Ignacio Obeso

A fronto–striato–subthalamic–pallidal network for goal-directed and habitual inhibition

Classically, the basal ganglia have been considered to have a role in producing habitual and goal-directed behaviours. In this article, we review recent evidence that expands this role, indicating that the basal ganglia are also involved in neural and behavioural inhibition in the motor and non-motor domains. We then distinguish between goal-directed and habitual (also known as automatic) inhibition mediated by fronto–striato–subthalamic–pallido–thalamo–cortical networks. We also suggest that imbalance between goal-directed and habitual action and inhibition contributes to some manifestations of Parkinsons disease, Tourette syndrome and obsessive–compulsive disorder. Finally, we propose that basal ganglia surgery improves these disorders by restoring a functional balance between facilitation and inhibition.

Parkinson's Disease, the Subthalamic Nucleus, Inhibition, and Impulsivity

Although Parkinsons disease (PD) is primarily considered a disorder of initiation of actions, patients also have deficits in inhibitory control, both in the motor and cognitive domains. Impulse control disorders, which can develop in association with dopaminergic medication in a small proportion of patients with PD, are the symptoms most commonly considered as representing inhibitory deficits. However, there is now also a body of evidence suggesting a role for the subthalamic nucleus (STN), which is ordinarily hyperactive in PD, in inhibitory control. Here, we review evidence from animal studies, imaging studies, and investigations recording STN activity intra‐ or perioperatively in patients with PD having surgery for DBS of the STN (STN‐DBS). We also highlight relevant hypotheses about the role of the STN and consider evidence from studies that have examined the effect of STN‐DBS in patients with PD on performance of experimental tasks requiring inhibition of prepotent or habitual responses or decision making under conflict, as well as the psychiatric side effects of STN‐DBS. Though the results are not always consistent, nevertheless, this body of evidence supports the role of the STN in inhibitory and executive control.

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.

Semantic and phonemic verbal fluency in Parkinson's disease: Influence of clinical and demographic variables.

Changes of cognitive function in PD have been extensively documented and defined as a ‘frontal’ type executive dysfunction. One of the main components of this executive dysfunction is the impairment of verbal fluency. The aim of the present study was to assess semantic and phonemic fluency in a large sample of PD patients and to investigate the effect of clinical and sociodemographic variables on verbal fluency in this patient group. Three hundred patients with idiopathic Parkinsons disease who were consecutive referrals to our clinic and 50 age and education matched healthy controls completed the phonemic and semantic verbal fluency tasks. Both phonemic and semantic verbal fluency were significantly impaired in PD patients relative to matched controls. Stage of illness, presence of depression, education and age influenced verbal fluency measures. Regression analyses established that global measures of cognitive ability (MMSE) and executive function (FAB) and side of onset of motor symptoms predicted 36–37% of variance of phonemic or semantic verbal fluency measures. Thus, future studies aimed at assessing cognitive functioning in PD patients treated by deep brain stimulation (DBS) should adequately take into account several factors (stage of illness, depression, executive functioning) which may potentially influence performance on verbal fluency tasks.

Focused ultrasound subthalamotomy in patients with asymmetric Parkinson's disease: a pilot study

BACKGROUNDnAblative neurosurgery has been used to treat Parkinsons disease for many decades. MRI-guided focused ultrasound allows focal lesions to be made in deep brain structures without skull incision. We investigated the safety and preliminary efficacy of unilateral subthalamotomy by focused ultrasound in Parkinsons disease.nnnMETHODSnThis prospective, open-label pilot study was done at CINAC (Centro Integral de Neurociencias), University Hospital HM Puerta del Sur in Madrid, Spain. Eligible participants had Parkinsons disease with markedly asymmetric parkinsonism. Patients with severe dyskinesia, history of stereotactic surgery or brain haemorrhage, a diagnosis of an unstable cardiac or psychiatric disease, or a skull density ratio of 0·3 or less were excluded. Enrolled patients underwent focused ultrasound unilateral subthalamotomy. The subthalamic nucleus was targeted by means of brain images acquired with a 3-Tesla MRI apparatus. Several sonications above the definitive ablation temperature of 55°C were delivered and adjusted according to clinical response. The primary outcomes were safety and a change in the motor status of the treated hemibody as assessed with part III of the Movement Disorders Society-Unified Parkinsons Disease Rating Scale (MDS-UPDRS III) in both off-medication and on-medication states at 6 months. Adverse events were monitored up to 48 h after treatment and at scheduled clinic visits at 1, 3, and 6 months after treatment. The study is registered with ClinicalTrials.gov, number NCT02912871.nnnFINDINGSnBetween April 26 and June 14, 2016, ten patients with markedly asymmetric parkinsonism that was poorly controlled pharmacologically were enrolled for focused ultrasound unilateral subthalamotomy. By 6 months follow-up, 38 incidents of adverse events had been recorded, none of which were serious or severe. Seven adverse events were present at 6 months. Three of these adverse events were directly related to subthalamotomy: off-medication dyskinesia in the treated arm (one patient, almost resolved by 6 months); on-medication dyskinesia in the treated arm (one patient, resolved after levodopa dose reduction); and subjective speech disturbance (one patient). Four of the adverse events present at 6 months were related to medical management (anxiety and fatigue [one patient each] and weight gain [two patients]). The most frequent adverse events were transient gait ataxia (related to subthalamotomy, six patients), transient pin-site head pain (related to the head frame, six patients), and transient high blood pressure (during the procedure, five patients). Transient facial asymmetry (one patient) and moderate impulsivity (two patients) were also recorded. The mean MDS-UPDRS III score in the treated hemibody improved by 53% from baseline to 6 months in the off-medication state (16·6 [SD 2·9] vs 7·5 [3·9]) and by 47% in the on-medication state (11·9 [3·1] vs 5·8 [3·5]).nnnINTERPRETATIONnMRI-guided focused ultrasound unilateral subthalamotomy was well tolerated and seemed to improve motor features of Parkinsons disease in patients with noticeably asymmetric parkinsonism. Large randomised controlled trials are necessary to corroborate these preliminary findings and to assess the potential of such an approach to treat Parkinsons disease.nnnFUNDINGnFundación de investigación HM Hospitales and Insightec.

The Effectiveness of Transcranial Brain Stimulation in Improving Clinical Signs of Hyperkinetic Movement Disorders

Repetitive transcranial magnetic stimulation (rTMS) is a safe and painless method for stimulating cortical neurons. In neurological realm, rTMS has prevalently been applied to understand pathophysiological mechanisms underlying movement disorders. However, this tool has also the potential to be translated into a clinically applicable therapeutic use. Several available studies supported this hypothesis, but differences in protocols, clinical enrollment, and variability of rTMS effects across individuals complicate better understanding of efficient clinical protocols. The aim of this present review is to discuss to what extent the evidence provided by the therapeutic use of rTMS may be generalized. In particular, we attempted to define optimal cortical regions and stimulation protocols that have been demonstrated to maximize the effectiveness seen in the actual literature for the three most prevalent hyperkinetic movement disorders: Parkinsons disease (PD) with levodopa-induced dyskinesias (LIDs), essential tremor (ET) and dystonia. A total of 28 rTMS studies met our search criteria. Despite clinical and methodological differences, overall these studies demonstrated that therapeutic applications of rTMS to “normalize” pathologically decreased or increased levels of cortical activity have given moderate progress in patients quality of life. Moreover, the present literature suggests that altered pathophysiology in hyperkinetic movement disorders establishes motor, premotor or cerebellar structures as candidate regions to reset cortico-subcortical pathways back to normal. Although rTMS has the potential to become a powerful tool for ameliorating the clinical outcome of hyperkinetic neurological patients, until now there is not a clear consensus on optimal protocols for these motor disorders. Well-controlled multicenter randomized clinical trials with high numbers of patients are urgently required.

Theta burst magnetic stimulation over the pre-supplementary motor area improves motor inhibition

BACKGROUNDnStopping 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.nnnMETHODSnWe 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).nnnRESULTSnStimulation 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.nnnCONCLUSIONSnThe improvement of SSRT with cTBS over the pre-SMA suggests its critical contribution to stopping ongoing movements.

Transcranial Non-Invasive Brain Stimulation in Parkinson's Disease Patients with Dyskinesias. Where is the Optimal Target?

Dear Editor, The treatment of secondary effects of levodopa treatments in Parkinson’s disease (PD) patients is an actual necessity and priority in clinical practice. The paper made by Ferrucci et al. [1] represents an additional confirmation that levodopainduced dyskinesias (LIDs) are potentially treatable by neuromodulation techniques. Differently from previous literature, this is the first study using transcranial direct current stimulation (tDCS) to reduce dyskinetic movements in PD. Indeed, until now, nine papers had provided evidence on the effectiveness of non-invasive brain stimulation (NIBS) administered as repetitive transcranial magnetic stimulation (rTMS). However, despite methodological and technical differences (tDCS vs. rTMS; single vs. prolonged stimulation sessions; inhibitory vs. excitatory; and unilateral vs. bilateral) what merits to be focused after the current article is where stimulation should be applied. In other words, which is the main brain region to be targeted in LIDs patients: the Motor Cortex? Supplementary Motor Area (SMA)? Cerebellum? Or Inferior Frontal Cortex (IFC)? The target location problem in LIDs is strongly dependent upon the current pathophysiological model. In the last few years, a considerable effort has been made to understand the neurobiological basis of this motor complication. LIDs are classically ascribed to the degree of nigrostriatal neurodegeneration and striatal changes associated with chronic levodopa therapy [2]. These interact to induce maladaptive striatal plasticity, which has the effect of altering neuronal activity in striatopallidal circuits. The first step in imaging of LIDs was made by Rascol [3] and Brooks [4], who demonstrated that these abnormal neuronal firing patterns extended on the brain cortex mainly including the sensorimotor areas of the corticobasal ganglia loop. Guided by these first neurofunctional results, neuromodulation over regions showing functional overactivity in LIDs was tested either for the primary motor cortex (M1) [4–10] or for the SMA [11, 12]. Although, Ferrucci et al. [1] demonstrated that noninvasive brain stimulation over the M1 improved LIDs, the present literature is characterized by conflicting findings. First of all, Wagle-Shukla et al. [5], by using a prolonged session (2 weeks) of low frequency (1HZ) rTMS, reported no evident clinical improvements in six PD patients with LIDs. This preliminary lack of significant effects has also been confirmed in two recent studies [6, 10], despite the employment of different rTMS protocols. Otherwise, three additional studies demonstratedmoderate evidence about the role of theM1 as potential stimulation site for LIDs treatment. First, Filipovic et al. [7], using low-frequency rTMS (1 Hz) for 4 consecutive days in ten PD patients with LIDs, reported residual beneficial clinical effects in dyskinesia severity. With the same TMS protocol, these authors found an increased beneficial effect also in one PD patient with diphasic dyskinesia [8]. Finally, in another case report, rTMS over the M1 significantly reduced the painful dystonia and walking disturbances in one dyskinetic patient with painful off-period dystonia [9]. Despite these conflicting findings, a central role of M1 in the genesis of LIDs may be hypothesized since it has been * Antonio Cerasa a.cerasa@unicz.it

Unilateral subthalamotomy in Parkinson's disease: Cognitive, psychiatric and, neuroimaging changes

Unilateral subthalamotomy is an effective treatment for the cardinal motor features of Parkinsons disease (PD). However, non-motor changes possibly associated with right or left subthalamotomy remain unknown. Our aim was to assess cognitive, psychiatric and neuroimaging changes after treatment with unilateral subthalamotomy. Fourteen medicated patients with PD were evaluated before and after (mean 6 months after operation) unilateral subthalamotomy (5 right, 9 left). In addition to motor assessments, cognitive (global cognition and executive functions), psychiatric (apathy, depression, anxiety, mania, hypo- and hyperdopaminergic behaviours, impulsivity), quality of life evaluations and volume of lesions were obtained. After surgery, significant improvement of motor signs was observed. Unilateral subthalamotomy improved general cognitive status, but left subthalamotomy reduced semantic verbal fluency compared to the pre-operative state. Depression and quality of life were improved with both right and left subthalamotomy. However, hyper-emotionality was present after surgery and right subthalamotomy increased impulsivity and disinhibition (on NeuroPsychiatric Inventory and Ardouin Scale for Behaviour in PD), a result linked to larger lesion volumes. We conclude that unilateral subthalamotomy is effective for treating the cardinal motor features of PD and improves mood. Right subthalamotomy is associated with greater risk of impulsivity and disinhibition, while left subthalamotomy induces further impairment of semantic verbal fluency.