Aggravated stuttering following subthalamic deep brain stimulation in Parkinson's disease - two cases

Stuttering is a speech disorder with disruption of verbal fluency which is occasionally present in patients with Parkinson's disease (PD). Long-term medical management of PD is frequently complicated by fluctuating motor functions and dyskinesias. High-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment of motor fluctuations and is the most common surgical procedure in PD. Here we report the re-occurrence and aggravation of stuttering following STN-DBS in two male patients treated for advanced PD. In both patients the speech fluency improved considerably when the neurostimulator was turned off, indicating that stuttering aggravation was related to neurostimulation of the STN itself, its afferent or efferent projections and/or to structures localized in the immediate proximity. This report supports previous studies demonstrating that lesions of the basal ganglia-thalamocortical motor circuit, including the STN, is involved in the development of stuttering. In advanced PD STN-DBS is generally an effective and safe treatment. However, patients with PD and stuttering should be informed about the risk of aggravated symptoms following surgical therapy.     

Controlling mechanism of absence seizures by deep brain stimulus applied on subthalamic nucleus

Based on a classical model of the basal ganglia thalamocortical network, in this paper, we employed a type of the deep brain stimulus voltage on the subthalamic nucleus to study the control mechanism of absence epilepsy seizures. We found that the seizure can be well controlled by turning the period and the duration of current stimulation into suitable ranges. It is the very interesting bidirectional periodic adjustment phenomenon. These parameters are easily regulated in clinical practice, therefore, the results obtained in this paper may further help us to understand the treatment mechanism of the epilepsy seizure.     

脑深部电刺激的临床应用

脑深部电刺激(deep brain stimulation,DBS)是近20年来神经外科领域发展最迅猛的技术。DBS是通过刺激发生器发出的高频电脉冲信号刺激脑神经核团或神经传导束来调节异常的神经环路。DBS已经成为治疗特发性震颤、帕金森病、肌张力障碍等运动障碍病的常规手术方法。自1997年深部脑刺激通过美国FDA认证用于治疗特发性震颤以来,已有超过数万名运动障碍患者接受该疗法,而国内脑深部电刺激最早在1999年应用于帕金森病临床治疗,迄今也有数千例患者接受了植入手术。近年,脑起搏器的临床适应症不断扩大,从最初的运动障碍病逐渐发展到治疗其他神经和精神疾病,如抽动秽语综合征、强迫症、抑郁症、神经性厌食症、难治性疼痛、癫痫、植物状态和阿尔茨海默病等,虽然DBS的治疗机理还不很清楚,但可以预见未来DBS将成为众多神经和精神疾病的重要治疗方法。     

Translational principles of deep brain stimulation

Deep brain stimulation (DBS) has shown remarkable therapeutic benefits for patients with otherwise treatment-resistant movement and affective disorders. This technique is not only clinically useful, but it can also provide new insights into fundamental brain functions through direct manipulation of both local and distributed brain networks in many different species. In particular, DBS can be used in conjunction with non-invasive neuroimaging methods such as magnetoencephalography to map the fundamental mechanisms of normal and abnormal oscillatory synchronization that underlie human brain function. The precise mechanisms of action for DBS remain uncertain, but here we give an up-to-date overview of the principles of DBS, its neural mechanisms and its potential future applications.     

Increase in body weight is a non-motor side effect of deep brain stimulation of the subthalamic nucleus in Parkinson's disease

Deep brain stimulation of the subthalamic nucleus (DBS STN) is an effective treatment method in advanced Parkinson's disease (PD) providing marked improvement of its major motor symptoms. In addition, non-motor effects have been reported including weight gain in PD patients after DBS STN. Using retrospective survey, we aimed to evaluate weight changes in our patients with advanced PD treated with DBS STN. We inquired 25 PD patients (16 men, 9 women), of mean age 55 (42-65) years, mean PD duration 15 (9-21) years, who previously received bilateral DBS STN. We obtained valid data from 23 patients. In the first survey, 1 to 45 months after DBS, weight gain was found in all patients comparing to pre-DBS period. The mean increase was 9.4 kg (from 1 to 25 kg). The patients' mean body mass index (BMI) increased from 23.7 to 27.0 kg/m2, i.e. by 3.3 kg/m2 (+2 to +6.1 kg/m2). In the repeated survey one year later, in 12 of the patients body weight moderately decreased, 3 did not change, and 6 patients further increased their weight. Possible explanations of body weight gain after DBS STN include a reduction of energy output related to elimination of dyskinesias, improved alimentation or direct influence on function of lateral hypothalamus by DBS STN.     

New insights offered by a computational model of deep brain stimulation

Deep brain stimulation (DBS) is a standard neurosurgical procedure used to treat motor symptoms in about 5% of patients with Parkinson's disease (PD). Despite the indisputable success of this procedure, the biological mechanisms underlying the clinical benefits of DBS have not yet been fully elucidated. The paper starts with a brief review on the use of DBS to treat PD symptoms. The second section introduces a computational model based on the population density approach and the Izhikevich neuron model. We explain why this model is appropriate for investigating macroscopic network effects and exploring the physiological mechanisms which respond to this treatment strategy (i.e., DBS). Finally, we present new insights into the ways this computational model may help to elucidate the dynamic network effects produced in a cerebral structure when DBS is applied.     

Modulation of visual processing by attention and emotion: windows on causal interactions between human brain regions

Visual processing is not determined solely by retinal inputs. Attentional modulation can arise when the internal attentional state (current task) of the observer alters visual processing of the same stimuli. This can influence visual cortex, boosting neural responses to an attended stimulus. Emotional modulation can also arise, when affective properties (emotional significance) of stimuli, rather than their strictly visual properties, influence processing. This too can boost responses in visual cortex, as for fear-associated stimuli. Both attentional and emotional modulation of visual processing may reflect distant influences upon visual cortex, exerted by brain structures outside the visual system per se. Hence, these modulations may provide windows onto causal interactions between distant but interconnected brain regions. We review recent evidence, noting both similarities and differences between attentional and emotional modulation. Both can affect visual cortex, but can reflect influences from different regions, such as fronto-parietal circuits versus the amygdala. Recent work on this has developed new approaches for studying causal influences between human brain regions that may be useful in other cognitive domains. The new methods include application of functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) measures in brain-damaged patients to study distant functional impacts of their focal lesions, and use of transcranial magnetic stimulation concurrently with fMRI or EEG in the normal brain. Cognitive neuroscience is now moving beyond considering the putative functions of particular brain regions, as if each operated in isolation, to consider, instead, how distinct brain regions (such as visual cortex, parietal or frontal regions, or amygdala) may mutually influence each other in a causal manner.     

Closed-loop deep brain stimulation is superior in ameliorating parkinsonism

Continuous high-frequency deep brain stimulation (DBS) is a widely used therapy for advanced Parkinson's disease (PD) management. However, the mechanisms underlying DBS effects remain enigmatic and are the subject of an ongoing debate. Here, we present and test a closed-loop stimulation strategy for PD in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model of PD. Application of pallidal closed-loop stimulation leads to dissociation between changes in basal ganglia (BG) discharge rates and patterns, providing insights into PD pathophysiology. Furthermore, cortico-pallidal closed-loop stimulation has a significantly greater effect on akinesia and on cortical and pallidal discharge patterns than standard open-loop DBS and matched control stimulation paradigms. Thus, closed-loop DBS paradigms, by modulating pathological oscillatory activity rather than the discharge rate of the BG-cortical networks, may afford more effective management of advanced PD. Such strategies have the potential to be effective in additional brain disorders in which a pathological neuronal discharge pattern can be recognized.     

Desynchronizing double-pulse phase resetting and application to deep brain stimulation

 Based on a stochastic phase-resetting approach, three different double-pulse stimulation techniques are presented here which make it possible to effectively desynchronize a population of phase oscillators in the presence of noise. In the three sorts of double pulses the first, stronger pulse restarts the cluster independent of its initial dynamic state. The three methods differ with respect to the mechanism through which the second, weaker pulse desynchronizes the cluster. Both first and second pulses are delivered to the same site. Because of the oscillators' global couplings in the model under consideration, the incoherent state is unstable, so that after the desynchronization the cluster tends to resynchronize. However, resynchronization is effectively blocked by repeated administration of a double pulse. The experimental application of double-pulse stimulation is explained in detail. In particular, demand-controlled deep brain double-pulse stimulation is suggested for the therapy of patients suffering from Parkinson's disease or essential tremor. Received: 22 November 2000 / Accepted in revised form: 26 April 2001     

Noninvasive ultrasound deep brain stimulation of nucleus accumbens induces behavioral avoidance

Ultrasound stimulation is an emerging noninvasive option in treating neuropsychiatric disorders. The present study investigates the behavioral alterations resulting from ultrasound stimulation on the nucleus accumbens(NAc) in freely moving mice. Our results show that an acute ultrasound stimulation on the NAc, rather than the visual cortex or auditory cortex, led to a pronounced avoidance behavior, while repeated NAc ultrasound stimulation resulted in an obvious conditioned place aversion with changes in synaptic protein(Glu A1/2 subunit) expression. Notably, NAc ultrasound stimulation suppressed the morphine-induced conditioned place preference. The results provide evidence that NAc ultrasound stimulation can be applied as a potential noninvasive therapeutic option in treating psychiatric disorders.     

Nociceptive processing in the human brain

Since the advent of modern neuroimaging techniques, studies have been carried out to examine nociceptive processing within the human brain non-invasively. Combined with advances in immunohistochemistry, histology and genetics, we have been able to correlate more objective measures of nociceptive processing with the subjective experience that is pain. The result has produced a dramatic shift in our thinking about the neural circuitry involved in nociceptive processing, revealing that pain is much more than a submodality of the sense of touch.     

Subthalamic nucleus deep brain stimulation impacts language in early Parkinson's disease

Although deep brain stimulation (DBS) of the basal ganglia improves motor outcomes in Parkinson's disease (PD), its effects on cognition, including language, remain unclear. This study examined the impact of subthalamic nucleus (STN) DBS on two fundamental capacities of language, grammatical and lexical functions. These functions were tested with the production of regular and irregular past-tenses, which contrast aspects of grammatical (regulars) and lexical (irregulars) processing while controlling for multiple potentially confounding factors. Aspects of the motor system were tested by contrasting the naming of manipulated (motor) and non-manipulated (non-motor) objects. Performance was compared between healthy controls and early-stage PD patients treated with either DBS/medications or medications alone. Patients were assessed on and off treatment, with controls following a parallel testing schedule. STN-DBS improved naming of manipulated (motor) but not non-manipulated (non-motor) objects, as compared to both controls and patients with just medications, who did not differ from each other across assessment sessions. In contrast, STN-DBS led to worse performance at regulars (grammar) but not irregulars (lexicon), as compared to the other two subject groups, who again did not differ. The results suggest that STN-DBS negatively impacts language in early PD, but may be specific in depressing aspects of grammatical and not lexical processing. The finding that STN-DBS affects both motor and grammar (but not lexical) functions strengthens the view that both depend on basal ganglia circuitry, although the mechanisms for its differential impact on the two (improved motor, impaired grammar) remain to be elucidated.     

Capitalizing on deep brain stimulation: thalamus as a language monitor

In this issue of Neuron, Wahl et al. demonstrate via invasive recordings from Deep Brain Stimulation leads that the thalamus (but not basal ganglia) is sensitive to certain linguistic violations, consistent with a subcortical role in selective recruitment of language-related cortical areas.     

Hypothalamic deep brain stimulation reduces weight gain in an obesity-animal model

Prior studies of appetite regulatory networks, primarily in rodents, have established that targeted electrical stimulation of ventromedial hypothalamus (VMH) can alter food intake patterns and metabolic homeostasis. Consideration of this method for weight modulation in humans with severe overeating disorders and morbid obesity can be further advanced by modeling procedures and assessing endpoints that can provide preclinical data on efficacy and safety. In this study we adapted human deep brain stimulation (DBS) stereotactic methods and instrumentation to demonstrate in a large animal model the modulation of weight gain with VMH-DBS. Female Göttingen minipigs were used because of their dietary habits, physiologic characteristics, and brain structures that resemble those of primates. Further, these animals become obese on extra-feeding regimens. DBS electrodes were first bilaterally implanted into the VMH of the animals (n = 8) which were then maintained on a restricted food regimen for 1 mo following the surgery. The daily amount of food was then doubled for the next 2 mo in all animals to produce obesity associated with extra calorie intake, with half of the animals (n = 4) concurrently receiving continuous low frequency (50 Hz) VMH-DBS. Adverse motoric or behavioral effects were not observed subsequent to the surgical procedure or during the DBS period. Throughout this 2 mo DBS period, all animals consumed the doubled amount of daily food. However, the animals that had received VMH-DBS showed a cumulative weight gain (6.1±0.4 kg; mean ± SEM) that was lower than the nonstimulated VMH-DBS animals (9.4±1.3 kg; p<0.05), suggestive of a DBS-associated increase in metabolic rate. These results in a porcine obesity model demonstrate the efficacy and behavioral safety of a low frequency VMH-DBS application as a potential clinical strategy for modulation of body weight.     

Stimulation on demand: closing the loop on deep brain stimulation

High-frequency open-loop deep brain stimulation (DBS) has been used to alleviate Parkinson's symptoms for almost 20 years. In this issue of Neuron, Rosin et?al. present a closed-loop real-time approach that improves DBS and shines light on the etiology of motor symptoms in Parkinson's disease.     

Modulation of semantic processing by spatial selective attention

The effects of spatial selective attention upon ERPs associated with the processing of word stimuli were investigated. While subjects maintained central eye fixation, ERPs were recorded to words presented to the left and right visual fields. In each of 6 runs, subjects focussed attention to alternate fields to perform a category-detection task. Pairs of semantically related and repeated words were embedded in the word lists presented to the attended and unattended visual fields. Consistent with prior studies, the P1-N1 visual ERP was larger when elicited by words in attended spatial locations. A large negative slow wave identified as N400 was elicited by attended, but not unattended, words. For attended words, N400 was smaller for semantically primed or repeated words. We concluded that spatial selective attention can modulate the degree to which words are processed, and that the cognitive processes associated with N400 are not automatic.