Expectation Modulates the Effect of Deep Brain Stimulation on Motor and Cognitive Function in Tremor-Dominant Parkinson's Disease

Expectation contributes to placebo and nocebo responses in Parkinson''s disease (PD). While there is evidence for expectation-induced modulations of bradykinesia, little is known about the impact of expectation on resting tremor. Subthalamic nucleus (STN) deep brain stimulation (DBS) improves cardinal PD motor symptoms including tremor whereas impairment of verbal fluency (VF) has been observed as a potential side-effect. Here we investigated how expectation modulates the effect of STN-DBS on resting tremor and its interaction with VF. In a within-subject-design, expectation of 24 tremor-dominant PD patients regarding the impact of STN-DBS on motor symptoms was manipulated by verbal suggestions (positive [placebo], negative [nocebo], neutral [control]). Patients participated with (MedON) and without (MedOFF) antiparkinsonian medication. Resting tremor was recorded by accelerometry and bradykinesia of finger tapping and diadochokinesia were assessed by a 3D ultrasound motion detection system. VF was quantified by lexical and semantic tests. In a subgroup of patients, the effect of STN-DBS on tremor was modulated by expectation, i.e. tremor decreased (placebo response) or increased (nocebo response) by at least 10% as compared to the control condition while no significant effect was observed for the overall group. Interestingly, nocebo responders in MedON were additionally characterized by significant impairment in semantic verbal fluency. In contrast, bradykinesia was not affected by expectation. These results indicate that the therapeutic effect of STN-DBS on tremor can be modulated by expectation in a subgroup of patients and suggests that tremor is also among the parkinsonian symptoms responsive to placebo and nocebo interventions. While positive expectations enhanced the effect of STN-DBS by further decreasing the magnitude of tremor, negative expectations counteracted the therapeutic effect and at the same time exacerbated a side-effect often associated with STN-DBS. The present findings underscore the potency of patients'' expectation and its relevance for therapeutic outcomes.     

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.     

Effects of subthalamic nucleus stimulation on emotional prosody comprehension in Parkinson's disease

Background

Although impaired decoding of emotional prosody has frequently been associated with Parkinson''s disease (PD), to date only few reports have sought to explore the effect of Parkinson''s treatment on disturbances of prosody decoding. In particular, little is known about how surgical treatment approaches such as high frequency deep brain stimulation (DBS) affect emotional speech perception in patients with PD. Accordingly, the objective of this study was to evaluate the effect of subthalamic nucleus (STN) stimulation on prosody processing.

Methodology/Principal Findings

To this end the performance of 13 PD patients on three tasks requiring the decoding of emotional speech was assessed and subsequently compared to the performance of healthy control individuals. To delineate the effect of STN-DBS, all patients were tested with stimulators turned on as well as with stimulators turned off. Results revealed that irrespective of whether assessments were made “on” or “off” stimulation, patients'' performance was less accurate as compared to healthy control participants on all tasks employed in this study. However, while accuracy appeared to be unaffected by stimulator status, a facilitation of reactions specific to highly conflicting emotional stimulus material (i.e. stimulus material presenting contradicting emotional messages on a verbal and non-verbal prosodic level) was observed during “on” stimulation assessments.

Conclusion

In sum, presented results suggest that the processing of emotional speech is indeed modulated by STN-DBS. Observed alterations might, on the one hand, reflect a more efficient processing of highly conflicting stimulus material following DBS. However, on the other hand, given the lack of an improvement in accuracy, increased impulsivity associated with STN stimulation needs to be taken into consideration.     

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.     

The clinical efficacy of -DOPA and STN-DBS share a common marker: reduced GABA content in the motor thalamus

At odd with traditional views, effective sub-thalamic nucleus (STN) deep brain stimulation (DBS), in Parkinson''s disease (PD) patients, may increase the discharge rate of the substantia nigra pars reticulata and the internal globus pallidus (GPi), in combination with increased cyclic guanosine monophosphate (cGMP) levels. How these changes affect the basal ganglia (BG) output to the motor thalamus, the crucial structure conveying motor information to cortex, is critical. Here, we determined the extracellular GABA concentration in the ventral anterior nucleus (VA) during the first delivery of STN-DBS (n=10) or following levodopa (LD) (n=8). Both DBS and subdyskinetic LD reversibly reduced (−30%) VA GABA levels. A significant correlation occurred between clinical score and GABA concentration. By contrast, only STN-DBS increased GPi cGMP levels. Hence, STN-ON and MED-ON involve partially different action mechanisms but share a common target in the VA. These findings suggest that the standard BG circuitry, in PD, needs revision as relief from akinesia may take place, during DBS, even in absence of reduced GPi excitability. However, clinical amelioration requires fast change of thalamic GABA, confirming, in line with the old model, that VA is the core player in determining thalamo-cortical transmission.     

Reduced Verbal Fluency following Subthalamic Deep Brain Stimulation: A Frontal-Related Cognitive Deficit?

Objective

The decrease in verbal fluency in patients with Parkinson’s disease (PD) undergoing subthalamic nucleus deep brain stimulation (STN-DBS) is usually assumed to reflect a frontal lobe-related cognitive dysfunction, although evidence for this is lacking.

Methods

To explore its underlying mechanisms, we combined neuropsychological, psychiatric and motor assessments with an examination of brain metabolism using F-18 fluorodeoxyglucose positron emission tomography, in 26 patients with PD, 3 months before and after surgery. We divided these patients into two groups, depending on whether or not they exhibited a postoperative deterioration in either phonemic (10 patients) or semantic (8 patients) fluency. We then compared the STN-DBS groups with and without verbal deterioration on changes in clinical measures and brain metabolism.

Results

We did not find any neuropsychological change supporting the presence of an executive dysfunction in patients with a deficit in either phonemic or semantic fluency. Similarly, a comparison of patients with or without impaired fluency on brain metabolism failed to highlight any frontal areas involved in cognitive functions. However, greater changes in cognitive slowdown and apathy were observed in patients with a postoperative decrease in verbal fluency.

Conclusions

These results suggest that frontal lobe-related cognitive dysfunction could play only a minor role in the postoperative impairment of phonemic or semantic fluency, and that cognitive slowdown and apathy could have a more decisive influence. Furthermore, the phonemic and semantic impairments appeared to result from the disturbance of distinct mechanisms.     

Bilateral Deep Brain Stimulation of the Subthalamic Nucleus under Sedation with Propofol and Fentanyl

Awakening during deep brain stimulation (DBS) surgery may be stressful to patients. The aim of the current study was to evaluate the effect on MER signals and their applicability to subthalmic nucleus (STN) DBS surgery for patients with Parkinson’s disease (PD) under sedation with propofol and fentanyl. Sixteen consecutive patients with PD underwent STN-DBS surgery with propofol and fentanyl. Their MER signals were achieved during the surgery. To identify the microelectrodes positions, the preoperative MRI and postoperative CT were used. Clinical profiles were also collected at the baseline and at 6 months after surgery. All the signals were slightly attenuated and contained only bursting patterns, compared with our previous report. All electrodes were mostly located in the middle one third part of the STN on both sides of the brain in the fused images. Six months later, the patients were improved significantly in the medication-off state and they met with less dyskinesia and less off-duration. Our study revealed that the sedation with propofol and fentanyl was applicable to STN-DBS surgery. There were no significant problems in precise positioning of bilateral electrodes. The surgery also improved significantly clinical outcomes in 6-month follow-up.     

Modulation of human time processing by subthalamic deep brain stimulation

Timing in the range of seconds referred to as interval timing is crucial for cognitive operations and conscious time processing. According to recent models of interval timing basal ganglia (BG) oscillatory loops are involved in time interval recognition. Parkinsońs disease (PD) is a typical disease of the basal ganglia that shows distortions in interval timing. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a powerful treatment of PD which modulates motor and cognitive functions depending on stimulation frequency by affecting subcortical-cortical oscillatory loops. Thus, for the understanding of BG-involvement in interval timing it is of interest whether STN-DBS can modulate timing in a frequency dependent manner by interference with oscillatory time recognition processes. We examined production and reproduction of 5 and 15 second intervals and millisecond timing in a double blind, randomised, within-subject repeated-measures design of 12 PD-patients applying no, 10-Hz- and ≥ 130-Hz-STN-DBS compared to healthy controls. We found under(re-)production of the 15-second interval and a significant enhancement of this under(re-)production by 10-Hz-stimulation compared to no stimulation, ≥ 130-Hz-STN-DBS and controls. Milliseconds timing was not affected. We provide first evidence for a frequency-specific modulatory effect of STN-DBS on interval timing. Our results corroborate the involvement of BG in general and of the STN in particular in the cognitive representation of time intervals in the range of multiple seconds.     

Subthalamic Nucleus Deep Brain Stimulation Modulate Catecholamine Levels with Significant Relations to Clinical Outcome after Surgery in Patients with Parkinson’s Disease

Aims

Although subthalamic nucleus deep brain stimulation (STN-DBS) is effective in patients with advanced Parkinson’s disease (PD), its physiological mechanisms remain unclear. Because STN-DBS is effective in patients with PD whose motor symptoms are dramatically alleviated by L-3,4-dihydroxyphenylalanine (L-DOPA) treatment, the higher preoperative catecholamine levels might be related to the better clinical outcome after surgery. We aimed to examine the correlation between the preoperative catecholamine levels and postoperative clinical outcome after subthalamic nucleus deep brain stimulation. The effectiveness of STN-DBS in the patient who responded well to dopaminergic medication suggest the causal link between the dopaminergic system and STN-DBS. We also examined how catecholamine levels were modulated after subthalamic stimulation.

Methods

In total 25 patients with PD were enrolled (Mean age 66.2 ± 6.7 years, mean disease duration 11.6 ± 3.7 years). Mean levodopa equivalent doses were 1032 ± 34.6 mg before surgery. Cerebrospinal fluid and plasma catecholamine levels were measured an hour after oral administration of antiparkinsonian drugs before surgery. The mean Unified Parkinson’s Disease Rating Scale scores (UPDRS) and the Parkinson’s disease Questionnaire-39 (PDQ-39) were obtained before and after surgery. Of the 25 patients, postoperative cerebrospinal fluid and plasma were collected an hour after oral administration of antiparkinsonian drugs during on stimulation at follow up in 11 patients.

Results

Mean levodopa equivalent doses significantly decreased after surgery with improvement in motor functions and quality of life. The preoperative catecholamine levels had basically negative correlations with postoperative motor scores and quality of life, suggesting that higher preoperative catecholamine levels were related to better outcome after STN-DBS. The preoperative plasma levels of L-DOPA had significantly negative correlations with postoperative UPDRS- III score in off phase three months after STN-DBS. The preoperative cerebrospinal fluid (CSF) 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxytryptamine (5-HT) levels had significantly negative correlations with postoperative UPDRS- III score in off phase one year after STN-DBS and the preoperative CSF homovanilic acid (HVA) levels had significant negative correlations with postoperative UPDRS- III score in on phase three months after STN-DBS. In PDQ-39 SI (summary index), preoperative plasma dopamine (DA) level had significantly negative correlations with postoperative PDQ-39 SI one year after STN-DBS suggesting that higher preoperative plasma DA level resulted in better quality of life (QOL) one year after STN-DBS. The stepwise multiple linear regression study revealed that higher preoperative plasma HVA levels had negative influence on the postoperative motor symptoms (i.e., increase in the score of UPDRS), whereas higher preoperative CSF L-DOPA levels had positive influence on the postoperative motor symptoms and QOL (decrease in the score of UPDRS and PDQ-39 SI) The catecholamine levels were not significantly reduced postoperatively in 11 patients despite the significant reduction in levodopa equivalent doses. Unexpectedly, CSF HVA levels significantly increased from 0.00089±0.0003 ng/μl to 0.002±0.0008 ng/μl after STN-DBS.

Conclusion

The preoperative catecholamine levels might affect the postoperative motor symptoms and quality of life. The catecholamine levels were not significantly reduced postoperatively despite the significant reduction in levodopa equivalent doses.     

Weight Gain following Pallidal Deep Brain Stimulation: A PET Study

The mechanisms behind weight gain following deep brain stimulation (DBS) surgery seem to be multifactorial and suspected depending on the target, either the subthalamic nucleus (STN) or the globus pallidus internus (GPi). Decreased energy expenditure following motor improvement and behavioral and/or metabolic changes are possible explanations. Focusing on GPi target, our objective was to analyze correlations between changes in brain metabolism (measured with PET) and weight gain following GPi-DBS in patients with Parkinson’s disease (PD). Body mass index was calculated and brain activity prospectively measured using 2-deoxy-2[18F]fluoro-D-glucose PET four months before and four months after the start of GPi-DBS in 19 PD patients. Dopaminergic medication was included in the analysis to control for its possible influence on brain metabolism. Body mass index increased significantly by 0.66 ± 1.3 kg/m2 (p = 0.040). There were correlations between weight gain and changes in brain metabolism in premotor areas, including the left and right superior gyri (Brodmann area, BA 6), left superior gyrus (BA 8), the dorsolateral prefrontal cortex (right middle gyrus, BAs 9 and 46), and the left and right somatosensory association cortices (BA 7). However, we found no correlation between weight gain and metabolic changes in limbic and associative areas. Additionally, there was a trend toward a correlation between reduced dyskinesia and weight gain (r = 0.428, p = 0.067). These findings suggest that, unlike STN-DBS, motor improvement is the major contributing factor for weight gain following GPi-DBS PD, confirming the motor selectivity of this target.     

A biophysically inspired microelectrode recording-based model for the subthalamic nucleus activity in Parkinson's disease

The subthalamic nucleus (STN) plays a central role in movement actuation and manifestation of movement disorders (i.e., tremor, rigidity, akynesia and postural instability) in Parkinson's disease (PD) patients. Moreover, it has been recently revealed that an opportune electrical stimulation of the STN, called deep brain stimulation (DBS), can strongly contribute to the annihilation of the PD-related motor disorders. Currently, a great effort is made both in Medicine, Neurosciences and Engineering for understanding and modeling in details how the STN works, how PD determines its pathological behavior and DBS restores the correct motor function.The paper is organized in two parts. Firstly some stochastic properties of the STN electrical activity are obtained by analyzing a preliminary set of experimental data coming from microelectrode recordings (MERs) in two PD patients who underwent the surgical implantation of DBS electrodes. Then, a nonlinear, stochastic, continuous-state model describing the global electrical behavior of the STN in PD patients is proposed. It is inspired by the fundamental physiologic features of the subthalamic cells and a fictitious vector state is introduced to represent the main dynamics. Its numerical parameters and stochastic properties are chosen by fitting the available data.     

Deep brain stimulation

During the last decade deep brain stimulation (DBS) has become a routine method for the treatment of advanced Parkinsons disease (PD), leading to striking improvements in motor function and quality of life of PD patients. It is associated with minimal morbidity. The rationale of targeting specific structures within basal ganglia such as the subthalamic nucleus (STN) or the internal segment of the globus pallidus (GPi) is strongly supported by the current knowledge of the basal ganglia pathophysiology, which is derived from extensive experimental work and which provides the theoretical basis for surgical therapy in PD. In particular, the STN has advanced to the worldwide most used target for DBS in the treatment of PD, due to the marked improvement of all cardinal symptoms of the disease. Moreover on-period dyskinesias are reduced in parallel with a marked reduction of the equivalent daily levodopa dose following STN–DBS. The success of the therapy largely depends on the selection of the appropriate candidate patients and on the precise implantation of the stimulation electrode, which necessitates careful imaging-based pre-targeting and extensive electrophysiological exploration of the target area. Despite the clinical success of the therapy, the fundamental mechanisms of high-frequency stimulation are still not fully elucidated. There is a large amount of evidence from experimental and clinical data that stimulation frequency represents a key factor with respect to clinical effect of DBS. Interestingly, high-frequency stimulation mimics the functional effects of ablation in various brain structures. The main hypotheses for the mechanism of high-frequency stimulation are: (1) depolarization blocking of neuronal transmission through inactivation of voltage dependent ion-channels, (2) jamming of information by imposing an efferent stimulation-driven high-frequency pattern, (3) synaptic inhibition by stimulation of inhibitory afferents to the target nucleus, (4) synaptic failure by stimulation-induced neurotransmitter depletion. As the hyperactivity of the STN is considered a functional hallmark of PD and as there is experimental evidence for STN-mediated glutamatergic excitotoxicity on neurons of the substantia nigra pars compacta (SNc), STN–DBS might reduce glutamatergic drive, leading to neuroprotection. Further studies will be needed to elucidate if STN–DBS indeed provides a slow-down of disease progression.     

Investigating the effects of subthalamic Nucleus–Deep brain stimulation on the voice quality

Abstract

Introduction: Deep brain stimulation (DBS) is a standard surgical treatment method which is generally applied to subthalamic nucleus in Parkinson’s patients in cases where medical treatment is insufficient in treating the motor symptoms. It is known that Subthalamic Nucleus Deep Brain Stimulation (STN-DBS) treats many motor symptoms. However, the results of studies on speech and voice vary. The aim of the study is analysing the effect of STN-DBS on the characteristics of voice.

Materials/methods: A total of 12 patients, (8 male–4 female) with an age average of 58.8?±?9.6, who have been applied DBS surgery on STN included in the study. The voice recordings of the patients have been done prior to surgery and 6?months after the surgery. The evaluation of voice has been carried out through the instrumental method. The patients’ voice recordings of the /a,e,i/ vowels have been done. The obtained recordings were evaluated by the Praat programme and the effects on jhitter, shimmer, fundamental frequency (F0) and noise harmonic rate (NHR) were analysed.

Results: Numerical values of F0 of all female participants have been decreased for all of the vowels postoperatively. In the females; jhitter and fraction parameters were found to be significantly different (0.056 and 0.017, perspectively) for the vowel /e/. In addition, p values in the shimmer for vowels /e,i/ were thought to be clinically significant (.087, .079 and .076) respectively. All these changes in second measurements were found to indicate worsening vocal quality after the DBS in females. In males, there is not any significant difference observed between two measures in any of the parameters of any vowels.

Conclusions: Acoustic voice quality deteriorated after STN-DBS predominantly for females however this deterioration was not prominent audio-perceptually. This finding commented as a result of the fact that that voice quality deviance of the participants was not severe.     

Therapeutic Subthalamic Nucleus Deep Brain Stimulation Reverses Cortico-Thalamic Coupling during Voluntary Movements in Parkinson's Disease

Deep brain stimulation of the subthalamic nucleus (STN DBS) has become an accepted treatment for patients experiencing the motor complications of Parkinson''s disease (PD). While its successes are becoming increasingly apparent, the mechanisms underlying its action remain unclear. Multiple studies using radiotracer-based imaging have investigated DBS-induced regional changes in neural activity. However, little is known about the effect of DBS on connectivity within neural networks; in other words, whether DBS impacts upon functional integration of specialized regions of cortex. In this work, we report the first findings of fMRI in 10 subjects with PD and fully implanted DBS hardware receiving efficacious stimulation. Despite the technical demands associated with the safe acquisition of fMRI data from patients with implanted hardware, robust activation changes were identified in the insula cortex and thalamus in response to therapeutic STN DBS. We then quantified the neuromodulatory effects of DBS and compared sixteen dynamic causal models of effective connectivity between the two identified nodes. Using Bayesian model comparison, we found unequivocal evidence for the modulation of extrinsic (between region), i.e. cortico-thalamic and thalamo-cortical connections. Using Bayesian model parameter averaging we found that during voluntary movements, DBS reversed the effective connectivity between regions of the cortex and thalamus. This casts the therapeutic effects of DBS in a fundamentally new light, emphasising a role in changing distributed cortico-subcortical interactions. We conclude that STN DBS does impact upon the effective connectivity between the cortex and thalamus by changing their sensitivities to extrinsic afferents. Furthermore, we confirm that fMRI is both feasible and is tolerated well by these patients provided strict safety measures are adhered to.     

帕金森病丘脑底核神经元的电活动特点

本研究探讨了帕金森病(Parkinson′s disease, PD)患者丘脑底核(subthalamic nucleus, STN)神经元电活动的特点及其与PD症状的关系. 35例PD患者在接受手术治疗的同时, 应用微电极细胞记录和EMG记录技术, 记录手术靶点STN及其周围结构神经元的电活动以及手术对侧肢体的EMG. 应用分析软件甄别单细胞电活动, 分析其特点及其与肢体EMG的关系. 结果表明, STN及其周围结构具有特征性放电活动.在36个记录针道中, 共发现436个STN神经元, 平均放电频率44.0±20.5 Hz. 其中, 56%的神经元呈不规则簇状放电; 15%呈紧张性放电; 29%呈规则的簇状放电, 其放电节律与肢体震颤的EMG高度一致(r2=0.66, P<0.01), 称之为震颤细胞. 在PD震颤型患者的STN中发现大量震颤细胞, 且80%位于STN中上部, 而在PD僵直型患者的STN中均发现与运动相关的细胞电活动. 本研究提示, 通过微电极记录技术可准确地判断STN的位置和范围; 与震颤活动相关的细胞放电和与运动相关细胞的放电与PD症状有内在关系; STN参与PD运动障碍的病理生理过程.     

A cortical network processes auditory error signals during human speech production to maintain fluency

Hearing one’s own voice is critical for fluent speech production as it allows for the detection and correction of vocalization errors in real time. This behavior known as the auditory feedback control of speech is impaired in various neurological disorders ranging from stuttering to aphasia; however, the underlying neural mechanisms are still poorly understood. Computational models of speech motor control suggest that, during speech production, the brain uses an efference copy of the motor command to generate an internal estimate of the speech output. When actual feedback differs from this internal estimate, an error signal is generated to correct the internal estimate and update necessary motor commands to produce intended speech. We were able to localize the auditory error signal using electrocorticographic recordings from neurosurgical participants during a delayed auditory feedback (DAF) paradigm. In this task, participants hear their voice with a time delay as they produced words and sentences (similar to an echo on a conference call), which is well known to disrupt fluency by causing slow and stutter-like speech in humans. We observed a significant response enhancement in auditory cortex that scaled with the duration of feedback delay, indicating an auditory speech error signal. Immediately following auditory cortex, dorsal precentral gyrus (dPreCG), a region that has not been implicated in auditory feedback processing before, exhibited a markedly similar response enhancement, suggesting a tight coupling between the 2 regions. Critically, response enhancement in dPreCG occurred only during articulation of long utterances due to a continuous mismatch between produced speech and reafferent feedback. These results suggest that dPreCG plays an essential role in processing auditory error signals during speech production to maintain fluency.

Hearing one’s own voice is critical for fluent speech production, allowing detection and correction of vocalization errors in real-time. This study shows that the dorsal precentral gyrus is a critical component of a cortical network that monitors auditory feedback to produce fluent speech; this region is engaged specifically when speech production is effortful during articulation of long utterances.     

The Role of the Subthalamic Nucleus in L-DOPA Induced Dyskinesia in 6-Hydroxydopamine Lesioned Rats

L-DOPA is the most effective treatment for Parkinson's disease (PD), but prolonged use leads to disabling motor complications including dyskinesia. Strong evidence supports a role of the subthalamic nucleus (STN) in the pathophysiology of PD whereas its role in dyskinesia is a matter of controversy. Here, we investigated the involvement of STN in dyskinesia, using single-unit extracellular recording, behavioural and molecular approaches in hemi-parkinsonian rats rendered dyskinetic by chronic L-DOPA administration. Our results show that chronic L-DOPA treatment does not modify the abnormal STN activity induced by the 6-hydroxydopamine lesion of the nigrostriatal pathway in this model. Likewise, we observed a loss of STN responsiveness to a single L-DOPA dose both in lesioned and sham animals that received daily L-DOPA treatment. We did not find any correlation between the abnormal involuntary movement (AIM) scores and the electrophysiological parameters of STN neurons recorded 24 h or 20-120 min after the last L-DOPA injection, except for the axial subscores. Nonetheless, unilateral chemical ablation of the STN with ibotenic acid resulted in a reduction in global AIM scores and peak-severity of dyskinesia. In addition, STN lesion decreased the anti-dyskinetogenic effect of buspirone in a reciprocal manner. Striatal protein expression was altered in dyskinetic animals with increases in ΔFosB, phosphoDARPP-32, dopamine receptor (DR) D3 and DRD2/DRD1 ratio. The STN lesion attenuated the striatal molecular changes and normalized the DRD2/DRD1 ratio. Taken together, our results show that the STN plays a role, if modest, in the physiopathology of dyskinesias.     

Subthalamic Nucleus Deep Brain Stimulation Does Not Improve Visuo-Motor Impairment in Parkinson’s Disease

Objective

To evaluate how bilateral subthalamic nucleus deep brain stimulation (STN-DBS) affects visuo-motor coordination (VMC) in patients with Parkinson’s disease (PD).

Background

VMC involves multi-sensory integration, motor planning, executive function and attention. VMC deficits are well-described in PD. STN-DBS conveys marked motor benefit in PD, but pyscho-cognitive complications are recognized and the effect on VMC is not known.

Methods

Thirteen PD patients with bilateral STN-DBS underwent neurological, cognitive, and mood assessment before VMC testing with optimal DBS stimulation parameters (‘on-stimulation’) and then, on the same day without any medication changes, after DBS silencing and establishing motor function deterioration (‘off-stimulation’). Twelve age-matched healthy controls performed 2 successive VMC testing sessions, with a break of similar duration to that of the PD group. The computer cursor was controlled with a dome-shaped ‘mouse’ hidden from view that minimized tremor effects. Movement duration, hand velocity, tracking continuity, directional control variables, and feedback utilization variables were measured. MANOVA was performed on (1) clinically measured motor function, (2) VMC performance and (3) mood and attention, looking for main and interaction effects of: (1) group (controls/PD), (2) test-order (controls: first/second, PD: on-stimulation/off-stimulation), (3) path (sine/square/circle) and (4) hand (dominant/non-dominant).

Results

Unified PD Rating Scale (UPDRS) Part III worsened off-stimulation versus on-stimulation (mean: 42.3 versus 21.6, p = 0.02), as did finger tapping (p = 0.02), posture-gait (p = 0.01), upper limb function (p<0.001) and backwards digit span (p = 0.02). Stimulation state did not affect mood. PD patients performed worse in non-velocity related VMC variables than controls (F_(5,18) = 8.5, p<0.001). In the control group there were significant main effects of hand (dominant/non-dominant), path (sine/square/circle) and test-order (Test_1/Test_2). In the PD group, hand and path effects, but no test-order (on-stimulation/off-stimulation), were found.

Conclusions

‘Low-level’ clinically-measured motor function responds to STN-DBS but ‘high-level’ motor and cognitive functions relating to VMC may be unresponsive to STN-DBS.     

Relief of pain by infiltration of autonomic ganglia with steroids.

When parents are concerned about the development of stuttering in their child they often consult their pediatrician or family physician. Theories on the development of stuttering are briefly examined in this article, and guidelines are provided to help the physician determine if the child''s dysfluencies are within the normal range. Referral to a speech therapist should be considered when any of the following are noted: excessive repetition of the first syllable of words; tremor of the muscles of mouth or jaw, increase in pitch or loudness, or evidence of fear or emotion as the child struggles with a word; evidence that the child avoids certain words or situations; and excessive concern of parents, teachers or the dysfluent individual. Two approaches to therapy, traditional and behavioural, are described. The latter has resulted in significant gains in fluency among stutterers.     

Resting-state brain activity in adult males who stutter

Although developmental stuttering has been extensively studied with structural and task-based functional magnetic resonance imaging (fMRI), few studies have focused on resting-state brain activity in this disorder. We investigated resting-state brain activity of stuttering subjects by analyzing the amplitude of low-frequency fluctuation (ALFF), region of interest (ROI)-based functional connectivity (FC) and independent component analysis (ICA)-based FC. Forty-four adult males with developmental stuttering and 46 age-matched fluent male controls were scanned using resting-state fMRI. ALFF, ROI-based FCs and ICA-based FCs were compared between male stuttering subjects and fluent controls in a voxel-wise manner. Compared with fluent controls, stuttering subjects showed increased ALFF in left brain areas related to speech motor and auditory functions and bilateral prefrontal cortices related to cognitive control. However, stuttering subjects showed decreased ALFF in the left posterior language reception area and bilateral non-speech motor areas. ROI-based FC analysis revealed decreased FC between the posterior language area involved in the perception and decoding of sensory information and anterior brain area involved in the initiation of speech motor function, as well as increased FC within anterior or posterior speech- and language-associated areas and between the prefrontal areas and default-mode network (DMN) in stuttering subjects. ICA showed that stuttering subjects had decreased FC in the DMN and increased FC in the sensorimotor network. Our findings support the concept that stuttering subjects have deficits in multiple functional systems (motor, language, auditory and DMN) and in the connections between them.