OBJECTIVE: Functional magnetic resonance imaging and transcranial magnetic stimulation studies suggest that human cortex shows evidence of neuroplasticity. Preclinical studies in rats and monkeys suggest that motor cortical stimulation can enhance plasticity and improve recovery after stroke. This study assesses the safety and preliminary efficacy of targeted subthreshold epidural cortical stimulation delivered concurrently with intensive rehabilitation therapy while using an investigational device in patients with chronic hemiparetic stroke. METHODS: This is a prospective, multicenter, and nonblinded trial randomizing patients to rehabilitation with or without cortical stimulation. Patients aged 20 to 75 years who had had an ischemic stroke at least 4 months previously causing persistent moderate weakness of the arm were included. Functional magnetic resonance imaging localized hand motor function before surgery to place an epidural cortical electrode. Both groups then underwent rehabilitation for 3 weeks after which the electrode was removed. Outcome measures were obtained at baseline, during therapy, and at 1, 4, 8, and 12 weeks postprocedure. RESULTS: Ten patients were randomized; six patients to surgery, four to the control group. No patient deaths, neurological deterioration, or seizures occurred. There were two infections from nonprotocol-related causes. Of the eight patients completing the treatment, the stimulation plus rehabilitation group improved significantly better than controls in the Upper Extremity Fugl-Meyer ( P ! 0.003 overall) and the hand function score of the Stroke Impact Scale ( P ! 0.001 overall). CONCLUSION: The technique of cortical stimulation to enhance stroke recovery is well tolerated and safe.

THE INTRODUCTION OF multiple front-end technologies during the past quarter century has generated an emerging futurism for the discipline of neurological surgery. Driven primarily by synergistic developments in science and engineering, neurosurgery has always managed to harness the potential of the latest technical developments. Robotics represents one such technology. Progress in development of this technology has resulted in new uses for robotic devices in our discipline, which are accompanied by new potential dangers and inherent risks. The recent surge in robot-assisted interventions in other disciplines suggests that this technology may be considered one of a spectrum of frontier technologies poised to fuel the development of neurosurgery and consolidate the era of minimalism. On a more practical level, if the introduction of robotics in neurosurgery proves beneficial, neurosurgeons will need to become facile with this technology and learn to harness its potential so that the best surgical results may be achieved in the least invasive manner. This article reviews the role of robotic technology in the context of neurosurgery.

OBJECTIVE:Although hemorrhage is a well-known complication of microelectrode-guided deep brain stimulation (DBS) surgery, risk factors for the development of hemorrhage have not been well defined. We analyzed the risk factors for symptomatic and asymptomatic hemorrhage in a large series of DBS implantations into the subthalamic nucleus, ventrolateral thalamus, and internal globus pallidus. METHODS:All DBS procedures performed by a single surgeon at our institution between June 1998 and May 2004 were included in this study. All patients had postoperative imaging (magnetic resonance imaging or computed tomography) 4 to 24 hours after surgery. Hematomas were noted and scored as symptomatic or asymptomatic. Statistical correlation of factors affecting risk of hematoma formation was performed by use of logistic regression analysis. RESULTS:The total number of lead implantations was 481. There were 6 symptomatic hematomas and 10 asymptomatic hematomas. Three of the symptomatic hematomas resulted in permanent new neurological deficit. The risk of hematoma (of any type) per lead implantation was 3.3%, whereas the risk of permanent deficit from hematoma was 0.6%. Patients who developed hematomas had a slightly greater number of microelectrode recording penetrations than patients who did not have hematomas, but this difference did not reach statistical significance. There was not a statistically significant relationship between risk of hematoma and patient age or diagnosis. There was a significant effect of brain target (P = 0.001), with only 1 hemorrhage detected after thalamic DBS. CONCLUSION:DBS is generally safe, with only 0.6% of implantations associated with permanent neurological deficit. The incremental risk of successive serial microelectrode penetrations is small.

Rezai, Ali R. M.D.; Baker, Kenneth B. Ph.D.; Tkach, Jean A. Ph.D.; Phillips, Michael M.D.; Hrdlicka, Greg B.S.E.E.; Sharan, Ashwini D. M.D.; Nyenhuis, John Ph.D.; Ruggieri, Paul M.D.; Shellock, Frank G. Ph.D.; Henderson, Jaimie M.D. Author Information

OBJECTIVE:We evaluated somatosensory and motor interhemispheric integration in four patients who underwent transection of different portions of the anterior corpus callosum (CC) for removal of an intraventricular cyst. The study goal was to relate their performances to the topographical organization of the CC.METHODS:Experimental tasks included bimanual coordination, tactile cross-localization, and intermanual and interfield comparisons of somesthetic information. Response accuracy and response times were measured. In addition, interhemispheric transmission times were obtained in the somesthetic modality.RESULTS:Section of the middle portion of the genu caused a deficit in motor coordination, which was absent in patients with more posteriorly located lesions, whereas section of more rostral portions of the genu seemed to interfere with motor planning. The most posterior section in our sample, including the anterior portion of the body of the corpus, abolished interhemispheric transfer of simple somesthetic information (perception of touch) but not tactile discrimination (intermanual comparisons of shapes). We speculate that more complex somesthetic information is transferred through the caudal region of the body of the CC, which was spared in all patients. Thus, it seems that section of different portions of the anterior CC (genu and anterior body) produces specific deficits in interhemispheric integration in the motor and somesthetic modalities. These deficits are consistent with the anteroposterior topography of anterior callosal fibers.CONCLUSION:The specific disconnections deficits observed in this study may provide the surgeon with information regarding the consequences of anterior callosotomy and allow for remedial measures to be implemented if required.

Summary: Purpose: Left cervical vagus nerve stimulation (VNS) decreases complex partial seizures (CPS) by unknown mechanisms of action. We hypothesized that therapeutic VNS alters synaptic activities at vagal afferent terminations and in sites that receive polysynaptic projections from these medullary nuclei. Methods: Ten patients with partial epilepsy underwent positron emission tomographic (PET) measurements of cerebral blood flow (BF) three times before and three times during VNS. Parameters for VNS were at high levels for 5 patients and at low levels for 5. Resting BF measurements were subtracted from measurements during VNS in each subject. Subtraction data were averaged in each of 2 groups of 5 patients. t Tests were applied to BF changes in brain regions that receive vagal afferents and projections (significant at p < O.05, corrected for repeated measures). Results: In both the low‐ and high‐stimulation groups during VNS, brain BF was (a) increased in the rostral, dorsal‐central medulla; (b) increased in the right postcentral gyrus, (c) increased bilaterally in the hypothalami, thalami, and insular cortexes, and in cerebellar hemispheres inferiorly; and (d) decreased bilaterally in hippocampus, amygdala, and posterior cingulate gyri. The high‐stimulation group had greater volumes of activation and deactivation sites. Conclusions: Our findings suggest that left cervical VNS acutely increases synaptic activity in structures directly innervated by central vagal structures and areas that process left‐sided somatosensory information, but VNS also acutely alters synaptic activity in multiple limbic system structures bilaterally. These findings may reflect sites of therapeutic actions of VNS.

High frequency (>100Hz) electrical stimulation in both the external (GPe) and internal (GPi) segments of the globus pallidus was effective in improving parkinsonian motor signs. Improvement generally occurred at short latency (<5–10 seconds) in both GPe and GPi but was often (50% of the time) delayed in GPi. Dyskinetic movements were observed during stimulation within GPe and GPi but were more frequent in GPe (20% vs. 9%). These findings suggest that electrical stimulation in both GPe and GPi may ameliorate parkinsonian motor signs. The mechanisms responsible for these observations, however, may differ. The tendency for delayed responses with GPi stimulation suggests a more complex spatial–temporal profile of stimulation on the electrical activity of GPi neurons and/or its effect on network activity in pallido‐thalamo‐cortical circuitry. The rarity of delayed effects with GPe stimulation suggests a more direct role of synaptic inhibition or normalization of neuronal activity of GPi either directly by means of activation of striatopallidal fibers passing through GPe (direct pathway), by means of activation of GPe→GPi or GPe→subthalamic nucleus projections (indirect pathway) or indirectly by means of the tonic activation of adjacent fiber pathways. These data provide a rationale for the exploration of electrical stimulation in GPe in patients with medically intractable Parkinson's disease and provide a basis on which to develop further investigations into the use of chronic electrical stimulation for the treatment of Parkinson's disease and other movement disorders. © 2004 Movement Disorder Society

Evaluation of the safety and efficacy of unilateral stereotactic implantation of cultured human retinal pigment epithelial (hRPE) cells attached to microcarriers (Spheramine) in patients with advanced PD in an open label pilot study. Six patients with advanced PD (3 males; 3 females; mean age 52.2 years; mean duration of PD 10.2 years; mean Hoehn and Yahr stage "off" 3.75) were assessed at baseline and post-operatively using the modified CAPIT. Each patient underwent MRI-guided stereotactic transplantation of 325,000 hRPE cells attached to microcarriers in 5 tracts, 5 mm apart in the post-commissural putamen contralateral to the most affected side. Immunosuppression was not used. The UPDRS Motor (UPDR-M) score in the practically defined "off" state was the primary outcome measure. At 6 months post-op, the mean UPDRS-M (off) score improved to 35 (34%) from a pre-op baseline mean of 52 (p <.001). Secondary outcome measures improved including the total UPDRS (33%), Timed Motor Tests (on, 14%; off, 23%), PDQ39 QOL (30%), and Schwab and England score (on, 11%; off, 30%). Bilateral improvements have been observed in motor symptoms, with the greatest effect seen contralateral to the implants. Three of six patients currently have lower Dyskinesia Rating Scale scores than at baseline, while the scores of the other three are unchanged from baseline values. No "off-state" dyskinesias have been observed. Thus Spheramine implantation therapy appears to be safe and well tolerated for 6 months post-implantation.

Background: Pharmacologic interventions (e.g., beta blockers) and thalamic lesions have failed to alter the pathophysiology of essential tremor (ET) beyond a reduction in tremor amplitude. Deep brain stimulation (DBS) of the ventral intermediate (VIM) nucleus of the thalamus successfully reduces tremor rating scores. It is unknown how VIM DBS alters the pathophysiologic characteristics of ET. Objective: To determine the effects of VIM DBS on the neurophysiologic characteristics of ET. Methods: Hand tremor and EMG activity of forearm extensor and flexor muscles were recorded in six patients with ET ON-DBS and OFF-DBS and from six age- and sex-matched control subjects. Hand tremor was assessed across different inertial loads. The amplitude, frequency, regularity, and tremor-EMG coherence were analyzed. Results: VIM DBS reduced the amplitude, increased the frequency, decreased the regularity, and reduced the 1 to 8 Hz tremor-EMG coherence of ET. ON-DBS, patients with ET had greater tremor amplitude, lower frequency, more regularity, and greater tremor-EMG coherence compared to control subjects. Conclusions: Whereas pharmacologic and thalamic lesions have previously failed to change characteristics of ET beyond amplitude reduction, VIM DBS modified multiple features of ET. The changes in ET after VIM DBS provide strong evidence for clinical efficacy.

We report two cases of transient hypomanic behavior following pallidotomy. Both of the reported patients had lesions involving non-motor portions of the globus pallidus. Patient 1 had a lesion in the left anteromedial portion of GPi, while patient 2 had one lesion involving the anteromedial portion of GPi on the right and a second lesion involving the postero-ventral most portion of the putamen on the left. These cases emphasize the importance of placing lesions within the sensori-motor portion of GPi without infringing on adjacent non-motor portions. Cases involving transient manic behavior after pallidotomy have not been previously reported. Centers performing pallidotomy or DBS should be aware that lesions or stimulation too anterior in the GPi might lead to manic behavior.

OBJECTIVEThe subthalamic nucleus (STN) is a target in the surgical treatment of Parkinson’s disease (PD). The mechanism by which electrical stimulation of the STN ameliorates symptoms of PD remains unknown. One consistent aspect of STN stimulation is the ability to reduce the dosage of dopaminergic medications; sometimes they can be eliminated altogether. Furthermore, nigrostriatal projection axons are apposed to the dorsal surface of the STN and are likely affected by the application of current in this region. We sought to determine whether STN stimulation could release endogenous striatal dopamine. METHODSFive patients with PD, who had previously undergone surgical implantation of bilateral STN stimulators, underwent [11C]raclopride positron emission tomographic scanning. l-dopa was withheld for 12 hours, and both stimulators were turned off 9 hours before scanning. We assayed for striatal dopamine release by measuring radioligand displacement as a consequence of turning on the right STN stimulator after 45 minutes of a 90-minute [11C]raclopride infusion. Patients were evaluated with the motor section of the Unified Parkinson’s Disease Rating Scale before and after the studies. RESULTSComparisons between the right and left striata, before and after right STN stimulation, demonstrated no significant differences in [11C]raclopride binding, despite significant improvements in Unified Parkinson’s Disease Rating Scale motor scores with unilateral stimulation (mean improvement, 26.0 ± 16.4%; P < 0.05). This finding was also noted when the striatum was partitioned into dorsal and ventral caudate and putamen and the four regions were analyzed separately. CONCLUSIONOur results suggest that STN stimulation does not mediate its anti-PD effects via the release of dopamine, as assessed with [11C]raclopride displacement.

OBJECTIVE:To investigate the potential operative morbidity in posteroventral pallidotomy (PVP) for patients with Parkinson's disease.METHODS:We designed a retrospective study that included 796 consecutive patients (mean age, 64.9 yr; male, 559; female, 237) with Parkinson's disease. All PVPs (simultaneous bilateral PVP, n = 272; sequential bilateral PVP, n = 88; unilateral PVP, n = 436) were performed during a 7-year period. The total number of operations was 884, and the number of PVP procedures was 1156. In 108 patients, ventral intermediate nucleus thalamotomy was performed simultaneously.RESULTS:The overall complication rate, including temporary problems, was 15.3% of 884 operations. Permanent complications occurred in 3.6% of total operations. Intracranial hemorrhage occurred in 24 operations (2.7%). In seven of them, the patients required craniotomy and hematoma evacuation and sustained a disabling motor deficit (0.8%). Intracranial hemorrhage occurred more often in patients who underwent microelectrode recording and had a history of chronic hypertension. Hemiparesis without intracranial hematoma occurred in 12 operations (1.4%). Microelectrode recording was a risk factor for postoperative hemiparesis without hemorrhage. In 19 operations (2.1%), patients developed a partial visual field deficit. Speech disturbance after surgery was observed in 23 operations (2.6%) but resolved in 17 by 1 week after surgery. In 55 operations (6.2%), patients developed postoperative confusion. This occurred more often in elderly patients and those with advanced disease. In 17 operations (1.9%), patients required observation in the intensive care unit because of postoperative hypotension.CONCLUSION:Complications from stereotactic pallidotomy were not frequent. However, the residual symptoms from complications can be serious in many cases.

OBJECTIVE: To assess the efficacy and complication rates of magnetic resonance imaging-guided stereotactic limbic leukotomy for the treatment of intractable major depressive disorder (MDD) and obsessive-compulsive disorder (OCD).METHODS: We conducted preoperative evaluations and postoperative follow-up assessments of efficacy and complications for 21 patients who underwent limbic leukotomy. Efficacy was based on physician- and patient-rated global assessments of functioning, as well as evaluations using disease-specific rating scales commonly used in studies of MDD and OCD.RESULTS: The mean time from limbic leukotomy to follow-up assessment was 26 months. On the basis of standard outcome measures, 36 to 50% of patients were considered to be treatment responders. Although permanent surgical morbidity was rare, there were reports of postoperative sequelae, including apathy, urinary incontinence, and memory complaints, which occurred in a substantial minority of cases.CONCLUSION: For this cohort of 21 patients with chronic severe MDD or OCD, who had experienced failure with an exhaustive array of previous treatments, limbic leukotomy was associated with substantial benefit for 36 to 50%. This rate is comparable to those of previous studies of limbic system surgery and indicates that limbic leukotomy is a feasible treatment option for severe, treatment-refractory MDD or OCD. Adverse consequences associated with the procedure included affective, cognitive, and visceromotor sequelae, which were generally transient.

OBJECTIVE:To determine the nature and frequency of cognitive impairments in nondemented patients with advanced PD and their relationship to other variables potentially predictive of neuropsychological performance.METHODS:The neuropsychological performance of nondemented, nondepressed patients with idiopathic PD (n = 61) was quantified with respect to clinically available normative data. The relationship of neuropsychological measures to motor symptoms, age, years of education, disease duration, age at disease onset, disease deterioration rate, and dopaminergic therapy was assessed.RESULTS:Impairment was most frequent on measures sensitive to frontal lobe function (67% on Wisconsin Card Sorting Test number of categories, 30% on letter fluency, 30% on verbal learning). Poorer performance on multiple neuropsychological measures was related to greater overall motor abnormality (total Unified Parkinson's Disease Rating Scale score), increased bradykinesia on medication, older age, longer disease duration, and reduced education.CONCLUSIONS:Even in the absence of dementia or depression, patients with advanced PD are likely to show clinically significant impairments on neuropsychological measures sensitive to changes in dorsolateral prefrontal regions participating in cognitive basal ganglia-thalamocortical circuits.