OBJECT:Verbal fluency (VF) is the cognitive test which shows the most consistent and persistent post-operative decline after subthalamic deep brain stimulation (STN-DBS) in Parkinson's disease (PD). However, the reasons are not completely understood, and the debate has focused on two hypotheses: a surgical effect or an acute STN-DBS effect.METHODS:We recruited 3 PD samples: (1) a group assessed before and after STN-DBS surgery (2) a group assessed On vs. Off STN-DBS and (3) an unoperated PD control group. All groups performed letter, category and switching category VF tasks. The total number of correct words generated were noted and measures of clustering and switching were also obtained.RESULTS:We found a significant effect of STN-DBS surgery on all VF tasks which was associated with a post-operative decline in the total number of words generated, and a reduction of phonemic switching during the letter and category VF tasks, and a reduction of semantic clustering for category VF. By contrast to the effects of surgery, acute On vs. Off stimulation did not influence the number of words generated on any of the VF tasks. Acute stimulation only produced two effects on the category VF task: increased semantic cluster size and decreased number of semantic switches when STN-DBS was switched On.CONCLUSIONS:This study differentiates between the effects of STN-DBS surgery and acute stimulation on VF performance. Our findings indicate that the STN-DBS effect on VF are a surgical and not an acute STN stimulation effect.

BACKGROUND:Proactive interference (PI) refers to the interference of previously learned materials with new learning and reflects the failure of inhibitory processes in memory. Retroactive interference (RI) refers to the unfavorable effect of new learning on the later recall of previously learned information. Although subthalamic nucleus deep brain stimulation (STN-DBS) does not affect global cognition in Parkinson's disease (PD), it has negative effects on specific aspects of cognition, including verbal fluency and executive inhibitory control of action.To this end, we set to test the acute effect of STN-DBS on PI and RI during verbal learning. METHODS:Twenty PD patients with STN-DBS were tested on the California Verbal Learning Test-II using an ON/OFF stimulation design. RESULTS:The results showed that stimulation increased PI ON stimulation (P = 0.012) but had no effect on RI (P = 0.816). CONCLUSIONS:Our results extend the role of STN to the inhibitory control that is required during memory encoding or recall for prevention of PI. © 2020 International Parkinson and Movement Disorder Society.

BACKGROUND:Stopping an ongoing motor response or resolving conflict induced by conflicting stimuli are associated with activation of a right-lateralized network of inferior frontal gyrus (IFG), pre-supplementary motor area (pre-SMA) and subthalamic nucleus (STN). However, the roles of the right IFG and pre-SMA in stopping a movement and in conflict resolution remain unclear. We used continuous theta burst stimulation (cTBS) to examine the involvement of the right IFG and pre-SMA in inhibition and conflict resolution using the conditional stop signal task.METHODS:We measured stop signal reaction time (SSRT, measure of reactive inhibition), response delay effect (RDE, measure of proactive action restraint) and conflict induced slowing (CIS, measure of conflict resolution).RESULTS:Stimulation over the pre-SMA resulted in significantly shorter SSRTs (improved inhibition) compared to sham cTBS. This effect was not observed for CIS, RDE, or any other measures. cTBS over the right IFG had no effect on SSRT, CIS, RDE or on any other measure.CONCLUSIONS:The improvement of SSRT with cTBS over the pre-SMA suggests its critical contribution to stopping ongoing movements.

Inhibitory repetitive transcranial magnetic stimulation (rTMS) of the primary motor area (M1) impairs motor sequence-learning, but not basic motor function. It is unknown if this is specific for motor forms of procedural learning or a more general effect. To investigate, we tested the effect of M1-inhibition on the weather prediction task (WPT), a learning task with minimal motor learning component. In the WPT, participants learn arbitrary, probabilistic, associations between sets of meaningless cues and fictional outcomes. In our "Feedback" (FB) condition, they received monetary rewards/punishments during learning. In the "paired associate" (PA) condition they learned the same information by passive observation of associations. The observational and feedback learning conditions were matched for their non-learning-specific motor demands. In each of two FB or PA sessions, we delivered Real (inhibitory) or Sham continuous theta-burst (cTBS) to the left-M1, before 150 training-trials. We then tested learning with 42 trials without feedback immediately after learning and again 1-h after cTBS. Compared to Sham, Real cTBS reduced performance during FB-learning, when learning was immediately reinforced, but not when knowledge was tested after PA learning. Furthermore, when FB-based memory was tested after learning without immediate incentive, there was no effect of TMS compared to post-PA test performance, showing the TMS effect operated only in the presence of incentive and feedback. We conclude that M1 is a node in a network underlying feedback-driven procedural learning and inhibitory rTMS there results in decreased network efficiency.

Empirical evidence suggests that levodopa medication used to treat the motor symptoms of Parkinson's disease (PD) may either improve, impair or not affect specific cognitive processes. This evidence led to the 'dopamine overdose' hypothesis that levodopa medication impairs performance on cognitive tasks if they recruit fronto-striatal circuits which are not yet dopamine-depleted in early PD and as a result the medication leads to an excess of dopamine. This hypothesis has been supported for various learning tasks including conditional associative learning, reversal learning, classification learning and intentional deterministic sequence learning, on all of which PD patients demonstrated significantly worse performance when tested on relative to off dopamine medication. Incidental sequence learning is impaired in PD, but how such learning is affected by dopaminergic therapy remains undetermined. The aim of the current study was to investigate the effect of dopaminergic medication on incidental sequence learning in PD. We used a probabilistic serial reaction time task (SRTT), a sequence learning paradigm considered to make the sequence less apparent and more likely to be learned incidentally rather than intentionally. We compared learning by the same group of PD patients (n=15) on two separate occasions following oral administration of levodopa medication (on state) and after overnight withdrawal of medication (off state). Our results demonstrate for the first time that levodopa medication enhances incidental learning of a probabilistic sequence on the serial reaction time task in PD. However, neither group significantly differed from performance of a control group without a neurological disease, which indicates the importance of within group comparisons for identifying deficits. Levodopa medication enhanced incidental learning by patients with PD on a probabilistic sequence learning paradigm even though the patients were not aware of the existence of the sequence or their acquired knowledge. The results suggest a role in acquiring incidental motor sequence learning for dorsal striatal areas strongly affected by dopamine depletion in early PD.

The evidence on the impact of subthalamic nucleus deep brain stimulation (STN-DBS) on action restraint on Go/NoGO reaction time (RT) tasks in Parkinson's disease (PD) is inconsistent; with some studies reporting no effect and others finding that STN stimulation interferes with withholding of responses and results in more commission errors relative to STN-DBS off. We used a task in which the probability of Go stimuli varied from 100 % (simple RT task) to 80, 50 and 20 % (probabilistic Go/NoGo RT task), thus altering the prepotency of the response and the difficulty in withholding it on NoGo trials. Twenty PD patients with STN-DBS, ten unoperated PD patients and ten healthy controls participated in the study. All participants were tested twice; the order of on versus off stimulation for STN-DBS PD patients was counterbalanced. Both STN-DBS and unoperated PD patients were tested on medication. The results indicated that STN-DBS selectively decreased discriminability when the response was most prepotent (high-80 %, as compared to low Go probability trials-50 and 20 %). Movement times were faster with STN stimulation than with DBS off across different Go probability levels. There was neither an overall nor a selective effect of STN-DBS on RTs depending on the level of Go probability. Furthermore, compared to healthy controls, both STN-DBS and unoperated PD patients were more prone to making anticipatory errors; which was not influenced by STN stimulation. The results provide evidence for 'load-dependent' effects of STN stimulation on action restraint as a function of the prepotency of the Go response.

Incidental learning of appropriate stimulus-response associations is crucial for optimal functioning within our complex environment. Positive and negative prediction errors (PEs) serve as neural teaching signals within distinct ('direct'/'indirect') dopaminergic pathways to update associations and optimize subsequent behavior. Using a computational reinforcement learning model, we assessed learning from positive and negative PEs on a probabilistic task (Weather Prediction Task - WPT) in three populations that allow different inferences on the role of dopamine (DA) signals: (1) Healthy volunteers that repeatedly underwent [C-11]raclopride Positron Emission Tomography (PET), allowing for assessment of striatal DA release during learning, (2) Parkinson's disease (PD) patients tested both on and off L-DOPA medication, (3) early Huntington's disease (HD) patients, a disease that is associated with hyper-activation of the 'direct' pathway. Our results show that learning from positive and negative feedback on the WPT is intimately linked to different aspects of dopaminergic transmission. In healthy individuals, the difference in [C-11]raclopride binding potential (BP) as a measure for striatal DA release was linearly Parkinson's disease associated with the positive learning rate. Further, asymmetry between baseline DA tone Huntington's disease in the left and right ventral striatum was negatively associated with learning from positive PEs. Female patients with early HD exhibited exaggerated learning rates from positive feedback. In contrast, dopaminergic tone predicted learning from negative feedback, as indicated by an inverted u-shaped association observed with baseline [C-11]raclopride BP in healthy controls and the difference between PD patients' learning rate on and off dopaminergic medication. Thus, the ability to learn from positive and negative feedback is a sensitive marker for the integrity of dopaminergic signal transmission in the 'direct' and 'indirect' dopaminergic pathways. The present data are interesting beyond clinical context in that imbalances of dopaminergic signaling have not only been observed for neurological and psychiatric conditions but also been proposed for obesity and adolescence. (C) 2016 Elsevier Ltd. All rights reserved.

Sub-domains of executive functions, including problems with planning, accuracy, impulsivity, and inhibition, are core features of Huntington's disease. It is known that the decline of cognitive function in Huntington's disease is related to the anatomical progression of pathology in the basal ganglia. However, it remains to be determined whether the severity of executive dysfunction depends on the stage of the disease. To examine the severity of sub-domains of executive dysfunction in early- and late-stage Huntington's disease, we studied performance in the Tower of London task of two groups of Huntington's disease patients (Group 1: early, n = 23, and Group 2: late stage, n = 29), as well as a third group of age, education, and IQ matched healthy controls (n = 34). During the task, we measured the total number of problems solved, total planning time, and total number of breaks taken. One aspect of executive function indexed by the number of solved problems seems to progress in the course of the disease. Late-stage Huntington's disease patients scored significantly worse than early-stage patients and controls, and early-stage patients scored significantly worse than controls on this measure of accuracy. In contrast, late- and early-stage HD patients did not differ in terms of planning time and number of breaks. Early- and late-stage HD pathology has a different impact on executive sub-domains. While accuracy differs between early- and late-stage HD patients, other domains like planning time and number of breaks do not. Striatal degeneration, which is a characteristic feature of the disease, might not affect all aspects of executive function in HD.

Inhibitory transcranial magnetic stimulation (TMS), of which continuous theta burst stimulation (cTBS) is a common form, has been used to inhibit cortical areas during investigations of their function. cTBS applied to the primary motor area (M1) depresses motor output excitability via a local effect and impairs procedural motor learning. This could be due to an effect on M1 itself and/or to changes in its connectivity with other nodes in the learning network. To investigate this issue, we used functional magnetic resonance imaging to measure changes in brain activation and connectivity during implicit procedural learning after real and sham cTBS of M1. Compared to sham, real cTBS impaired motor sequence learning, but caused no local or distant changes in brain activation. Rather, it reduced functional connectivity between motor (M1, dorsal premotor & supplementary motor areas) and visual (superior & inferior occipital gyri) areas. It also increased connectivity between frontal associative (superior & inferior frontal gyri), cingulate (dorsal & middle cingulate), and temporal areas. This potentially compensatory shift in coupling, from a motor-based learning network to an associative learning network accounts for the behavioral effects of cTBS of M1. The findings suggest that the inhibitory TMS affects behavior via relatively subtle and distributed effects on connectivity within networks, rather than by taking the stimulated area “offline”.

Declarative and procedural learning have been considered distinct learning systems, recruiting different brain networks. Procedural learning can be further subdivided into motor and perceptual/cognitive. A variety of tasks have been developed and used to assess specific types of procedural learning. Procedural learning involves different stages including cognitive, associative, and autonomous phases and is subject to off-line processes of consolidation. Dissociations between declarative and procedural memory deficits in patients with amnesic syndromes and neurodegenerative disorders including Parkinson's and Huntington's diseases together with evidence from brain imaging and animal studies indicated that the medial temporal lobe and basal ganglia mediate declarative and procedural learning, respectively. More recent evidence supports the notion of declarative and procedural learning as interacting rather than independent systems, depending on task demands.

Feedback and monetary reward can enhance motor skill learning, suggesting reward system involvement. Continuous theta burst (cTBS) transcranial magnetic stimulation (TMS) of the primary motor area (M1) disrupts processing, reduces excitability and impairs motor learning. To see whether feedback and reward can overcome the learning impairment associated with M1 cTBS, we delivered real or sham stimulation to two groups of participants before they performed a motor sequence learning task with and without feedback. Participants were trained on two intermixed sequences, one occurring 85% of the time (the "probable" sequence) and the other 15% of the time (the "improbable" sequence). We measured sequence learning as the difference in reaction time (RT) and error rate between probable and improbable trials (RT and error difference scores). Participants were also tested for sequence recall with the same indices of learning 60 min after cTBS. Real stimulation impaired initial sequence learning and sequence knowledge recall as measured by error difference scores and impaired sequence knowledge recall as measured by RT difference score. Relative to non-feedback learning, the introduction of feedback during sequence learning improved subsequent sequence knowledge recall indexed by RT difference score, in both real and sham stimulation groups and feedback reversed the RT difference score based sequence knowledge recall impairment from real cTBS that we observed in the non-feedback learning condition. Only the real cTBS group in the non-feedback condition showed no evidence of explicit sequence knowledge when tested at the end of the study. Feedback improves recall of implicit and explicit motor sequence knowledge and can protect sequence knowledge against the effect of M1 inhibition. Adding feedback and monetary reward/punishment to motor skill learning may help overcome retention impairments or accelerate training in clinical and other settings.

BACKGROUND:Deep brain stimulation of the subthalamic nucleus (STN DBS) ameliorates the motor symptoms of Parkinson's disease (PD). However, some aspects of executive control are impaired with STN DBS. OBJECTIVE:We tested the prediction that (i) STN DBS interferes with switching from automatic to controlled processing during fast-paced random number generation (RNG) (ii) STN DBS-induced cognitive control changes are load-dependent. METHODS:Fifteen PD patients with bilateral STN DBS performed paced-RNG, under three levels of cognitive load synchronised with a pacing stimulus presented at 1, 0.5 and 0.33 Hz (faster rates require greater cognitive control), with DBS on or off. Measures of output randomness were calculated. Countscore 1 (CS1) indicates habitual counting in steps of one (CS1). Countscore 2 (CS2) indicates a more controlled strategy of counting in twos. RESULTS:The fastest rate was associated with an increased CS1 score with STN DBS on compared to off. At the slowest rate, patients had higher CS2 scores with DBS off than on, such that the differences between CS1 and CS2 scores disappeared. CONCLUSIONS:We provide evidence for a load-dependent effect of STN DBS on paced RNG in PD. Patients could switch to more controlled RNG strategies during conditions of low cognitive load at slower rates only when the STN stimulators were off, but when STN stimulation was on, they engaged in more automatic habitual counting under increased cognitive load. These findings are consistent with the proposal that the STN implements a switch signal from the medial frontal cortex which enables a shift from automatic to controlled processing.

The aim of our study was to investigate two inter-related hypotheses about the role of the subthalamic nucleus. First that the subthalamic nucleus plays a role in adjusting response thresholds and speed-accuracy trade-offs and second that it is involved in reactive and proactive inhibition and conflict resolution. These were addressed by comparing the performance of 10 patients with Parkinson's disease treated with right subthalamotomy and 12 patients with left subthalamotomy, to 14 unoperated patients with Parkinson's disease and 23 age-matched healthy control participants on a conditional stop signal task and applying the drift diffusion model. Unilateral subthalamotomy significantly improved Parkinson's disease motor signs. Patients with right subthalamotomy had significantly faster Go reaction times with their contra-lesional hand than the unoperated patients and did not differ from the control participants, indicating their speed of response initiation was 'normalized'. However, operated patients made significantly more discrimination errors than unoperated patients and controls, suggesting that subthalamotomy influenced speed-accuracy trade-offs. This was confirmed by the drift diffusion model, revealing that while the unoperated patients had significantly lower drift rate and higher response thresholds than the control participants, the response thresholds for the operated groups did not differ from the controls and the patients with right subthalamotomy had a significantly higher drift rate than unoperated patients and similar to that of controls. The drift diffusion model further established that unlike the control participants, operated patients failed to show context-dependent strategic modulation of response thresholds. The patients with right subthalamotomy could not engage in late phase, fast inhibition of the response and showed minimal proactive inhibition when tested with the contra-lesional hand. These results provide strong evidence that the subthalamic nucleus is involved in response inhibition, in modulating the rate of information accumulation and the response threshold and influencing the balance between speed and accuracy of performance. Accordingly, the subthalamic nucleus can be considered a key component of the cerebral inhibitory network.

The basal ganglia (BG) mediate certain types of procedural learning, such as probabilistic classification learning on the weather prediction task' (WPT). Patients with Parkinson's disease (PD), who have BG dysfunction, are impaired at WPT-learning, but it remains unclear what component of the WPT is important for learning to occur. We tested the hypothesis that learning through processing of corrective feedback is the essential component and is associated with release of striatal dopamine. We employed two WPT paradigms, either involving learning via processing of corrective feedback (FB) or in a paired associate manner (PA). To test the prediction that learning on the FB but not PA paradigm would be associated with dopamine release in the striatum, we used serial C-11-raclopride (RAC) positron emission tomography (PET), to investigate striatal dopamine release during FB and PA WPT-learning in healthy individuals. Two groups, FB, (n=7) and PA (n=8), underwent RAC PET twice, once while performing the WPT and once during a control task. Based on a region-of-interest approach, striatal RAC-binding potentials reduced by 13-17% in the right ventral striatum when performing the FB compared to control task, indicating release of synaptic dopamine. In contrast, right ventral striatal RAC binding non-significantly increased by 9% during the PA task. While differences between the FB and PA versions of the WPT in effort and decision-making is also relevant, we conclude striatal dopamine is released during FB-based WPT-learning, implicating the striatum and its dopamine connections in mediating learning with FB. Hum Brain Mapp 35:5106-5115, 2014. (c) 2014 The Authors. Human Brain Mapping Published by Wiley Periodicals, Inc.

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.

Executive dysfunction, including problems with decision-making, inhibition of prepotent responses, and verbal fluency, are main features of Huntington's disease (HD). The decline of executive function in HD is related to the anatomical progression of HD pathology in the basal ganglia, where the earliest changes of neuronal cell death are seen in the dorsolateral caudate. To examine the specific pattern of executive dysfunction in early HD, 18 patients with early HD were assessed on: (1) the Iowa Gambling Task to measure risky decision making, (2) the Stroop test to measure inhibition of prepotent responses, and (3) the verbal fluency test to measure internally guided word search and production, necessitating suppression of retrieval/production of inappropriate words and monitoring of the output. Patients with early HD were significantly impaired on the Stroop and verbal fluency tests relative to controls. However, Iowa Gambling Task performance was comparable across the 2 groups. This pattern of selective executive dysfunction in early HD probably reflects the fact that inhibitory processing involved in both the Stroop and verbal fluency tests recruits the dorsolateral caudate and its cortical connections, which are dysfunctional in early HD, whereas risky decision-making during the Iowa Gambling Task recruits the ventromedial caudate and its connections, which remain spared early on in the disease. The current results demonstrate that the deterioration of executive functioning in HD is variable and that some types of executive processing might already be impaired in early HD, whereas others remain intact.

Normal actions and behaviors often require inhibition of unwanted and inadequate movements. Motor inhibition has been studied using the stop signal task, in which participants are instructed to respond to a go signal. Sporadically, a stop signal is also delivered after a short interval following the go signal, prompting participants to inhibit their already started response to the go signal. Functional MRI studies using this paradigm have implicated the activation of the subthalamic nucleus in motor inhibition. We directly recorded subthalamic nucleus activity from bilaterally implanted deep brain stimulation electrodes in a group of 10 patients with Parkinson's disease, during performance of the stop signal task. Response inhibition was associated with specific changes in subthalamic activity in three different frequency bands. Response preparation was associated with a decrease in power and cortico-subthalamic coherence in the beta band (12–30 Hz), which was smaller and shorter when the response was successfully inhibited. In the theta band, we observed an increase in frontal cortico-subthalamic coherence related to the presence of the stop signal, which was highest when response inhibition was unsuccessful. Finally, a specific differential pattern of gamma activity was observed in the “on” motor state. Performance of the response was associated with a significant increase in power and cortico-subthalamic coherence, while successful inhibition of the response was associated with a bilateral decrease in subthalamic power and cortico-subthalamic coherence. Importantly, this inhibition-related decrease in gamma activity was absent in the four patients with dopamine-agonist related impulse-control disorders. Our results provide direct support for the involvement of the subthalamic nucleus in response inhibition and suggest that this function may be mediated by a specific reduction in gamma oscillations in the cortico-subthalamic connection.

It has been proposed that the subthalamic nucleus (STN) mediates response inhibition and conflict resolution through the fronto-basal ganglia pathways. Our aim was to compare the effects of deep brain stimulation (DBS) of the STN on reactive and proactive inhibition and conflict resolution in Parkinson's disease using a single task. We used the conditional Stop signal reaction time task that provides the Stop signal reaction time (SSRT) as a measure of reactive inhibition, the response delay effect (RDE) as a measure of proactive inhibition and conflict-induced slowing (CIS) as a measure of conflict resolution. DBS of the STN significantly prolonged SSRT relative to stimulation off. However, while the RDE measure of proactive inhibition was not significantly altered by DBS of the STN, relative to healthy controls, RDE was significantly lower with DBS off but not DBS on. DBS of the STN did not alter the mean CIS but produced a significant differential effect on the slowest and fastest RTs on conflict trials, further prolonging the slowest RTs on the conflict trials relative to DBS off and to controls. These results are the first demonstration, using a single task in the same patient sample, that DBS of the STN produces differential effects on reactive and proactive inhibition and on conflict resolution, suggesting that these effects are likely to be mediated through the impact of STN stimulation on different fronto-basal ganglia pathways: hyperdirect, direct and indirect.

Deep brain stimulation of the subthalamic nucleus is an effective treatment for the motor symptoms of Parkinson's disease. Although a range of psychiatric and behavioral problems have been documented following deep brain stimulation, the short‐term effects of subthalamic nucleus stimulation on patients' mood have only been investigated in a few studies. Our aim was to compare self‐reported mood in Parkinson's patients with deep brain stimulation of the subthalamic nucleus ON versus OFF. Twenty‐three Parkinson's patients with bilateral deep brain stimulation of the subthalamic nucleus and 11 unoperated Parkinson's patients completed a mood visual analogue scale twice. Operated patients were tested with deep brain stimulation of the subthalamic nucleus both ON and OFF. All were assessed on medication. The operated Parkinson's group reported feeling significantly better coordinated, stronger, and more contented with deep brain stimulation ON compared to OFF. Fourteen of the 16 mood scales changed in a positive direction when deep brain stimulation of the subthalamic nucleus was ON. When changes in motor scores were taken into account, the operated patients still reported feeling better‐coordinated, but also less gregarious with stimulation ON. Unoperated Parkinson's patients showed no differences on any of these measures between their 2 ratings. Short‐term changes in deep brain stimulation of the subthalamic nucleus have a small and mostly positive effect on mood, which may be partly related to improvements in motor symptoms. The implications for day‐to‐day management of patients with deep brain stimulation of the subthalamic nucleus are discussed. © 2012 Movement Disorder Society