Saccadometry: A novel clinical tool for quantification of the motor effects of subthalamic nucleus stimulation in Parkinson's disease

Introduction

High frequency stimulation of the subthalamic nucleus (STN HFS) is the therapy of choice in the surgical management of patients suffering from advanced Parkinson's disease (PD). Worldwide, more than 30 000 patients have undergone this procedure. At present, there is a need for a rapid method of assessing its therapeutic effect that is ideally also target-specific, objective, automated, quantitative, and with high overall reliability. Saccadic latency, that reflects the operation of central decision-making mechanisms, is increasingly being used as a way of obtaining quantitative, objective information about cerebral performance in general.

Objective

In this study we investigated the possible application of saccadic eye movements as a tool for assessing the therapeutic motor effects of STN HFS in patients with advanced PD.

Methods

Patients received bilateral STN HFS and were evaluated in stimulation and medication on and off conditions, together with conventional motor assessments under the same conditions.

Results

We found that saccadometry can provide a sensitive and objective measure of the effects of STN HFS in PD patients that correlates well with conventional, subjective, evaluation of motor impairment. The effect appears to be specific to the site of stimulation, and in terms of the LATER model appears to be due to an increase in the mean rate of rise of the underlying decision signal, combined with a degree of suppression of the mechanism responsible for the early component.

Interpretation

A possible interpretation of our findings is that electrical stimulation of the STN, which is known to have a powerful influence on substantia nigra pars reticulata, enhances both the descending facilitation that passes from the cortex to the colliculus via the basal ganglia, thus increasing the mean rate of rise of the decision signal, and also the tonic background inhibition that normally suppresses unwanted early responses.     

Posttraumatic hemiballism with focal discrete hemorrhage in contralateral subthalamic nucleus

Although head trauma has occasionally been described as a cause of hemiballism, relevant traumatic lesion involving subthalamic nucleus (STN) has rarely been reported. We report a 49-year-old man with focal and discrete traumatic STN hemorrhage, which presented as transient contralateral hemiballism. Although such discrete STN lesion is not infrequently found in patients with post-stroke hemiballism, it has not been reported in posttraumatic hemiballism.     

Fear recognition is impaired by subthalamic nucleus stimulation in Parkinson's disease

Behavioural disturbances such as disorders of mood, apathy or indifference are often observed in Parkinson's disease (PD) patients with chronic high frequency deep brain stimulation of subthalamic nucleus (STN DBS). Neuropsychological modifications causing these adverse events induced by STN DBS remain unknown, even if limbic disturbances are hypothesised. The limbic system supports neural circuits processing emotional information. The aim of this work is to evaluate changes of emotional recognition in PD patients induced by STN DBS. Thirty PD patients were assessed using a computerised paradigm of recognition of emotional facial expressions [Ekman, P., & Friesen, W. V. (1976). Pictures of facial affect. Palo Alto, CA: Consulting Psychologists Press], 15 before STN DBS and 15 after. The two patients groups were compared to a group of 15 healthy control subjects. One series of 55 pictures of emotional facial expressions was presented to each patient. Patients had to classify the pictures according to seven basic emotions (happiness, sadness, fear, surprise, disgust, anger and no emotion). The intact ability to percept faces was firstly assured using the Benton Recognition Test. Recognition of fear expressions was significantly and selectively reduced in the post-operative group in comparison to both pre-operative and control groups. Our results demonstrate for the first time a selective reduction of recognition of facial expressions of fear by STN DBS. This impairment could be the first neuropsychological marker of a more general limbic dysfunction, thought to be responsible for the behavioural disorders reported after STN DBS.     

Excitatory effects of dopamine on subthalamic nucleus neurons: in vitro study of rats pretreated with 6-hydroxydopamine and levodopa

Increased output from the subthalamic nucleus (STN) following chronic dopamine depletion has been linked to the rigidity and tremor seen in Parkinson's disease (PD). We used extracellular microelectrode recordings from rat brain slices to investigate effects of dopamine on STN neurons. In brain slices prepared from rats that received unilateral 6-hydroxydopamine (6-OHDA) treatment, the spontaneous firing rate of STN neurons was reduced by 63%, and the firing pattern was more irregular, compared to STN neurons from normal rats. However, treatment with levodopa (50 mg/kg, i.p., daily) for 4 weeks normalized the firing rate and pattern of STN neurons in the 6-OHDA-treated rats. Dopamine (3-300 microM), added to the superfusate, significantly increased the firing rates of STN neurons in a concentration-dependent fashion, and also produced a more regular firing pattern in 6-OHDA-lesioned tissue. This excitatory effect of dopamine was mimicked by a D2 receptor agonist (quinpirole), and was reduced by the D2 antagonists haloperidol, clozapine and sulpiride. Antagonists of the D1 receptor (SCH-23390) and ionotropic glutamatergic receptors (CNQX and AP5) could not block the effect of dopamine on firing rate. These results suggest that dopamine exerts a direct excitatory influence on STN neurons via the activation of D2-like receptors.     

Stimulation-induced inhibition of neuronal firing in human subthalamic nucleus

The subthalamic nucleus (STN) is an important component of the basal ganglia (BG) and plays a major role in the pathogenesis of Parkinsons disease (PD). Hyperactivity of STN as a consequence of the loss of dopaminergic inputs to the BG is believed to be a major factor in producing the motor symptoms of PD. High-frequency (HF) deep brain stimulation (DBS) of the STN has recently become an important treatment in PD patients where medications no longer provide satisfactory therapy. However, the mechanisms underlying DBS therapy are unknown, and there is seemingly conflicting data suggesting inhibition or excitation of STN neurons. This study directly examined the effects of stimulation in STN on the activity of STN neurons in PD patients during functional stereotactic mapping prior to insertion of DBS electrodes. Electrical stimulation in STN was investigated in twelve PD patients by recording the neural activity of a cell in STN with one electrode while applying current pulses through a second electrode located about 600 µm away. Stimulation at high frequencies (100–300 Hz) was found to produce inhibition following the stimulus train in 42% of the 60 cells tested. Inhibition during the train was seen in 13 of 15 neurons where it was possible to detect such activity. Furthermore, in 44% of the cases where HF stimulation produced inhibition there was an early inhibition followed by rebound excitation and a further inhibitory period, suggesting that the inhibitions observed are due to hyperpolarization. In eight of the 25 neurons inhibited by HF stimulation, the effects of single stimuli were determined and revealed that in seven of these there was an inhibitory period of 15–20 ms following each stimulus. Thus, the present findings suggest that local HF stimulation inhibits many STN neurons. However, these studies could not determine whether the stimulus also directly excited the cell and/or its axon, but other recent findings suggest that this is likely the case. Therefore, the overall effects of DBS stimulation in STN are likely to be inhibition of intrinsic and synaptically mediated activity, and its replacement by regular high-frequency firing.     

Activity of neurons of the subthalamic nucleus in relation to motor performance in the cat

The activity of subthalamic nucleus neurons related to motor performance was studied in three unrestrained cats operantly conditioned to perform a lever-release movement. The movement was initiated either rapidly after the trigger stimulus (a brief sound) in a simple reaction-time paradigm or after a delay in trials identified by a tone cue. These paradigms were randomly presented. The activity of 171 neurons was recorded in the contralateral and in the ipsilateral subthalamic nucleus, with respect to the performing limb. The mean spontaneous activity of cells in the ipsilateral side (18.5±13.8 imp/s, mean±SD) was higher than that in the contralateral side (8.5±8.1 imp/s). A total of 145 cells (85%) presented significant changes in activity in relation to the lever-release movement (task-related cells). The remaining 26 cells were either related to other events of the task (n=15; lever-press or reinforcement occurrence) or not related at all to the task performance (n=11). The majority of changes of activity of task-related cells were initial increases in discharge, which started on average, 127 ms before movement onset and lasted several hundreds of milliseconds. These increases in discharge were more frequent in the contralateral side (75 of 80 task-related cells, 94%) than in the ipsilateral side (43 of 65 task-related cells, 66%). The changes in activity, either increases or decreases, occurred early after the trigger stimulus, since 62% of them had a latency of less than 100 ms. Although the mean latency of initial increases was rather similar in both sides (97 ms contralateral versus 104 ms ipsilateral), the contralateral side was characterized by a high proportion of very early responses (less than 20 ms). For most neurons, the early changes in activity described above were absent after the trigger stimulus in the delayed condition. For certain neurons, the changes in activity prior to movement were different in reactiontime condition and in delayed condition, showing that the pattern of activity preceding movement might depend on the temporal requirements for motor initiation. The results suggest that a significant proportion of subthalamic cells are involved in the preparation and the initiation phases of the lever-release movement studied, although other hypotheses (e.g. stimulus-related responses) cannot be definitely ruled out. The timings and patterns of the changes in activity observed in the subthalamic nucleus in the present study, and in the pallidal complex previously, cannot be explained easily by the classical scheme where the external pallidum inhibits the subthalamic nucleus. The results suggest rather that the subthalamic nucleus, driven by a yet-to-be-determined excitatory input, exerts an excitatory influence on the pallidum and plays a crucial role in the control of the basal ganglia output neurons.     

Gait-related frequency modulation of beta oscillatory activity in the subthalamic nucleus of parkinsonian patients

BackgroundAbnormal beta band activity in the subthalamic nucleus (STN) is known to be exaggerated in patients with Parkinson’s disease, and the amplitude of such activity has been associated with akinetic rigid symptoms. New devices for deep brain stimulation (DBS) that operate by adapting the stimulation parameters generally rely on the detection of beta activity amplitude modulations in these patients. Movement-related frequency modulation of beta oscillatory activity has been poorly investigated, despite being an attractive variable for extracting information about basal ganglia activity.ObjectiveWe studied the STN oscillatory activity associated with locomotion and proposed a new approach to extract movement related information from beta band activity.MethodsWe recorded bilateral local field potential of the STN in eight parkinsonian patients implanted with DBS electrodes during upright quiet standing and unperturbed walking. Neurophysiological recordings were combined with kinematic measurements and individual molecular brain imaging studies. We then determined the information carried by the STN oscillatory activity about locomotion and we identified task-specific biomarkers.ResultsWe found a gait-related peak frequency modulation of the beta band of STN recordings of parkinsonian patients. This novel biomarker and the associated power modulations were highly informative to detect the walking state (with respect to standing) in each single patient.ConclusionFrequency modulation in the human STN represents a fundamental aspect of information processing of locomotion. Our information-driven approach could significantly enrich the spectrum of Parkinson’s neural markers, with input signals encoding ongoing tasks execution for an appropriate online tuning of DBS delivery.     

咪唑安定对鼠中枢杏仁核神经元电活动的影响

目的：观察咪唑安定及其拮抗药对杏仁核神经元峰电位发放频率的影响。方法：在40例小鼠脑薄片标本上对杏仁核簇神经元进行电生理全细胞膜片箍记录。结果：咪唑安定增加神经元放电频率，咪唑安定的这种作用起效迅速，作用时间短，其拮抗药氟马西尼可完全逆转现象。结论：咪唑安定兴奋大脑边缘系统杏仁核，通过与神经细胞膜上苯二氮卓受体 产生抗焦虚，催眠和镇静作用，其作用能完全被氟马西尼拮抗。     

Subthalamic stimulation improves orienting gaze movements in Parkinson’s disease

OBJECTIVE: To determine the effect of subthalamic stimulation on visually triggered eye and head movements in patients with Parkinson's disease (PD). METHODS: We compared the gain and latency of visually triggered eye and head movements in 12 patients bilaterally implanted into the subthalamic nucleus (STN) for severe PD and six age-matched control subjects. Visually triggered movements of eye (head restrained), and of eye and head (head unrestrained) were recorded in the absence of dopaminergic medication. Bilateral stimulation was turned OFF and then turned ON with voltage and contact used in chronic setting. The latency was determined from the beginning of initial horizontal eye movements relative to the target onset, and the gain was defined as the ratio of the amplitude of the initial movement to the amplitude of the target movement. RESULTS: Without stimulation, the initiation of the head movement was significantly delayed in patients and the gain of head movement was reduced. Our patients also presented significantly prolonged latencies and hypometry of visually triggered saccades in the head-fixed condition and of gaze in head-free condition. Bilateral STN stimulation with therapeutic parameters improved performance of orienting gaze, eye and head movements towards the controls' level CONCLUSIONS: These results demonstrate that visually triggered saccades and orienting eye-head movements are impaired in the advanced stage of PD. In addition, subthalamic stimulation enhances amplitude and shortens latency of these movements. SIGNIFICANCE: These results are likely explained by alteration of the information processed by the superior colliculus (SC), a pivotal visuomotor structure involved in both voluntary and reflexive saccades. Improvement of movements with stimulation of the STN may be related to its positive input either on the STN-Substantia Nigra-SC pathway or on the parietal cortex-SC pathway.     

丘脑底核脑深部电刺激治疗帕金森病临床SPECT随访

目的探讨丘脑底核脑深部电刺激(STN DBS)治疗帕金森病(PD)患者症状的改善及单光子放射计算机断层扫描(SPECT)的影像学变化。方法4例施行单侧STN DBS患者术前和给予电刺激后进行帕金森病综合评分(UPDRS)和SPECT测定。结果STN DBS术后临床症状明显改善,UPDRS运动评分缓解60%。3例改善良好的患者SPECT检查提示纹状体区域多巴胺转运体(DAT)含量较术前提高,另1例疗效欠佳的患者DAT含量降低,所有的患者多巴胺D2受体(D2R)检测与术前无明显差异。结论STN DBS可以明显改善PD患者的临床症状,SPECT检查显示刺激侧纹状体区DAT含量的升高提示STN DBS可能改善了多巴胺的代谢,而这种改善可能是STN DBS缓解PD症状的作用机制之一。