Action reprogramming in Parkinson's disease: response to prediction error is modulated by levels of dopamine.

Humans are able to use knowledge of previous events to estimate the probability of future actions. Consequently, an unexpected event will elicit a prediction error as the prepared action has to be replaced by an unprepared option in a process known as "action reprogramming" (AR). Here we show that people with Parkinson's disease (PD) have a dopamine-sensitive deficit in AR that is proportional to the size of the prediction error. Participants performed a probabilistic reaction time (RT) task in the context of either a predictable or unpredictable environment. For an overall predictable sequence, PD patients, on and off dopamine medication, and healthy controls showed similar improvements in RT. However, in the context of a generally predictable sequence, PD patients off medication were impaired in reacting to unexpected events that elicit large prediction errors and require AR. Critically, this deficit in AR was modulated by the prediction error associated with the upcoming event. The prolongation of RT was not observed during an overall unpredictable sequence, in which relatively unexpected events evoke little prediction error and the requirement for AR should be minimal, given the context. The data are compatible with recent theoretical accounts suggesting that levels of dopamine encode the reliability, i.e., precision, of sensory information. In this scheme, PD patients off medication have low dopamine levels and may therefore be less confident about incoming sensory information and more reliant on top-down predictions. Consequently, when these internal predictions are incorrect, PD patients take longer to respond appropriately to unexpected sensory information.

Subthalamic nucleus gamma oscillations mediate a switch from automatic to controlled processing: a study of random number generation in Parkinson's disease.

In paced random number generation (RNG) participants are asked to generate numbers between 1 and 9 in a random fashion, in synchrony with a pacing stimulus. Successful task performance can be achieved through control of the main biases known to exist in human RNG compared to a computer generated series: seriation, cycling through a set of available numbers, and repetition avoidance. A role in response inhibition and switching from automatic to controlled processing has previously been ascribed to the subthalamic nucleus (STN). We sought evidence of frequency-specific changes in STN oscillatory activity which could be directly related to use of such strategies during RNG. Local field potentials (LFPs) were recorded from depth electrodes implanted in the STN of 7 patients (14 sides) with Parkinson's disease (PD), when patients were on dopaminergic medication. Patients were instructed to (1) generate a series of 100 numbers between 1 and 9 in a random fashion, and (2) undertake a control serial counting task, both in synchrony with a 0.5 Hz pacing stimulus. Significant increases in LFP power (p ≤ 0.05) across a narrow gamma frequency band (45-60 Hz) during RNG, compared to the control counting task, were observed. Further, the number of 'repeated pairs' (a decline in which reflects repetition avoidance bias in human RNG) was positively correlated with these gamma increases. We therefore suggest that STN gamma activity is relevant for controlled processing, in particular the active selection and repetition of the same number on successive trials. These results are consistent with a frequency-specific role of the STN in executive processes such as suppression of habitual responses and 'switching-on' of more controlled processing strategies.

Implementing Remote Memory Clinics to Enhance Clinical Care During and After COVID-19.

Social isolation is likely to be recommended for older adults due to COVID-19, with ongoing reduced clinical contact suggested for this population. This has increased the need for remote memory clinics, we therefore review the literature, current practices and guidelines on organizing such remote memory clinics, focusing on assessment of cognition, function and other relevant measurements, proposing a novel pathway based on three levels of complexity: simple telephone or video-based interviews and testing using available tests (Level 1), digitized and validated methods based on standard pen-and-paper tests and scales (Level 2), and finally fully digitized cognitive batteries and remote measurement technologies (RMTs, Level 3). Pros and cons of these strategies are discussed. Remotely collected data negates the need for frail patients or carers to commute to clinic and offers valuable insights into progression over time, as well as treatment responses to therapeutic interventions, providing a more realistic and contextualized environment for data-collection. Notwithstanding several challenges related to internet access, computer skills, limited evidence base and regulatory and data protection issues, digital biomarkers collected remotely have significant potential for diagnosis and symptom management in older adults and we propose a framework and pathway for how technologies can be implemented to support remote memory clinics. These platforms are also well-placed for administration of digital cognitive training and other interventions. The individual, societal and public/private costs of COVID-19 are high and will continue to rise for some time but the challenges the pandemic has placed on memory services also provides an opportunity to embrace novel approaches. Remote memory clinics' financial, logistical, clinical and practical benefits have been highlighted by COVID-19, supporting their use to not only be maintained when social distancing legislation is lifted but to be devoted extra resources and attention to fully potentiate this valuable arm of clinical assessment and care.

Bilateral nucleus basalis of Meynert deep brain stimulation for dementia with Lewy bodies: A randomised clinical trial.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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. TRIAL REGISTRATION NUMBER: NCT02263937.

Globus pallidal deep brain stimulation for Tourette syndrome: Effects on cognitive function.

INTRODUCTION: In a double-blind randomized crossover trial, we previously established that bilateral deep brain stimulation of the anteromedial globus pallidus internus (GPiam-DBS) is effective in significantly reducing tic severity in patients with refractory Tourette syndrome (TS). Here, we report the effects of bilateral GPiam-DBS on cognitive function in 11 of the 13 patients who had participated in our double-blind cross-over trial of GPi-DBS. METHODS: Patients were assessed at baseline (4 weeks prior to surgery) and at the end of each of the three-month blinded periods, with stimulation either ON or OFF. The patients were evaluated on tests of memory (California Verbal Learning Test-II (CVLT-II); Corsi blocks; Short Recognition Memory for Faces), executive function (D-KEFS Stroop color-word interference, verbal fluency, Trail-making test, Hayling Sentence Completion test), and attention (Paced Auditory Serial Addition Test, Numbers and Letters Test). RESULTS: GPiam-DBS did not produce any significant change in global cognition. Relative to pre-operative baseline assessment verbal episodic memory on the CVLT-II and set-shifting on the Trail-making Test were improved with DBS OFF. Performance on the cognitive tests were not different with DBS ON versus DBS OFF. GPiam-DBS did not alter aspects of cognition that are impaired in TS such as inhibition on the Stroop interference task or the Hayling Sentence Completion test. CONCLUSIONS: This study extends previous findings providing data showing that GPiam-DBS does not adversely affect cognitive domains such as memory, executive function, verbal fluency, attention, psychomotor speed, and information processing. These results indicate that GPiam-DBS does not produce any cognitive deficits in TS.

Patients with Parkinson's disease learn to control complex systems via procedural as well as non-procedural learning.

The striatum is considered to mediate some forms of procedural learning. Complex dynamic control (CDC) tasks involve an individual having to make a series of sequential decisions to achieve a specific outcome (e.g. learning to operate and control a car), and they involve procedural learning. The aim of this study was to test the hypothesis that patients with Parkinson's disease who have striatal dysfunction, are impaired on CDC tasks only when learning involves procedural learning. 26 patients with Parkinson's disease (PD) and 26 age-matched controls performed two CDC tasks, one in which training was observation-based (non-procedural), and a second in which training was action-based (procedural). Both groups were able to control the system to a specific criterion equally well, regardless of the training condition. However, when reporting their knowledge of the underlying structure of the system, both groups showed poorer accuracy when learning took place through observation-based compared with action-based training. Moreover, the controls' accuracy in reporting the underlying structure of the systems was superior to that of PD patients. The findings suggest that the striatal dysfunction in Parkinson's disease is not associated with impairment of procedural learning, regardless of whether the task involved procedural learning or not. It is possible that the learning and performance on CDC tasks are mediated by perceptual priming mechanisms in the neocortex.

Bilateral Deep Brain Stimulation of the Nucleus Basalis of Meynert for Parkinson Disease Dementia: A Randomized Clinical Trial.

Importance: Deep brain stimulation of the nucleus basalis of Meynert (NBM DBS) has been proposed as a treatment option for Parkinson disease dementia. Objective: To evaluate the safety and potential symptomatic effects of NBM DBS in patients with Parkinson disease dementia. Design, Setting, and Participants: A randomized, double-blind, crossover clinical trial evaluated the results of 6 patients with Parkinson disease dementia who were treated with NBM DBS at a neurosurgical referral center in the United Kingdom from October 26, 2012, to July 31, 2015. Eligible patients met the diagnostic criteria for Parkinson disease dementia, had motor fluctuations, were appropriate surgical candidates aside from the coexistence of dementia, were age 35 to 80 years, were able to give informed consent, had a Mini-Mental State Examination score of 21 to 26, had minimal atrophy seen on results of brain magnetic resonance imaging, and lived at home with a caregiver-informant. Interventions: After surgery, patients were assigned to receive either active stimulation (bilateral, low-frequency [20 Hz] NBM DBS) or sham stimulation for 6 weeks, followed by the opposite condition for 6 weeks. Main Outcomes and Measures: The primary outcome was the difference in scores on each item of an abbreviated cognitive battery (California Verbal Learning Test-II, Wechsler Adult Intelligence Scale-III digit span, verbal fluency, Posner covert attention test, and simple and choice reaction times) between the 2 conditions. Secondary outcomes were exploratory and included differences in scores on standardized measurements of cognitive, psychiatric, and motor symptoms and resting state functional magnetic resonance imaging. Results: Surgery and stimulation were well tolerated by all 6 patients (all men; mean [SD] age, 65.2 [10.7] years), with no serious adverse events during the trial. No consistent improvements were observed in the primary cognitive outcomes or in results of resting state functional magnetic resonance imaging. An improvement in scores on the Neuropsychiatric Inventory was observed with NBM DBS (8.5 points [range, 4-26 points]) compared with sham stimulation (12 points [range, 8-38 points]; median difference, 5 points; 95% CI, 2.5-8.5 points; P = .03) and the preoperative baseline (13 points [range, 5-25 points]; median difference, 2 points; 95% CI, -8 to 5.5 points; P = .69). Conclusions and Relevance: Low-frequency NBM DBS was safely conducted in patients with Parkinson disease dementia; however, no improvements were observed in the primary cognitive outcomes. Further studies may be warranted to explore its potential to improve troublesome neuropsychiatric symptoms. Trial Registration: clinicaltrials.gov Identifier: NCT01701544.

Infraorbital Nerve Decompression for Infraorbital Neuralgia/Causalgia following Blowout Orbital Fractures: A Case Series.

The purpose of this study was to present the management of a series of patients referred with infraorbital nerve paraesthesia that developed after insignificant orbital floor fracture without diplopia or exophthalmos, and that did not require initial surgical repair. This is a retrospective interventional case series. The main outcome and measures were assessment of preoperative symptoms including neuralgia and sensory symptoms; review of periorbital computed tomography (CT) scans; and assessment of postoperative effects of surgery for infraorbital nerve decompression. Nine patients were identified who developed neuralgia affecting the infraorbital nerve distribution from a cohort of 79 patients who presented with orbital floor fracture. Six were female and three were male. Age range was 22 to 73 years with a mean of 48 years. Six patients were clinically depressed due to the chronic pain. In addition, two patients had dizziness on upgaze; one patient had blurring of central vision on eye movements; and one patient had mood swings. Reviews of CT scans revealed subtle disruption of the infraorbital canal in all cases. All nine patients underwent infraorbital nerve decompression. Abnormal adhesions between the nerve and its bony canal were found in five of nine cases. Follow-up ranged from 3 to 37 months (mean: 18 months). Following surgery, after a variable period of time ranging from 1 day to 3 months, all patients had resolution of their symptoms. Mean follow-up was 18 months. Reconstructive surgeons should be aware that infraorbital nerve neuralgia, secondary to disruption of the nerve in the distorted bony canal, may be another indication for surgical intervention following orbital floor trauma in selected cases, in addition to more traditionally accepted indications. Neuralgia and causalgia are probably more common than previously thought and symptoms should be actively sought in the patient's history or else risk being overlooked and inappropriately managed. Long-term follow-up of such patients is unlikely to be practical. Patient and/or family practitioner education of possible sequelae may be one possible solution to detect this type of problem early. Nerve decompression, where indicated, may improve the patient's neuralgia and associated behavioral changes and quality of life. An optimal diagnostic and management algorithm is yet to be established.

Bilateral globus pallidus stimulation for severe Tourette's syndrome: a double-blind, randomised crossover trial.

BACKGROUND: Deep brain stimulation (DBS) has been proposed as a treatment option for severe Tourette's syndrome on the basis of findings from open-label series and small double-blind trials. We aimed to further assess the safety and efficacy of bilateral globus pallidus internus (GPi) DBS in patient's with severe Tourette's syndrome. METHODS: In a randomised, double-blind, crossover trial, we recruited eligible patients (severe medically refractory Tourette's syndrome, age ≥20 years) from two clinics for tertiary movement disorders in the UK. Enrolled patients received surgery for GPi DBS and then were randomly assigned in a 1:1 ratio (computer-generated pairwise randomisation according to order of enrolment) to receive either stimulation on-first or stimulation off-first for 3 months, followed by a switch to the opposite condition for a further 3 month period. Patients and rating clinicians were masked to treatment allocation; an unmasked clinician was responsible for programming the stimulation. The primary endpoint was difference in Yale Global Tic Severity Scale (YGTSS) total score between the two blinded conditions, assessed with repeated measures ANOVA, in all patients who completed assessments during both blinded periods. After the end of the blinded crossover phase, all patients were offered continued DBS and continued to have open-label stimulation adjustments and objective assessments of tic severity until database lock 1 month after the final patient's final trial-related visit. This trial is registered with ClinicalTrials.gov, number NCT01647269. FINDINGS: Between Nov 5, 2009, and Oct 16, 2013, we enrolled 15 patients (11 men, four women; mean age 34·7 years [SD 10·0]). 14 patients were randomly assigned and 13 completed assessments in both blinded periods (seven in the on-first group, six in the off-first group). Mean YGTSS total score in these 13 patients was 87·9 (SD 9·2) at baseline, 80·7 (SD 12·0) for the off-stimulation period, and 68·3 (SD 18·6) for the on-stimulation period. Pairwise comparisons in YGTSS total scores after Bonferroni correction were significantly lower at the end of the on-stimulation period compared with the off-stimulation period, with a mean improvement of 12·4 points (95% CI 0·1-24·7, p=0·048), equivalent to a difference of 15·3% (95% CI 5·3-25·3). All 15 patients received stimulation in the open-label phase. Overall, three serious adverse events occurred (two infections in DBS hardware at 2 and 7 weeks postoperatively, and one episode of deep-brain-stimulation-induced hypomania during the blinded on-stimulation period); all three resolved with treatment. INTERPRETATION: GPi stimulation led to a significant improvement in tic severity, with an overall acceptable safety profile. Future research should concentrate on identifying the most effective target for DBS to control both tics and associated comorbidities, and further clarify factors that predict individual patient response. FUNDING: UK National Health Service.

Pallidal stimulation for primary generalised dystonia: effect on cognition, mood and quality of life.

We investigated the effect of pallidal deep brain stimulation (GPi-DBS) in dystonia on cognition, mood, and quality of life and also assessed if DYT1 gene status influenced cognitive outcome following GPi-DBS. Fourteen patients with primary generalized dystonia (PGD) were assessed, measuring their estimated premorbid and current IQ, memory for words and faces, and working memory, language, executive function, and sustained attention, one month before and one year or more after surgery. Changes in mood and behaviour and quality of life were also assessed. There was a significant improvement of dystonia with GPi-DBS (69 % improvement in Burke-Fahn-Marsden score, p < 0.0001). Performance on five cognitive tests either improved or declined at post-surgical follow-up. Calculation of a reliable change index suggested that deterioration in sustained attention on the PASAT was the only reliable change (worse after surgery) in cognition with GPi-DBS. DYT1 gene status did not influence cognitive outcome following GPi-DBS. Depression, anxiety and apathy were not significantly altered, and ratings of health status on the EQ5D remained unchanged. In our sample, GPi-DBS was only associated with an isolated deficit on a test of sustained attention, confirming that GPi-DBS in PGD is clinically effective and safe, without adverse effects on the main domains of cognitive function. The dissociation between GPi-DBS improving dystonia, but not having a significant positive impact on the patients' QoL, warrants further investigation.

Deep brain stimulation of the subthalamic nucleus selectively improves learning of weakly associated cue combinations during probabilistic classification learning in Parkinson's disease.

OBJECTIVE: Evidence from functional imaging and clinical studies on patients with Parkinson's disease (PD) or Huntington's disease (HD) suggests that the basal ganglia play a crucial role in learning on the weather prediction task (WPT). Using deep brain stimulation (DBS) on versus off methodology, the aim of this study was to investigate the effect of altering the output from the basal ganglia to the prefrontal cortex on implicit probabilistic classification learning on the WPT by patients with PD. METHOD: Eleven PD patients with bilateral DBS of the subthalamic nucleus (STN) and 13 matched controls completed 200 trials of the WPT on 2 separate occasions, with the patients tested with DBS of the STN on or off. RESULTS: DBS of the STN had no effect on overall WPT learning. However, STN DBS selectively improved implicit learning of cue combinations that were weakly (implicitly), rather than strongly (explicitly), associated with the WPT outcome. CONCLUSIONS: Results suggest that the STN plays a role in implicit probabilistic classification learning by altering basal ganglia output to the frontal cortex.

A gamma band specific role of the subthalamic nucleus in switching during verbal fluency tasks in Parkinson's disease.

OBJECTIVE: Decline in verbal fluency is the most consistent and persistent cognitive impairment documented after deep brain stimulation of the subthalamic nucleus in Parkinson's disease. The mechanisms of this deficit are unclear. We aimed to identify and characterise verbal fluency related processing within the subthalamic nucleus through analysis of local field potentials. METHODS: Local field potentials were recorded from deep brain stimulation electrodes implanted in the subthalamic nuclei of 8 patients (16 sides) with Parkinson's disease, when patients were on medication. Patients performed phonemic and semantic verbal fluency tasks and a control word repetition task to control for the motor output involved in response generation. RESULTS: Significant increases in local field potential Power (p ≤ 0.05) were seen across a broad gamma frequency band (30-95 Hz) during both verbal fluency tasks, after controlling for motor output. Increases in gamma local field potential Power of +7.5% ± 2.3% (SEM) in the semantic fluency task and +6.9% ± 2.0% in the phonemic fluency task were derived when averaging across all electrode contact pairs. Gamma changes recorded from contacts lying in the left hemisphere (dominant in verbal fluency) correlated with average number of correct responses generated (r=0.81 p=0.015) and measures of 'switching' (r=0.79 p=0.020) particularly strongly in the semantic fluency task. INTERPRETATION: Frequency specific power changes observed during task performance are consistent with involvement of the subthalamic nucleus in switching during verbal fluency. Antagonism of such task-related activity with high frequency stimulation of this nucleus may explain the impairments reported.

Effects of dopamine medication on sequence learning with stochastic feedback in Parkinson's disease.

A growing body of evidence suggests that the midbrain dopamine system plays a key role in reinforcement learning and disruption of the midbrain dopamine system in Parkinson's disease (PD) may lead to deficits on tasks that require learning from feedback. We examined how changes in dopamine levels ("ON" and "OFF" their dopamine medication) affect sequence learning from stochastic positive and negative feedback using Bayesian reinforcement learning models. We found deficits in sequence learning in patients with PD when they were "ON" and "OFF" medication relative to healthy controls, but smaller differences between patients "OFF" and "ON". The deficits were mainly due to decreased learning from positive feedback, although across all participant groups learning was more strongly associated with positive than negative feedback in our task. The learning in our task is likely mediated by the relatively depleted dorsal striatum and not the relatively intact ventral striatum. Therefore, the changes we see in our task may be due to a strong loss of phasic dopamine signals in the dorsal striatum in PD.