic treatment with medications remains inadequate. Deep brain stimulation of the nucleus basalis of Meynert ...(NBM DBS) has been proposed as a potential new treatment option in dementias.
To assess the safety and tolerability of low frequency (20 Hz) NBM DBS in DLB patients and explore its potential effects on both clinical symptoms and functional connectivity in underlying cognitive networks.
We conducted an exploratory randomised, double-blind, crossover trial of NBM DBS in six DLB patients recruited from two UK neuroscience centres. Patients were aged between 50 and 80 years, had mild-moderate dementia symptoms and were living with a carer-informant. Patients underwent image guided stereotactic implantation of bilateral DBS electrodes with the deepest contacts positioned in the Ch4i subsector of NBM. Patients were subsequently assigned to receive either active or sham stimulation for six weeks, followed by a two week washout period, then the opposite condition for six weeks. Safety and tolerability of both the surgery and stimulation were systematically evaluated throughout. Exploratory outcomes included the difference in scores on standardised measurements of cognitive, psychiatric and motor symptoms between the active and sham stimulation conditions, as well as differences in functional connectivity in discrete cognitive networks on resting state fMRI.
Surgery and stimulation were well tolerated by all six patients (five male, mean age 71.33 years). One serious adverse event occurred: one patient developed antibiotic-associated colitis, prolonging his hospital stay by two weeks. No consistent improvements were observed in exploratory clinical outcome measures, but the severity of neuropsychiatric symptoms reduced with NBM DBS in 3/5 patients. Active stimulation was associated with functional connectivity changes in both the default mode network and the frontoparietal network.
Low frequency NBM DBS can be safely conducted in DLB patients. This should encourage further exploration of the possible effects of stimulation on neuropsychiatric symptoms and corresponding changes in functional connectivity in cognitive networks.
NCT02263937.
•Novel therapeutic strategies for dementia are urgently needed.•Deep brain stimulation of the nucleus basalis of Meynert has been proposed.•This intervention was well tolerated in patients with dementia with Lewy bodies.•It may impact upon neuropsychiatric symptoms.•Stimulation possibly induced functional connectivity changes in cognitive networks.
Deep brain stimulation of the subthalamic nucleus (STN DBS) has become an accepted treatment for patients experiencing the motor complications of Parkinson's disease (PD). While its successes are ...becoming increasingly apparent, the mechanisms underlying its action remain unclear. Multiple studies using radiotracer-based imaging have investigated DBS-induced regional changes in neural activity. However, little is known about the effect of DBS on connectivity within neural networks; in other words, whether DBS impacts upon functional integration of specialized regions of cortex. In this work, we report the first findings of fMRI in 10 subjects with PD and fully implanted DBS hardware receiving efficacious stimulation. Despite the technical demands associated with the safe acquisition of fMRI data from patients with implanted hardware, robust activation changes were identified in the insula cortex and thalamus in response to therapeutic STN DBS. We then quantified the neuromodulatory effects of DBS and compared sixteen dynamic causal models of effective connectivity between the two identified nodes. Using Bayesian model comparison, we found unequivocal evidence for the modulation of extrinsic (between region), i.e. cortico-thalamic and thalamo-cortical connections. Using Bayesian model parameter averaging we found that during voluntary movements, DBS reversed the effective connectivity between regions of the cortex and thalamus. This casts the therapeutic effects of DBS in a fundamentally new light, emphasising a role in changing distributed cortico-subcortical interactions. We conclude that STN DBS does impact upon the effective connectivity between the cortex and thalamus by changing their sensitivities to extrinsic afferents. Furthermore, we confirm that fMRI is both feasible and is tolerated well by these patients provided strict safety measures are adhered to.
Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an effective treatment for Parkinson’s disease (PD). In this study, we used an interpretative phenomenological analysis to explore how ...10 male people with PD experienced life after STN-DBS surgery. Two themes emerged. The first, “Healed and relieved: all that glitters is not gold,” highlights the benefits and the personal “costs” of surgery. The second, “The change within: new interpretations of the present and future unfold,” explores how patients reinterpreted their lives as individuals and members of society in the present and as they face their future. Relief, gratitude, disappointment, and the need for social support are expressed as well as a new appraisal of values and the future. STN-DBS alters the life course of people with PD, and this study provides new insight into psychological and social issues that surgery raises for the patient and their family system. These psychosocial issues should be taken into account when preparing the patient and their family for surgery or supporting them postoperatively.
The basal ganglia and cerebellum are considered to play a role in timing, although their differential roles in timing remain unclear. It has been proposed that the timing of short milliseconds-range ...intervals involves the cerebellum, whereas longer seconds-range intervals engage the basal ganglia (Ivry, 1996). We tested this hypothesis using positron emission tomography to measure regional cerebral blood flow in eight right-handed males during estimation and reproduction of long and short intervals. Subjects performed three tasks: (1) reproduction of a short 500 ms interval, (2) reproduction of a long 2 s interval, and (3) a control simple reaction time (RT) task. We compared the two time reproduction tasks with the control RT task to investigate activity associated with temporal processing once additional cognitive, motor, or sensory processing was controlled. We found foci in the left substantia nigra and the left lateral premotor cortex to be significantly more activated in the time reproduction tasks than the control RT task. The left caudate nucleus and right cerebellum were more active in the short relative to the long interval, whereas greater activation of the right putamen and right cerebellum occurred in the long rather than the short interval. These results suggest that the basal ganglia and the cerebellum are engaged by reproduction of both long and short intervals but play different roles. The fundamental role of the substantia nigra in temporal processing is discussed in relation to previous animal lesion studies and evidence for the modulating influence of dopamine on temporal processing.
We report on the quantitative electroencephalogram (qEEG) and cognitive effects of Neuroepo in Parkinson’s disease (PD) from a double-blind safety trial (
https://clinicaltrials.gov/
, number ...NCT04110678). Neuroepo is a new erythropoietin (EPO) formulation with a low sialic acid content with satisfactory results in animal models and tolerance in healthy participants and PD patients. In this study, 26 PD patients were assigned randomly to Neuroepo (
n
= 15) or placebo (
n
= 11) groups to test the tolerance of the drug. Outcome variables were neuropsychological tests and resting-state source qEEG at baseline and 6 months after administering the drug. Probabilistic Canonical Correlation Analysis was used to extract latent variables for the cognitive and for qEEG variables that shared a common source of variance. We obtained canonical variates for Cognition and qEEG with a correlation of 0.97. Linear Mixed Model analysis showed significant positive dependence of the canonical variate cognition on the dose and the confounder educational level (
p
= 0.003 and
p
= 0.02, respectively). Additionally, in the mediation equation, we found a positive dependence of Cognition with qEEG for (
p
= < 0.0001) and with dose (
p
= 0.006). Despite the small sample, both tests were powered over 89%. A combined mediation model showed that 66% of the total effect of the cognitive improvement was mediated by qEEG (
p
= 0.0001), with the remaining direct effect between dose and Cognition (
p
= 0.002), due to other causes. These results suggest that Neuroepo has a positive influence on Cognition in PD patients and that a large portion of this effect is mediated by brain mechanisms reflected in qEEG.
Recent imaging studies with the stop-signal task in healthy individuals indicate that the subthalamic nucleus, the pre-supplementary motor area and the inferior frontal gyrus are key components of ...the right hemisphere “inhibitory network”. Limited information is available regarding neural substrates of inhibitory processing in patients with asymmetric Parkinson’s disease. The aim of the current fMRI study was to identify the neural changes underlying deficient inhibitory processing on the stop-signal task in patients with predominantly left-sided Parkinson’s disease. Fourteen patients and 23 healthy controls performed a stop-signal task with the left and right hands. Behaviorally, patients showed delayed response inhibition with either hand compared to controls. We found small imaging differences for the right hand, however for the more affected left hand when behavior was successfully inhibited we found reduced activation of the inferior frontal gyrus bilaterally and the insula. Using the stop-signal delay as regressor, contralateral underactivation in the right dorsolateral prefrontal cortex, inferior frontal and anterior putamen were found in patients. This finding indicates dysfunction of the right inhibitory network in left-sided Parkinson’s disease. Functional connectivity analysis of the left subthalamic nucleus showed a significant increase of connectivity with bilateral insula. In contrast, the right subthalamic nucleus showed increased connectivity with visuomotor and sensorimotor regions of the cerebellum. We conclude that altered inhibitory control in left-sided Parkinson’s disease is associated with reduced activation in regions dedicated to inhibition in healthy controls, which requires engagement of additional regions, not observed in controls, to successfully stop ongoing actions.
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