Combination targeting of subthalamic nucleus and ventral intermediate thalamic nucleus with a single trajectory in deep brain stimulation for tremor-dominant Parkinson's disease.

Deep brain stimulation (DBS) has traditionally been used to target the subthalamic nucleus (STN) or globus pallidus internus (GPi) to treat Parkinson's disease (PD) and the ventral intermediate thalamic nucleus (VIM) to treat essential tremor (ET). Recent case reports have described targeting both the STN and VIM with a single trajectory and electrode to treat patients with tremor-dominant PD, yet outcome data for this procedure remains sparse. Our objective is to determine the safety and efficacy of combination STN-VIM DBS. We conducted a single-center retrospective case series of all patients who underwent combined STN-VIM DBS. Demographic, perioperative, and outcome data, including Unified Parkinson Disease Rating Scale-III (UPDRS) and tremor scores (OFF-medication), and levodopa equivalent daily dose (LEDD), were collected and analyzed. Nineteen patients underwent this procedure. Patients were 89% male and 11% female, with a mean age of 63.6 years. Mean preoperative UPDRS was 24.1, and LEDD was 811.8. At a mean follow-up of 33.8 months, UPDRS and LEDD decreased by an average of 9.2 (38.2%) and 326.3 (40.2%), respectively. Tremor scores decreased by 4.9 (59.0%), and 58% were able to decrease total medication burden. One patient developed transient left-sided weakness, yielding a complication rate of 5.3%. Combined targeting of STN and VIM thalamus via a single frontal trajectory for tremor-dominant Parkinson's Disease results in similar UPDRS outcomes to STN DBS and improved control of tremor symptoms. Larger multicenter studies are necessary to validate this as the optimal DBS target for tremor-dominant PD.

Real-Time Evaluation of Anterior Choroidal Artery Patency During Aneurysm Clipping.

Inadvertent occlusion of the anterior choroidal artery during aneurysm clipping can cause a disabling stroke in minutes. We evaluate the clinical utility of direct cortical motor evoked potential (MEP) monitoring during aneurysm clipping, as a real-time assessment of arterial patency, prior to performing indocyanine green videoangiography.   Direct cortical MEPs were recorded in seven patients undergoing surgery for aneurysms that involved or abutted the anterior choroidal artery. The aneurysms clipped in those seven patients included four anterior choroidal artery aneurysms and six posterior communicating artery aneurysms. Serial MEP recordings were performed during the intradural dissection, aneurysm exposure, and clip placement. A significant change in MEPs after clip placement would prompt immediate inspection and removal or repositioning of the clip. If the clip placement appeared satisfactory and MEP recordings were stable, then an intraoperative indocyanine green videoangiogram was performed to confirm obliteration of the aneurysm and patency of the arteries.  Seven patients underwent successful clipping of anterior choroidal artery aneurysms and posterior communicating artery aneurysms using direct cortical MEP monitoring, with good clinical and radiographic outcomes. In six patients, no changes in MEP amplitudes were observed following permanent clip placement. In one patient, a profound decrease in MEP amplitude occurred 220 seconds after placement of a permanent clip on a large posterior communicating aneurysm. An inspection revealed that the anterior choroidal artery was kinked. The clip was immediately removed, and the MEP signals returned to baseline shortly thereafter. A clip was then optimally placed, and the patient awoke without neurologic deficit.  Direct cortical MEPs are a useful adjunct to standard electrophysiologic monitoring in aneurysm surgery, particularly when the anterior choroidal artery or lenticulostriate arteries are at risk. When these arteries are occluded, infarction may occur before the occlusion is detected by indocyanine green videoangiography or intraoperative angiography. The use of MEPs allows real-time detection of ischemia to subcortical motor pathways.

Disorders of Upper Limb Movements in Ataxia-Telangiectasia.

Ataxia-telangiectasia is known for cerebellar degeneration, but clinical descriptions of abnormal tone, posture, and movements suggest involvement of the network between cerebellum and basal ganglia. We quantitatively assessed the nature of upper-limb movement disorders in ataxia-telangiectasia. We used a three-axis accelerometer to assess the natural history and severity of abnormal upper-limb movements in 80 ataxia-telangiectasia and 19 healthy subjects. Recordings were made during goal-directed movements of upper limb (kinetic task), while arms were outstretched (postural task), and at rest. Almost all ataxia-telangiectasia subjects (79/80) had abnormal involuntary movements, such as rhythmic oscillations (tremor), slow drifts (dystonia or athetosis), and isolated rapid movements (dystonic jerks or myoclonus). All patients with involuntary movements had both kinetic and postural tremor, while 48 (61%) also had resting tremor. The tremor was present in transient episodes lasting several seconds during two-minute recording sessions of all three conditions. Percent time during which episodic tremor was present was greater for postural and kinetic tasks compared to rest. Resting tremor had higher frequency but smaller amplitude than postural and kinetic tremor. Rapid non-rhythmic movements were minimal during rest, but were triggered during sustained arm postures and goal directed arm movements suggesting they are best considered a form of dystonic jerks or action myoclonus. Advancing age did not correlate with the severity of involuntary limb movements. Abnormal upper-limb movements in ataxia-telangiectasia feature classic cerebellar impairment, but also suggest involvement of the network between the cerebellum and basal ganglia.

Neurophysiologic intraoperative monitoring of trigeminal and facial nerves.

The trigeminal and facial nerves are placed at risk in a number of surgical procedures. The use of electromyography, nerve conduction studies, somatosensory evoked potentials, motor evoked potentials, and other techniques are described. Application to specific surgical types and the associated evidence for impact on surgical outcomes are discussed.

Resistance to MPTP-neurotoxicity in α-synuclein knockout mice is complemented by human α-synuclein and associated with increased ß-synuclein and Akt activation.

Genetic and biochemical abnormalities of α-synuclein are associated with the pathogenesis of Parkinson's disease. In the present study we investigated the in vivo interaction of mouse and human α-synuclein with the potent parkinsonian neurotoxin, MPTP. We find that while lack of mouse α-synuclein in mice is associated with reduced vulnerability to MPTP, increased levels of human α-synuclein expression is not associated with obvious changes in the vulnerability of dopaminergic neurons to MPTP. However, expressing human α-synuclein variants (human wild type or A53T) in the α-synuclein null mice completely restores the vulnerability of nigral dopaminergic neurons to MPTP. These results indicate that human α-synuclein can functionally replace mouse α-synuclein in regard to vulnerability of dopaminergic neurons to MPTP-toxicity. Significantly, α-synuclein null mice and wild type mice were equally sensitive to neurodegeneration induced by 2'NH(2)-MPTP, a MPTP analog that is selective for serotoninergic and noradrenergic neurons. These results suggest that effects of α-synuclein on MPTP like compounds are selective for nigral dopaminergic neurons. Immunoblot analysis of ß-synuclein and Akt levels in the mice reveals selective increases in ß-synuclein and phosphorylated Akt levels in ventral midbrain, but not in other brain regions, of α-synuclein null mice, implicating the α-synuclein-level dependent regulation of ß-synuclein expression in modulation of MPTP-toxicity by α-synuclein. Together these findings provide new mechanistic insights on the role α-synuclein in modulating neurodegenerative phenotypes by regulation of Akt-mediated cell survival signaling in vivo.

Extrapyramidal signs in normal pressure hydrocephalus: an objective assessment.

BACKGROUND: Beyond the classic Normal Pressure Hydrocephalus (NPH) triad of gait disturbance, incontinence, and dementia are characteristic signs of motor dysfunction in NPH patients. We used highly sensitive and objective methods to characterize upper limb extrapyramidal signs in a series of NPH subjects compared with controls. Concentrated evaluation of these profound, yet underappreciated movement disorders of NPH before and after techniques of therapeutic intervention may lead to improved diagnosis, insight into pathophysiology, and targeted treatment. METHODS: Twenty-two (22) consecutive NPH patients and 17 controls performed an upper limb motor task battery where highly sensitive and objective measures of akinesia/bradykinesia, tone, and tremor were conducted. NPH subjects performed this test battery before and more than 36 h after continuous CSF drainage via a spinal catheter over 72 h and, in those subjects undergoing permanent ventriculo-peritoneal shunt placement, at least 12 weeks later. Control subjects performed the task battery at the same dates as the NPH subjects. Statistical analyses were applied to group populations of NPH and control subjects and repeated measures for within subject performance. RESULTS: Twenty (20) NPH subjects remained in the study following CSF drainage as did 14 controls. NPH subjects demonstrated akinesia/bradykinesia (prolonged reaction and movement times) and increased resting tone compared with controls. Furthermore, the NPH group demonstrated increased difficulty with self-initiated tasks compared with stimulus-initiated tasks. Following CSF drainage, some NPH subjects demonstrated reduced movement times with greater improvement in self- versus stimulus-initiated tasks. Group reaction time was unchanged. Resting tremor present in one NPH subject resolved following shunt placement. Tone measures were consistent for all subjects throughout the study. CONCLUSION: Clinical motor signs of NPH subjects extend beyond gait deficits and include extrapyramidal manifestations of bradykinesia, akinesia, rigidity, and propensity to perform more poorly when external cues to move are absent. Objective improvement of some but not all of these features was seen following temporary or permanent CSF diversion.

MPTP and DSP-4 susceptibility of substantia nigra and locus coeruleus catecholaminergic neurons in mice is independent of parkin activity.

Mutations in the parkin gene cause autosomal recessive familial Parkinson's disease (PD). Parkin-deficient mouse models fail to recapitulate nigrostriatal dopaminergic neurodegeneration as seen in PD, but produce deficits in dopaminergic neurotransmission and noradrenergic-dependent behavior. Since sporadic PD is thought to be caused by a combination of genetic susceptibilities and environmental factors, we hypothesized that neurotoxic insults from catecholaminergic toxins would render parkin knockout mice more vulnerable to neurodegeneration. Accordingly, we investigated the susceptibility of catecholaminergic neurons in parkin knockout mice to the potent dopaminergic and noradrenergic neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) respectively. We report that nigrostriatal dopaminergic neurons in parkin knockout mice do not show increased susceptibility to the parkinsonian neurotoxin, MPTP, in acute, subacute and chronic dose regimens of the neurotoxin. Additionally, parkin knockout mice do not show increased vulnerability to the noradrenergic neurotoxin, DSP-4, regarding levels of norepinephrine in cortex, brain stem and spinal cord. These findings suggest that absence of parkin in mice does not increase susceptibility to the loss of catecholaminergic neurons upon exposure to both dopaminergic and noradrenergic neurotoxins.

Absence of inclusion body formation in the MPTP mouse model of Parkinson's disease.

Formation of alpha-synuclein aggregation and Lewy bodies (LBs) are hallmarks of Parkinson's disease (PD) and other related diseases. The dopaminergic neurotoxin, MPTP, replicates many of the pathological signs and motoric features of PD in primates and rodents by selective destruction of dopamine (DA) neurons of the substantia nigra. In this study, groups of adult wild-type C57BL6 mice were treated with MPTP either acutely (20 mg/kg, every 2 h x 4 for 1 day), semi-chronically (30 mg/kg/day for 5 days), or chronically (25 mg/kg MPTP with 250 mg/kg probenecid 2 times/week for 5 weeks). Mice brains were collected and processed at various time points for immunohistochemistry and HPLC assays. Our data showed that although there is a significant decrease in DA content and its metabolites and tyrosine hydroxylase immunoreactivity, there is no inclusion body formation following the various MPTP treatment regimens.

BAK alters neuronal excitability and can switch from anti- to pro-death function during postnatal development.

BAK is a pro-apoptotic BCL-2 family protein that localizes to mitochondria. Here we evaluate the function of BAK in several mouse models of neuronal injury including neuronotropic Sindbis virus infection, Parkinson's disease, ischemia/stroke, and seizure. BAK promotes or inhibits neuronal death depending on the specific death stimulus, neuron subtype, and stage of postnatal development. BAK protects neurons from excitotoxicity and virus infection in the hippocampus. As mice mature, BAK is converted from anti- to pro-death function in virus-infected spinal cord neurons. In addition to regulating cell death, BAK also protects mice from kainate-induced seizures, suggesting a possible role in regulating synaptic activity. BAK can alter neurotransmitter release in a direction consistent with its protective effects on neurons and mice. These findings suggest that BAK inhibits cell death by modifying neuronal excitability.

Correlation of reaction time in and out of the functional MR unit.

RATIONALE AND OBJECTIVES: The authors performed this study to determine whether reaction times (RTs) recorded in the functional magnetic resonance (MR) imaging environment reflect the performance of the patient outside the imaging room. MATERIALS AND METHODS: Fifteen healthy control subjects (mean age, 61.6 years) performed a simple reaction time (SRT) task outside the MR magnet and a visuomotor response time task inside the magnet with use of block-design and event-related paradigms. For both behavioral and functional MR imaging tests, subjects tapped the right index finger upon the appearance of a visual cue. The mean RTs for out-of-magnet and functional MR imaging paradigms were compared. Results. There was a statistically significant difference in RTs between block-design and single-event paradigms (t = 3.458, P < .004). The RT values during functional MR imaging and SRT tasks did not show significant differences (.65 < P < .7, paired t test). However, no correlation was found in RT values between event-related (p = -0.004, P = .15) or block-design (p = 0.03, P = .13) paradigms and SRT data. With the block-design functional MR imaging paradigm, the RT was significantly faster (P < .0003) at the beginning of the session than the end, illustrating the effect of anticipation. CONCLUSION: Functional MR imaging RTs must be used to determine the correlation between subjects' performance and the volume of brain activation in a functional MR imaging experiment. The effect of anticipation should be minimized, which could best be achieved by using event-related paradigms.

A novel in vivo post-translational modification of p53 by PARP-1 in MPTP-induced parkinsonism.

Sporadic Parkinson's disease (PD) affects primarily dopaminergic neurons of the substantia nigra pars compacta. There is evidence of necrotic and apoptotic neuronal death in PD, but the mechanisms behind selected dopaminergic neuronal death remain unknown. The tumor suppressor protein p53 functions to selectively destroy stressed or abnormal cells during life and development by means of necrosis and apoptosis. Activation of p53 leads to death in a variety of cells including neurons. p53 is a target of the nuclear enzyme Poly(ADP-ribose)polymerase (PARP), and PARP is activated following DNA damage that occurs following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. MPTP is the favored in vivo model of PD, and reproduces the pathophysiology, anatomy and biochemistry of PD. p53 protein normally exhibits a fleeting half-life, and regulation of p53 stability and activation is achieved mainly by post-translational modification. We find that p53 is heavily poly(ADP-ribosyl)ated by PARP-1 following MPTP intoxication. This post-translational modification serves to stabilize p53 and alters its transactivation of downstream genes. These influences of PARP-1 on p53 may underlie the mechanisms of MPTP-induced parkinsonism and other models of neuronal death.

Human alpha-synuclein-harboring familial Parkinson's disease-linked Ala-53 --> Thr mutation causes neurodegenerative disease with alpha-synuclein aggregation in transgenic mice.

Mutations in alpha-synuclein (alpha-Syn) cause Parkinson's disease (PD) in a small number of pedigrees with familial PD. Moreover, alpha-Syn accumulates as a major component of Lewy bodies and Lewy neurites, intraneuronal inclusions that are neuropathological hallmarks of PD. To better understand the pathogenic relationship between alterations in the biology of alpha-Syn and PD-associated neurodegeneration, we generated multiple lines of transgenic mice expressing high levels of either wild-type or familial PD-linked Ala-30 --> Pro (A30P) or Ala-53 --> Thr (A53T) human alpha-Syns. The mice expressing the A53T human alpha-Syn, but not wild-type or the A30P variants, develop adult-onset neurodegenerative disease with a progressive motoric dysfunction leading to death. Pathologically, affected mice exhibit neuronal abnormalities (in perikarya and neurites) including pathological accumulations of alpha-Syn and ubiquitin. Consistent with abnormal neuronal accumulation of alpha-Syn, brain regions with pathology exhibit increases in detergent-insoluble alpha-Syn and alpha-Syn aggregates. Our results demonstrate that the A53T mutant alpha-Syn causes significantly greater in vivo neurotoxicity as compared with other alpha-Syn variants. Further, alpha-Syn-dependent neurodegeneration is associated with abnormal accumulation of detergent-insoluble alpha-Syn.