Using STN DBS and medication reduction as a strategy to treat pathological gambling in Parkinson's disease

We describe two patients with Parkinson's disease (PD) who developed clinical criteria of pathological gambling addiction in the setting of increased dopamine replacement therapy (levodopa and dopamine agonist medications). The second patient showed also signs of dopamine dysregulation syndrome, with an addiction to dopaminergic medication. Neither patients responded to the standard therapy for gambling behavior, but dramatically improved after bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) and early postoperative withdrawal of dopaminergic therapy. The possible therapeutic role of subthalamic nucleus deep brain stimulation (STN-DBS) on such a disabling behavior needs to be investigated prospectively.     

Pallidal neuron activity determines responsiveness to deep brain stimulation in cervical dystonia

ObjectiveIn patients with cervical dystonia we sought for the differences in neuronal behavior of pallidal regions where deep brain stimulation resulted in favorable therapeutic response compared to those where the response was absent.MethodsWe compared single-unit activity of 564 neurons recorded from deep brain stimulation sensitive and non-sensitive regions in 17 cervical dystonia patients.ResultsGlobus pallidus internus regions responsive to the deep brain stimulation had lower firing rates and bursting compared to non-responsive areas. The differences were robust in locations where neuronal responses correlated with neck movements. Per the effects of deep brain stimulation, the pallidal regions were classified in weak, intermediate, and excellent responsive. Pallidal regions with weak response to deep brain stimulation had fewer burst neurons and higher firing rate compared to neurons in areas with excellent response. The burst index was significantly decreased in excellent response regions. There was a significant decrease in the alpha band oscillation score but a substantial increase in the gamma band in excellent response neurons.ConclusionThe pallidal region that would be responsive to deep brain stimulation has distinct physiology compared to the non-responsive region.SignificanceThese results provide novel insights into globus pallidus interna neurons' physiology in cervical dystonia.     

Designing a deep brain stimulator to suppress pathological neuronal synchrony

Some of neuropathologies are believed to be related to abnormal synchronization of neurons. In the line of therapy, designing effective deep brain stimulators to suppress the pathological synchrony among neuronal ensembles is a challenge of high clinical relevance. The stimulation should be able to disrupt the synchrony in the presence of latencies due to imperfect knowledge about parameters of a neuronal ensemble and stimulation impacts on the ensemble. We propose an adaptive desynchronizing deep brain stimulator capable of dealing with these uncertainties. We analyze the collective behavior of the stimulated neuronal ensemble and show that, using the designed stimulator, the resulting asynchronous state is stable. Simulation results reveal the efficiency of the proposed technique.     

Temporally irregular electrical stimulation to the epileptogenic focus delays epileptogenesis in rats

BackgroundVariation in the temporal patterns of electrical pulses in stimulation trains has opened a new field of opportunity for the treatment of neurological disorders, such as pharmacoresistant temporal lobe epilepsy. Whether this novel type of stimulation affects epileptogenesis remains to be investigated.ObjectiveThe purpose of this study was to analyze the effects of temporally irregular deep brain stimulation on kindling-induced epileptogenesis in rats.MethodsTemporally irregular deep brain stimulation was delivered at different times with respect to the kindling stimulation. Behavioral and electrographic changes on kindling acquisition were compared with a control group and a temporally regular deep brain stimulation-treated group. The propagation of epileptiform activity was analyzed with wavelet cross-correlation analysis, and interictal epileptiform discharge ratios were obtained.ResultsTemporally irregular deep brain stimulation delivered in the epileptogenic focus during the interictal period shortened the daily afterdischarge duration, slowed the progression of seizure stages, diminished the generalized seizure duration and interfered with the propagation of epileptiform activity from the seizure onset zone to the ipsi- and contralateral motor cortex. We also found a negative correlation between seizure severity and interictal epileptiform discharges in rats stimulated with temporally irregular deep brain stimulation.ConclusionThese results provide evidence that temporally irregular deep brain stimulation interferes with the establishment of epilepsy by delaying epileptogenesis by almost twice as long in kindling animals. Thus, temporally irregular deep brain stimulation could be a preventive approach against epilepsy.     

Deep brain stimulation of the subthalamic nucleus enhances emotional processing in Parkinson disease

BACKGROUND: High-frequency electrical stimulation of the subthalamic nucleus is a new and highly effective therapy for complications of long-term levodopa therapy and motor symptoms in advanced Parkinson disease (PD). Clinical observations indicate additional influence on emotional behavior. METHODS: Electrical stimulation of deep brain nuclei with pulse rates above 100 Hz provokes a reversible, lesioning-like effect. Here, the effect of deep brain stimulation of the subthalamic nucleus on emotional, cognitive, and motor performance in patients with PD (n = 12) was examined. The results were compared with the effects of a suprathreshold dose of levodopa intended to transiently restore striatal dopamine deficiency. Patients were tested during medication off/stimulation off (STIM OFF), medication off/stimulation on (STIM ON), and during the best motor state after taking levodopa without deep brain stimulation (MED). RESULTS: More positive self-reported mood and an enhanced mood induction effect as well as improvement in emotional memory during STIM ON were observed, while during STIM OFF, patients revealed reduced emotional performance. Comparable effects were revealed by STIM ON and MED. Cognitive performance was not affected by the different conditions and treatments. CONCLUSIONS: Deep brain stimulation of the subthalamic nucleus selectively enhanced affective processing and subjective well-being and seemed to be antidepressive. Levodopa and deep brain stimulation had similar effects on emotion. This finding may provide new clues about the neurobiologic bases of emotion and mood disorders, and it illustrates the important role of the basal ganglia and the dopaminergic system in emotional processing in addition to the well-known motor and cognitive functions.     

Adaptively controlling deep brain stimulation in essential tremor patient via surface electromyography

Abstract

Objectives: We present patient test outcomes to show that on–off control of deep brain stimulation sequences in essential tremor patients is achievable in a self-adaptive manner via non-invasive surface-electromyography, to prevent tremors in these patients.

Method: In our study, an essential tremor patient, who underwent bilateral deep brain stimulation implantation 8 years earlier, was subjected to deep brain stimulation at 130 pulses/second, with a 90-microsecond pulse-width, in packets of durations from 20 to 73 seconds and was monitored with surface-electromyography.

Results: At the end of these stimulation packets, tremor-free intervals followed, averaging over 20 seconds, before tremor reappeared. Wavelet analysis of the eletromyographic signals allowed predicting onset of tremors at the end of the tremor-free intervals and was successful in all test cycles. Furthermore, once stimulation was restarted, the tremors disappeared within 0.5 seconds on average. When restarting stimulation approximately 2 seconds ahead of the end of tremor-free post-simulation intervals as predicted by visual inspection of unprocessed electromyograms, no tremors occurred during three successive cycles of stimulation-on and stimulation-off. Maximal ratio of tremor-free duration to stimulation duration was computed, to determine a best DBS (deep brain stimulation) duration range (20–35 seconds).

Conclusions: We show existence of a tremor-free interval averaging over 20 seconds that follows applying stimulation packets of 20–35 seconds and that surface electomyogram allows predicting onset of tremor to facilitate activation of a next stimulation packet before tremor reappears. This establishes the feasibility of electromyographic-based predictive on–off control of deep brain stimulation in certain essential tremor patients. Best tremor-free duration to stimulation duration ratio may differ over the progression of the disorder and from patient to patient.     

Deep brain stimulation of the subthalamic nucleus transiently enhances loss-chasing behaviour in patients with Parkinson's disease

Dopaminergic treatments are associated with impulse control disorders such as pathological gambling in a subset of patients with Parkinson's Disease. While deep brain stimulation of the subthalamic nucleus has been reported to reduce symptoms of impulse control disorders in some Parkinson's Disease patients, little is known about its specific effects on gambling behaviour. In this experiment, we investigated the effects of deep brain stimulation of the subthalamic nucleus on one of the central features of pathological gambling: the tendency to chase losses. Loss-chasing is associated with impaired control over gambling behaviour and it is one of the most salient features of pathological gambling as it presents in the clinic. Twenty two patients with advanced idiopathic Parkinson's Disease and chronically implanted subthalamic nucleus electrodes for deep brain stimulation completed a simple laboratory model of loss-chasing behaviour twice: once with and once without stimulation. Exploratory analysis indicated that deep brain stimulation of the subthalamic nucleus increased the value of losses chased by patients with Parkinson's Disease when shifting from off- to on-stimulation. These effects were not attributable to changes in state affect or to the motor impairments produced by the withdrawal of deep brain stimulation of the subthalamic nucleus. The effects of the stimulation on the value of losses chased were more pronounced in female than in male patients and reduced in patients taking dopamine receptor agonists. Collectively, these results suggest that deep brain stimulation of the subthalamic nucleus can transiently alter the evaluation of accumulated losses during gambling episodes in idiopathic Parkinson's Disease.     

Deep brain stimulation in epilepsy.

Since the pioneering studies of Cooper et al. to influence epilepsy by cerebellar stimulation, numerous attempts have been made to reduce seizure frequency by stimulation of deep brain structures. Evidence from experimental animal studies suggests the existence of a nigral control of the epilepsy system. It is hypothesized that the dorsal midbrain anticonvulsant zone in the superior colliculi is under inhibitory control of efferents from the substantia nigra pars reticulata. Inhibition of the subthalamic nucleus (STN) could release the inhibitory effect of the substantia nigra pars reticulata on the dorsal midbrain anticonvulsant zone and thus activate the latter, raising the seizure threshold. Modulation of the seizure threshold by stimulation of deep brain structures-in particular, of the STN-is a promising future treatment option for patients with pharmacologically intractable epilepsy. Experimental studies supporting the existence of the nigral control of epilepsy system and preliminary results of STN stimulation in animals and humans are reviewed, and alternative mechanisms of seizure suppression by STN stimulation are discussed.     

Impact of discontinuing tremor suppressing medications following thalamic deep brain stimulation

BackgroundMany essential tremor patients continue to require tremor suppressing medications following deep brain stimulation. The true incidence of medication usage in the years following surgery remains unclear, and the use of medications has not been included in the post-operative analyses of tremor severity and also quality of life.MethodsAmong 28 essential tremor patients treated with deep brain stimulation at a single center between January 2002 and April 2010, we analyzed the prevalence and dosage of pre-operative tremor suppressing medications versus post-operative medications at 12 and 36 months following surgery. We also assessed the influence of medication continuation on clinical outcome measures, such as the Fahn-Tolosa-Marin Tremor Rating Scale, and the 36 item short-form health quality of life survey.ResultsBoth unilateral and bilateral deep brain stimulation resulted in a decrease in primidone use (p = 0.0082, 0.046, respectively), and bilateral deep brain stimulation patients used less tremor suppressing medications 36 months following surgery (p = 0.02). The decision to discontinue primidone after surgery resulted in a non-significant long-term improvement in tremor motor score (23 points versus 15 points, p = 0.19), and did not significantly influence the physical and mental composite quality of life scores (p = 0.81, 0.23, respectively).ConclusionsBilateral deep brain stimulation effectively eliminated the need for tremor suppressing medications, while unilateral stimulation was not as effective in reducing medication usage. Clinicians and patients should be aware that discontinuation of primidone after surgery may worsen tremor in unilateral deep brain stimulation cases, but discontinuation will not likely impact quality of life.     

脑深部电刺激治疗异动症模型大鼠的行为学研究

目的观察高频电刺激对帕金森病异动症大鼠模型的行为学影响。方法成功制备帕金森病、异动症和丘脑底核高频电刺激大鼠模型,随机分为"刺激组"、"假刺激组"和"假手术组",观察高频电刺激对旋转行为和不自主行为(AIM)评分的影响。结果高频电刺激可抑制模型大鼠的旋转行为;在左旋多巴甲酯和苄丝肼药效期内高频电刺激治疗后的"刺激组"模型大鼠AIM评分明显减低、旋转速度明显减慢。结论高频电刺激可改善左旋多巴诱导的异动症(LID)的症状;其作用并非刺激电极植入本身对丘脑底核(STN)损伤所致;STN-DBS治疗后LID症状可在一定时间内持续改善。     

Modulation of subthalamic alpha activity to emotional stimuli correlates with depressive symptoms in Parkinson's disease1

Background : Deep brain stimulation of the subthalamic nucleus is an effective treatment for patients with advanced Parkinson's disease. However, affective side effects following subthalamic deep brain stimulation have been reported. Here, we aim to elucidate the influence of affective state on emotional processing as indexed by local field potential activity and to identify neurophysiological markers in patients at risk of developing depressive symptoms during subthalamic deep brain stimulation. Methods : Subthalamic local field potentials were directly recorded via electrodes implanted for deep brain stimulation in 12 Parkinson's disease patients while viewing emotionally salient and neutral pictures. Parkinson's disease patients were assessed for depressive symptoms using the Beck depression inventory at the time of operation and 3 months after continuous subthalamic nucleus deep brain stimulation. Results : We found a significant event‐related desynchronization in the local alpha frequency band (8–12 Hz) for emotionally arousing but not neutral pictures. The the event‐related desynchronization (ERD) in the alpha frequency band was reduced for pleasant stimuli in patients with mild to moderate depressive symptoms compared with patients without depression. The alpha‐ERD to unpleasant stimuli showed the opposite pattern. Consistently, the index of event‐related alpha desynchronization (alpha ERD for pleasant stimuli minus alpha ERD for unpleasant stimuli) correlated with the Beck depression inventory at the time of the recordings and at 3 months after continuous deep brain stimulation. The alpha ERD to unpleasant pictures correlated significantly with the Beck depression inventory score at 3 months after chronic deep brain stimulation. Discusion : In conclusion, we found mood‐congruent stimulus processing in the subthalamic nucleus of Parkinson's disease patients. Electrophysiological markers such as event‐related desynchronization of subthalamic alpha activity reflect state‐dependent emotional processing and may potentially be used to predict depressive mood disturbances in Parkinson's disease patients with chronic subthalamic deep brain stimulation at an early stage. © 2011 Movement Disorder Society     

Dopamine dysregulation syndrome after deep brain stimulation of the subthalamic nucleus in Parkinson's disease

Dopamine dysregulation syndrome is a complication of the dopaminergic treatment for Parkinson's disease, probably related to sensitization of the mesolimbic dopamine system. The relationship between dopamine dysregulation syndrome and deep brain stimulation of the subthalamic nucleus remains unclear. We report three patients with Parkinson's disease who developed de novo dopamine dysregulation syndrome after deep brain stimulation of the subthalamic nucleus. We hypothesized that the combined effect of dopaminergic replacement therapy and deep brain stimulation on the limbic territory of the subthalamic nucleus could have precipitated the dopamine dysregulation syndrome in these patients, by inducing hyperstimulation of the mesolimbic dopamine system. The outcome of postoperative dopamine dysregulation syndrome is poor despite deep brain stimulation adjustments, attempts to reduce the dose of dopaminergic drugs and the addition of quetiapine or antidepressants.     

The thalamic reticular nucleus: A common nucleus of neuropsychiatric diseases and deep brain stimulation

This review focuses on the studies that have been reviewed to determine the influence of the thalamic reticular nucleus on neuropsychiatric diseases and deep brain stimulation. The literature reviewed to date describes how alterations in the thalamic reticular nucleus affect several functions that regulated brain rhythms and provokes symptoms of many disorders. The observations as the basis for the renewed interest in the thalamic reticular nucleus in experimental models and testing its effectiveness in patients with resistant neuropsychiatric disorders. The preclinical studies showed that deep brain stimulation in the thalamic reticular nucleus could have beneficial effects on EEG activity, including synchronization and desynchronization activity of the brain, as well as promoting an alleviate to neuropsychiatric diseases. These observations open up the possibility of studying the role played by neurotransmitters in the pathologic process and the deep brain stimulation in the thalamic reticular nucleus in experimental animal models and offer evidence of its possible action in the human brain.     

人用DBS系统在脑深部电刺激猴模型构建中的应用

目的探讨人用脑深部电刺激(DBS)系统在构建猴脑深部电刺激模型中的应用。方法 4只偏侧帕金森病(PD)猴模型,按照猴脑立体定向图谱,在右侧丘脑底核(STN)植入脑深部刺激电极(Medtronic 3389),其中刺激组2只猴同期皮下植入Medtronic 7495型连接导线和Soletra TM7426型脉冲发生器,术后一周给予慢性高频电刺激。另2只偏侧PD模型猴仅在右侧STN植入电极,不植入脉冲发生器,作为对照组。连续观察12个月,进行运动障碍评分观察和阿朴吗啡(APO)诱发旋转实验。结果术后影像学观察电极前端均位于STN核范围内;刺激组同期植入脉冲发生器给予慢性高频电刺激,猴偏侧帕金森样症状明显改善,有效高频电刺激可以立即停止APO所诱发的旋转,而对照组在观察期内症状无明显缓解。结论人用DBS系统通过立体定向技术植入猴脑内特定靶点,可以有效的建立DBS动物模型,为DBS在神经系统疾病中的应用研究提供了良好的实验模型。     

Subthalamic deep brain stimulation improves time perception in Parkinson's disease

Alterations in temporal estimation have been observed in Parkinson's disease (PD) and have been associated with dopaminergic dysfunction. To investigate whether deep brain stimulation might reverse these abnormalities in PD, patients treated with electrode implantation for subthalamic deep brain stimulation were required to reproduce time intervals in different experimental conditions (off deep brain stimulation/off therapy, on deep brain stimulation/off therapy, on therapy/off deep brain stimulation). Patients treated with deep brain stimulation in off deep brain stimulation/off therapy displayed the anomalous pattern of responses typically observed in PD. When subthalamic deep brain stimulation was turned on these abnormalities were significantly attenuated. Our findings reveal that subthalamic deep brain stimulation improves time perception in PD patients, supporting the critical role of basal ganglia in this cognitive function, probably mediated by facilitated thalamo-cortical projections to the prefrontal cortex.     

脑深部电刺激伏核对自身给药大鼠海洛因觅药行为的影响

目的观察脑深部电刺激(deep brain stimulation,DBS)伏核对大鼠海洛因自身给药觅药行为的影响。方法用固定比率程序建立大鼠海洛因自身给药复吸模型。将18只大鼠随机分成对照组、假刺激组和DBS组,假刺激组及DBS组大鼠行双侧伏核核心部微电极植入术。DBS组大鼠在消退期每天给予高频电刺激1h(刺激参数:方波,频率130 Hz,电流150μA,波宽100μs),共7d。消退后采用条件性线索和小剂量海洛因诱导引燃大鼠海洛因觅药行为。结果在条件性线索诱导的复吸测评中,DBS组大鼠有效鼻触数(8.00±5.33)明显少于对照组(36.50±9.16)和假手术组(34.00±7.93),具统计学意义(P<0.01);在小剂量海洛因诱导的复吸测评中,DBS组大鼠有效鼻触数(11.17±7.78)明显少于对照组(29.67±5.24)和假手术组(28.00±11.92),具统计学意义(P<0.01);DBS组、对照组和假手术组大鼠在总活动度和每阶段活动度上的差异均无统计学意义(P>0.01)。结论DBS高频电刺激伏核可减少海洛因自身给药大鼠条件性线索和小剂量海洛因诱导的觅药行为,且不会影响其活动度。     

Distinct perceptive pathways selected with tonic and bursting patterns of thalamic stimulation

BackgroundNovel patterns of electrical stimulation of the brain and spinal cord hold tremendous promise to improve neuromodulation therapies for diverse disorders, including tremor and pain. To date, there are limited numbers of experimental studies in human subjects to help explain how stimulation patterns impact the clinical response, especially with deep brain stimulation.We propose using novel stimulation patterns during electrical stimulation of somatosensory thalamus in awake deep brain stimulation surgeries and hypothesize that stimulation patterns will influence the sensory percept without moving the electrode.MethodsIn this study of 15 fully awake patients, the threshold of perception as well as perceptual characteristics were compared for tonic (trains of regularly-repeated pulses) and bursting stimulation patterns.ResultsIn a majority of subjects, tonic and burst percepts were located in separate, non-overlapping body regions (i.e., face vs. hand) without moving the stimulating electrode (p < 0.001; binomial test). The qualitative features of burst percepts also differed from those of tonic-evoked percepts as burst patterns were less likely to evoke percepts described as tingling (p = 0.013; Fisher’s exact test).ConclusionsBecause somatosensory thalamus is somatotopically organized, percept location can be related to anatomic thalamocortical pathways. Thus, stimulation pattern may provide a mechanism to select for different thalamocortical pathways. This added control could lead to improvements in neuromodulation - such as improved efficacy and side effect attenuation - and may also improve localization for sensory prostheses.     

Long-term time course of affective lability after subthalamic deep brain stimulation electrode implantation

The mechanism and time course of emotional side effects of subthalamic deep brain stimulation in Parkinson's disease are a matter for discussion. We report a 53-month follow-up of a patient with affective lability. Postoperative lesion plus bilateral stimulation strongly influenced mood in the first week in terms of laughing behavior, while voltage changes had only minor long-term impact up to 37 months on negative emotion, possibly caused by the right electrode stimulating the subthalamic nucleus and adjacent fiber tracts involving the internal capsule. Thus we conclude that affective lability can occur with different temporal dynamics of microlesion, and early and chronic stimulation.     

Electroencephalographic responses to intraoperative subthalamic stimulation

This study reports the effects of intraoperative stimulation of the subthalamic nucleus on brain electrical activity in advanced Parkinson's patients. To our knowledge, this is the first study about electroencephalographic responses in the very early phase of deep brain stimulation, during the implantation of the electrodes. We found an increase of gamma band bilaterally over the sensorimotor cortex in the range 45-55 Hz, which was associated with clinical improvement as assessed by means of muscle rigidity decrease. These results indicate that the electroencephalographic gamma responses to deep brain stimulation are present at the very beginning of the treatment process, and may help better understand the short and long-tem effects of deep brain stimulation.     

Memory enhancement induced by hypothalamic/fornix deep brain stimulation

Bilateral hypothalamic deep brain stimulation was performed to treat a patient with morbid obesity. We observed, quite unexpectedly, that stimulation evoked detailed autobiographical memories. Associative memory tasks conducted in a double-blinded "on" versus "off" manner demonstrated that stimulation increased recollection but not familiarity-based recognition, indicating a functional engagement of the hippocampus. Electroencephalographic source localization showed that hypothalamic deep brain stimulation drove activity in mesial temporal lobe structures. This shows that hypothalamic stimulation in this patient modulates limbic activity and improves certain memory functions.