Leonora Wilkinson

Intentional control and implicit sequence learning.

Sequence knowledge acquired by repeated exposure to targets in a speeded localization task was studied in 3 experiments that sought to test A. Destrebecqz and A. Cleeremanss (2001, 2003) claim that, under certain circumstances, the expression of such sequence knowledge cannot be brought under intentional control. In Experiment 1 participants were trained on either a deterministic or a probabilistic sequence and then performed a free-generation test under either inclusion or exclusion instructions. Participants were found to be capable of both expressing (inclusion) and avoiding expressing (exclusion) sequence knowledge. These results were confirmed in Experiment 2 with a more exact replication of Destrebecqz and Cleeremanss methodology. In Experiment 3 participants performed a trial-by-trial generation test under both inclusion and exclusion conditions after a much longer period of training. All the findings are consistent with the proposal that information acquired during sequence learning is explicit in nature.

Deficits in inhibitory control and conflict resolution on cognitive and motor tasks in Parkinson’s disease

Recent imaging studies in healthy controls with a conditional stop signal reaction time (RT) task have implicated the subthalamic nucleus (STN) in response inhibition and the pre-supplementary motor area (pre-SMA) in conflict resolution. Parkinson’s disease (PD) is characterized by striatal dopamine deficiency and overactivity of the STN and underactivation of the pre-SMA during movement. We used the conditional stop signal RT task to investigate whether PD produced similar or dissociable effects on response initiation, response inhibition and response initiation under conflict. In addition, we also examined inhibition of prepotent responses on three cognitive tasks: the Stroop, random number generation and Hayling sentence completion. PD patients were impaired on the conditional stop signal reaction time task, with response initiation both in situations with or without conflict and response inhibition all being significantly delayed, and had significantly greater difficulty in suppressing prepotent or habitual responses on the Stroop, Hayling and random number generation tasks relative to controls. These results demonstrate the existence of a generalized inhibitory deficit in PD, which suggest that PD is a disorder of inhibition as well as activation and that in situations of conflict, executive control over responses is compromised.

Relationship between priming and recognition in deterministic and probabilistic sequence learning.

Exposure to a repeating sequence of target stimuli in a speeded localization task can support both priming of sequence-consistent responses and recognition of sequence components. In 3 experiments with both deterministic and probabilistic sequences, the authors used a novel procedure in which measures or priming and recognition were taken concurrently and asked whether these measures can be dissociated. In all of these experiments, both measures were above chance at the group level and no evidence of dissociation was found. Item-level analyses of the data in Experiment 3 did reveal dissociations in that (a) recognition judgments were affected by response speed independently of old-new status and (b) items that were not discriminated in recognition nonetheless showed priming. However, the authors show that these data, together with the group-level results, are compatible with a formal model in which priming and recognition are based on a single common memory variable.

What can man do without basal ganglia motor output? The effect of combined unilateral subthalamotomy and pallidotomy in a patient with Parkinson's disease.

We have studied motor performance in a man with Parkinsons disease (PD) in whom thermolytic lesions of the left subthalamic and left globus pallidus nuclei interrupted the basal ganglia (BG)-thalamo-cortical motor circuit in the left hemisphere. This allowed us to study remaining motor capabilities in the absence of aberrant BG activity typical of PD. Movements of the left arm were slow and parkinsonian whereas movement speed and simple reaction times (RT) of the right (operated) arm were within the normal range with no obvious deficits in a range of daily life activities. Two main abnormalities were found with the right hand. (a) Implicit sequence learning in a probabilistic serial reaction time task was absent. (b) In a go/no-go task when the percent of no-go trials increased, the RT superiority with the right hand was lost. These deficits are best explained by a failure of the cortex, deprived of BG input, to facilitate responses in a probabilistic context. Our findings confirm the idea that it is better to stop BG activity than allowing faulty activity to disrupt the motor system but dispute earlier claims that interrupting BG output in PD goes without an apparent deficit. From a practical viewpoint, our observations indicate that the risk of persistent dyskinesias need not be viewed as a contraindication to subthalamotomy in PD patients since they can be eliminated if necessary by a subsequent pallidotomy without producing deficits that impair activities of daily life.

The role of the basal ganglia and its cortical connections in sequence learning: evidence from implicit and explicit sequence learning in Parkinson's disease.

Implicit (unconscious/incidental) and explicit (conscious/intentional) learning are considered to have distinct neural substrates. It is proposed that implicit learning is mediated by the basal ganglia (BG), while explicit learning has been linked to the medial temporal lobes (MTL). To test such a dissociation we investigated implicit and explicit sequence learning in Parkinsons disease (PD), a disorder characterized by striatal dysfunction. We studied both implicit and explicit learning of a 12-item sequence of target locations in 13 PD patients and 15 age-matched controls. In the implicit sequence learning task all participants completed 10 blocks of a probabilistic serial reaction time (SRT) task in which they were exposed to the sequence without explicit knowledge of it. Participants also completed between 1 and 10 blocks of an explicit sequence learning task in which the sequence was learned deliberately by trial-and-error. Both implicit and explicit sequence learning were significantly impaired in PD patients compared to controls. The results indicate that, in addition to playing a role in implicit sequence learning, the BG and its frontal projections are also involved in explicit sequence learning.

Combating depression in Huntington's disease: effective antidepressive treatment with venlafaxine XR.

Patients with Huntingtons disease (HD) often suffer from psychiatric symptoms including affective disorder, psychosis, irritability, and apathy, which may be present in all stages of the disease. However – despite the obvious likelihood that these symptoms may be reduced by antidepressive treatments – to date, the effectiveness of such treatments in HD has only ever been examined in case studies. Twenty-six HD patients (17 men), with a diagnosis of major depression, were studied. The symptoms of HD and depression were systematically measured using the Beck Depression Inventory and the Hamilton Rating Scale for Depression both at baseline and after 4 weeks of treatment with venlafaxine XR. After 4 weeks of venlafaxine XR treatment, the symptoms of depression in HD patients decreased significantly relative to baseline. However, approximately one in five patients developed significant venlafaxine-related side effects (nausea and irritability). Venlafaxine XR is highly effective in the treatment of depression in HD, although it may produce unpleasant side effects. Further studies are required to establish the most suitable treatment for depression in HD.

Levodopa medication does not influence motor inhibition or conflict resolution in a conditional stop-signal task in Parkinson’s disease

Evidence from animal, clinical, and imaging studies suggests that the basal ganglia and their frontal connections mediate motor inhibition, but the role of dopamine remains unclear. The aim of our study was to investigate, for the first time, whether levodopa medication influences motor inhibition and conflict resolution on the conditional stop-signal reaction time task in patients with Parkinson’s disease (PD) tested on or off their medication. Sixteen PD patients and 17 healthy controls performed the conditional stop-signal reaction time (SSRT) task, which requires inhibition of responses when a stop signal is presented on “critical” trials. Additionally, on “non-critical” trials, participants are instructed to ignore the stop signal and respond, thus generating conflict between motor inhibition and initiation; and conflict-induced slowing (CIS) on these “non-critical” trials. Levodopa medication did not significantly influence response initiation, inhibition (SSRT) or the measure of conflict resolution (CIS). Compared to healthy controls, PD patients showed significantly worse response initiation and inhibition both on and off their levodopa medication. Our results suggest that motor inhibition or conflict-induced slowing on the conditional stop-signal RT task are not altered by dopamine replacement in PD. This conclusion is consistent with evidence from animal studies and clinical pharmacological investigations suggesting a role for noradrenaline in motor inhibition and impulsivity.

The effect of feedback on non-motor probabilistic classification learning in Parkinson's disease

It has been proposed that procedural learning is mediated by the striatum and, it has been reported that patients with Parkinsons disease (PD) are impaired on the weather prediction task (WPT) which involves probabilistic classification learning with corrective feedback (FB). However, PD patients were not impaired on probabilistic classification learning when it was performed without corrective feedback, in a paired associate (PA) manner; suggesting that the striatum is involved in learning with feedback rather than procedural learning per se. In Experiment 1 we studied FB- and PA-based learning in PD patients and controls and, as an improvement on previous methods, used a more powerful repeated measures design and more equivalent test phases during FB and PA conditions (including altering the FB condition to remove time limits on responding). All participants (16 PD patients, H&Y I-III and 14 matched-controls) completed the WPT under both FB and PA conditions. In contrast to previous results, in Experiment 1 we did not find a selective impairment in the PD group on the FB version of the WPT relative to controls. In Experiment 2 we used a between groups design and studied learning with corrective FB in 11 PD patients (H&Y I.5-IV) and 13 matched controls on a more standard version of the WPT similar to that used in previous studies. With such a between groups design for comparison of FB and PA learning on the WPT in PD, we observed impaired learning in PD patients relative to controls across both the FB and PA versions of the WPT. Most importantly, in Experiment 2 we also failed to find a selective impairment on the FB version of the WPT coupled with normal learning on the PA version in PD patients relative to controls. Our results do not support the proposal that the striatum plays a specific role in probabilistic classification learning with feedback.

Bilateral stimulation of the subthalamic nucleus has differential effects on reactive and proactive inhibition and conflict-induced slowing in Parkinson’s disease

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.

The contribution of primary motor cortex is essential for probabilistic implicit sequence learning: Evidence from theta burst magnetic stimulation

Theta burst transcranial magnetic stimulation (TBS) is considered to produce plastic changes in human motor cortex. Here, we examined the inhibitory and excitatory effects of TBS on implicit sequence learning using a probabilistic serial reaction time paradigm. We investigated the involvement of several cortical regions associated with implicit sequence learning by examining probabilistic sequence learning in five age- and IQ-matched groups of healthy participants following continuous inhibitory TBS over primary motor cortex (M1); or the supplementary motor area (SMA) or dorsolateral prefrontal cortex (DLPFC) or following intermittent excitatory TBS of M1; or after sham TBS. Relative to sham TBS, probabilistic sequence learning was abolished by inhibitory TBS over M1, demonstrating that this region is critical for implicit motor sequence learning. Sequence learning was not significantly affected by inhibitory TBS over the SMA, DLPFC or excitatory TBS over M1. These results demonstrate that the M1 mediates implicit sequence learning.