Cardiovascular autonomic responses in patients with Parkinson disease to pedunculopontine deep brain stimulation.

PURPOSE: Dysautonomia can be a debilitating feature of Parkinson disease (PD). Pedunculopontine nucleus (PPN) stimulation may improve gait disorders in PD, and may also result in changes in autonomic performance. METHODS: To determine whether pedunculopontine nucleus stimulation improves cardiovascular responses to autonomic challenges of postural tilt and Valsalva manoeuver, eight patients with pedunculopontine nucleus deep brain stimulation were recruited to the study; two were excluded for technical reasons during testing. Participants underwent head up tilt and Valsalva manoeuver with stimulation turned ON and OFF. Continuous blood pressure and ECG waveforms were recorded during these tests. In a single patient, local field potential activity was recorded from the implanted electrode during tilt. RESULTS: The fall in systolic blood pressure after tilt was significantly smaller with stimulation ON (mean - 8.3% versus - 17.2%, p = 0.044). Valsalva ratio increased with stimulation from median 1.15 OFF to 1.20 ON (p = 0.028). Baroreflex sensitivity increased during Valsalva compared to rest with stimulation ON versus OFF (p = 0.028). The increase in baroreflex sensitivity correlated significantly with the mean depth of PPN stimulating electrode contacts. This accounted for 89% of its variance (r = 0.943, p = 0.005). CONCLUSION: PPN stimulation can modulate the cardiovascular system in patients with PD. In this study, it reduced the postural fall in systolic blood pressure during head-up tilt and improved the cardiovascular response during Valsalva, presumably by altering the neural control of baroreflex activation.

Understanding the human pedunculopontine nucleus in Parkinson's disease.

This paper presents the Brisbane experience of pedunculopontine nucleus (PPN) deep brain stimulation (DBS) in Parkinson's disease (PD). Clinical outcomes along with studies of the mechanisms and neurophysiology of PPN in PD patients with severe freezing of gait (FoG) and postural imbalance (PI) are summarised and presented. Our results indicate that PPN DBS improves FoG and falls in the relatively uncommon group of PD patients who respond well to medication other than for continuing on time FoG and falls. Our studies indicate that bilateral DBS is more beneficial than unilateral DBS, and that the more caudal region of the PPN seems preferable for stimulation. There is evidence that rapid-release programs for initiation and correction of gait and posture are modulated by the PPN, possibly to some extent independently of the cerebral cortex. These functions were found to be impaired in PD patients with severe FoG/PI, but to some extent corrected by bilateral PPN DBS.

Imagined gait modulates neuronal network dynamics in the human pedunculopontine nucleus.

The pedunculopontine nucleus (PPN) is a part of the mesencephalic locomotor region and is thought to be important for the initiation and maintenance of gait. Lesions of the PPN induce gait deficits, and the PPN has therefore emerged as a target for deep brain stimulation for the control of gait and postural disability. However, the role of the PPN in gait control is not understood. Using extracellular single-unit recordings in awake patients, we found that neurons in the PPN discharged as synchronous functional networks whose activity was phase locked to alpha oscillations. Neurons in the PPN responded to limb movement and imagined gait by dynamically changing network activity and decreasing alpha phase locking. Our results indicate that different synchronous networks are activated during initial motor planning and actual motion, and suggest that changes in gait initiation in Parkinson's disease may result from disrupted network activity in the PPN.

Bilateral deep brain stimulation of the nucleus accumbens for comorbid obsessive compulsive disorder and Tourette's syndrome.

We present the case of a 32-year-old Caucasian woman with severe treatment-refractory obsessive compulsive disorder (OCD) and Tourette's syndrome. Both conditions were present prior to age 5 and impacted significantly on the patient's functioning. Multiple trials of evidence-based pharmacological and behavioural therapies had not achieved remission of symptoms. Bilateral deep brain stimulation of the nucleus accumbens was undertaken to treat both illnesses but with a particular focus on OCD, as the patient identified this as the more debilitating of the two disorders. Following surgery there was an immediate improvement in OCD and tic severity. At follow-up 8 months later, there was a 90% improvement in OCD symptoms and a 57% improvement in tic severity. No intraoperative or postoperative complications or adverse events occurred and there were no undesired effects of stimulation.

A spatiotemporal analysis of gait freezing and the impact of pedunculopontine nucleus stimulation.

Gait freezing is an episodic arrest of locomotion due to an inability to take normal steps. Pedunculopontine nucleus stimulation is an emerging therapy proposed to improve gait freezing, even where refractory to medication. However, the efficacy and precise effects of pedunculopontine nucleus stimulation on Parkinsonian gait disturbance are not established. The clinical application of this new therapy is controversial and it is unknown if bilateral stimulation is more effective than unilateral. Here, in a double-blinded study using objective spatiotemporal gait analysis, we assessed the impact of unilateral and bilateral pedunculopontine nucleus stimulation on triggered episodes of gait freezing and on background deficits of unconstrained gait in Parkinson's disease. Under experimental conditions, while OFF medication, Parkinsonian patients with severe gait freezing implanted with pedunculopontine nucleus stimulators below the pontomesencephalic junction were assessed during three conditions; off stimulation, unilateral stimulation and bilateral stimulation. Results were compared to Parkinsonian patients without gait freezing matched for disease severity and healthy controls. Pedunculopontine nucleus stimulation improved objective measures of gait freezing, with bilateral stimulation more effective than unilateral. During unconstrained walking, Parkinsonian patients who experience gait freezing had reduced step length and increased step length variability compared to patients without gait freezing; however, these deficits were unchanged by pedunculopontine nucleus stimulation. Chronic pedunculopontine nucleus stimulation improved Freezing of Gait Questionnaire scores, reflecting a reduction of the freezing encountered in patients' usual environments and medication states. This study provides objective, double-blinded evidence that in a specific subgroup of Parkinsonian patients, stimulation of a caudal pedunculopontine nucleus region selectively improves gait freezing but not background deficits in step length. Bilateral stimulation was more effective than unilateral.

Pedunculopontine nucleus stimulation improves gait freezing in Parkinson disease.

BACKGROUND: Pedunculopontine nucleus (PPN) stimulation is a novel therapy for Parkinson disease. However, controversies remain regarding the clinical application of this new therapy, including patient selection, electrode positioning, and how best to assess outcomes. OBJECTIVE: To clarify the clinical application of PPN stimulation in Parkinson disease. METHODS: Five consecutive patients with Parkinson disease complicated by severe gait freezing, postural instability, and frequent falls (all persisting even while the patient was on medication) received bilateral stimulation of the mid-lower PPN without costimulation of other brain targets. Outcomes were assessed prospectively over 2 years with gait-specific questionnaires and the Unified Parkinson Disease Rating Scale (part III). RESULTS: The primary outcome, the Gait and Falls Questionnaire score, improved significantly with stimulation. Benefits were maintained over 2 years. Unified Parkinson Disease Rating Scale (part III) items assessing gait and posture were relatively insensitive to these treatment effects. Beneficial effects often appeared to outlast stimulation for hours or longer. Thus, single-session on- vs off-stimulation assessments may be susceptible to "delayed washout effects." Stimulation of the PPN did not change akinesia scores or dopaminergic medication requirements. CONCLUSION: Bilateral stimulation of the mid-lower PPN (more caudal than previous reports) without costimulation of other brain targets may be beneficial for the subgroup of patients with Parkinson disease who experience severe gait freezing and postural instability with frequent falls, which persist even while on medication. Choosing appropriate outcome measures and accounting for the possibility of prolonged stimulation washout effects appear to be important for detecting the clinical benefits.

A block to pre-prepared movement in gait freezing, relieved by pedunculopontine nucleus stimulation.

Gait freezing and postural instability are disabling features of Parkinsonian disorders, treatable with pedunculopontine nucleus stimulation. Both features are considered deficits of proximal and axial musculature, innervated predominantly by reticulospinal pathways and tend to manifest when gait and posture require adjustment. Adjustments to gait and posture are amenable to pre-preparation and rapid triggered release. Experimentally, such accelerated release can be elicited by loud auditory stimuli--a phenomenon known as 'StartReact'. We observed StartReact in healthy and Parkinsonian controls. However, StartReact was absent in Parkinsonian patients with severe gait freezing and postural instability. Pedunculopontine nucleus stimulation restored StartReact proximally and proximal reaction times to loud stimuli correlated with gait and postural disturbance. These findings suggest a relative block to triggered, pre-prepared movement in gait freezing and postural instability, relieved by pedunculopontine nucleus stimulation.

The impact of low-frequency stimulation of the pedunculopontine nucleus region on reaction time in parkinsonism.

OBJECTIVES: Attentional augmentation and enhanced motor function are potential mechanisms by which stimulation of the region of the pedunculopontine nucleus (PPN) may improve gait in parkinsonism. Here, the authors assess the impact of stimulation of this region on attentional and motor aspects of reaction task performance in patients with parkinsonism. METHODS: Eleven patients implanted with PPN stimulators underwent computerised assessment of simple, choice and digit vigilance reaction tasks. Patients were assessed 'off medication' during stimulation at different frequencies (0 Hz, 5 Hz, 10 Hz and 'therapeutic' 20-35 Hz). There were two primary endpoints: 'Speed of Reaction' (sum of the mean task reaction times) and 'Accuracy of Reaction' (reflecting omissions and percentage of correct responses). Baseline performance was compared with age- and sex-matched healthy controls. Clinical effects of stimulation were assessed using the Unified Parkinson's Disease Rating Scale and a falls frequency scale. RESULTS: Compared with healthy controls, subjects had significant deficits in 'Speed of Reaction' and in all mean task reaction times. 'Accuracy of Reaction' was not different from healthy controls and did not improve with stimulation. 'Speed of Reaction' significantly improved with stimulation at therapeutic frequencies (20-35 Hz). Of the individual tasks, only simple reaction time improved significantly. Simple reaction time distribution analysis revealed a general speeding of responses rather than a selective reduction in outliers. Acute PPN stimulation improved gait and balance but not akinesia scores. Chronic PPN stimulation significantly improved falls frequency. Falls score improvement significantly correlated with changes to simple reaction time with therapeutic stimulation. CONCLUSION: The pattern of reaction time improvement with stimulation of the PPN area suggests a benefit on motor performance, rather than augmentation of attention.

Subthalamic stimulation affects homophone meaning generation in Parkinson's disease.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) in individuals with Parkinson's disease (PD) has often been associated with reduced verbal fluency performance. This study aimed to directly assess semantic switching as a function of STN stimulation in PD participants with the Homophone Meaning Generation Test (HMGT). Seventeen participants with PD who had received STN DBS completed the HMGT in on and off stimulation conditions. Twenty-one non-neurologically impaired participants acted as controls. PD participants (in both on and off stimulation conditions) generated significantly fewer meanings than control participants and consistent with the previous reports of verbal fluency impairment, PD participants produced fewer definitions in the on stimulation condition. PD participants (in both on and off stimulation conditions) also had greater difficulty generating definitions for nonhomographic homophones compared with homographic homographs. The results of this study indicate that STN stimulation exacerbates impairment in semantic switching.

Lexical-semantic inhibitory mechanisms in Parkinson's disease as a function of subthalamic stimulation.

Inhibitory control may be affected by Parkinson's disease (PD) due to impairment within the non-motor basal ganglia-thalamocortical circuits. The present study aimed to identify the effects of chronic stimulation of the subthalamic nucleus (STN) on lexical-semantic inhibitory control. Eighteen participants with PD who had undergone surgery for deep brain stimulation (DBS) of the STN, completed a picture-word interference (PWI) task and the Hayling test in on and off stimulation conditions. The results of PD participants were compared with 21 non-neurologically impaired control participants. PD participants performed no differently from controls on the PWI task, and no significant differences between on and off stimulation conditions were revealed, therefore suggesting that PD participants are not impaired in lexical-semantic interference control. In contrast, in the off stimulation condition, PD participants had significantly delayed reaction times and increased errors on the inhibition section of the Hayling test compared with the STN stimulation condition and control participants. These results suggest that PD patients are impaired in aspects of inhibitory control that are dependent on behavioural inhibition (such as the suppression of prepotent responses) and selection from competing alternatives without the presence of external cues. Furthermore, STN stimulation acts to restore these behavioural inhibitory processes.

Semantic and affective priming as a function of stimulation of the subthalamic nucleus in Parkinson's disease.

Lexical-semantic and emotional processing deficits have been associated with Parkinson's disease. This study investigated automatic and controlled lexical-semantic processing, the automatic activation of emotional evaluations, and the processing of words conveying negative and neutral emotional connotations in a combined affective and semantic priming paradigm. Eighteen participants with Parkinson's disease who had undergone surgery for deep brain stimulation (DBS) of the subthalamic nucleus (STN) completed a lexical decision task at short and long stimulus onset asynchronies (SOAs), during on and off stimulation conditions. Nineteen non-neurologically impaired participants acted as controls. The results indicated that automatic lexical-semantic and emotional evaluative processes are unimpaired in Parkinson's disease as reflected in the presence of comparable semantic and affective priming effects at the short SOA in on and off stimulation conditions compared with healthy controls. In contrast, participants with Parkinson's disease in the off stimulation condition showed a pattern of aberrant controlled lexical-semantic processing as evidenced by a lack of semantic priming effects at the long SOA condition. Controlled semantic priming was present, however, when the participants with Parkinson's disease were receiving stimulation of the STN, suggesting that STN stimulation modulates basal ganglia-thalamocortical circuits involved in such processes. Finally, delayed reaction times for negatively valenced targets compared with neutrally valenced targets was evident in participants with Parkinson's disease in the on stimulation condition and control participants, but not for participants with Parkinson's disease in the off stimulation condition, suggesting that the incidental evaluation of negatively versus neutrally valenced words in Parkinson's disease is modulated by basal ganglia-thalamocortical circuits.