GDNF in treatment of Parkinson's disease: response to editorial.
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Clinical Trials as Topic↗
Biomedical subjects
Andres M Lozano
Publications and source records attributed to Andres M Lozano.
The motor thalamus in neurosurgery.
The motor thalamus is an important target for the treatment of tremor. It receives afferents from the cerebellum, globus pallidus internus, and substantia nigra and projects mainly to the motor cortex, premotor cortex, and supplementary motor area. Various nomenclatures have been proposed to subdivide the motor thalamus, none of which are universally accepted. Both thalamic lesions and high-frequency stimulation ameliorate tremor in diverse pathological conditions. Modern neurophysiological techniques have allowed the recording of the activity of thalamic neurons in patients with different clinical conditions. This has provided a better understanding of the functions of the motor thalamus in humans. The aim of the present article is to briefly review the major anatomic and physiological aspects of the motor thalamus as well as the electrophysiological findings described in humans undergoing surgical procedures.
Electrophysiology↗
Neural stimulation for Parkinson's disease: current therapies and future directions.
Neural stimulation has rapidly become an integral tool in the treatment of Parkinson's disease and other movement disorders. Today it serves as an important adjunct to medical therapy that continues to gain applicability to patients in whom the disease has progressed significantly. Studies have demonstrated efficacy in several deep-brain targets, with prolonged benefit exceeding 5-year follow-up times. Continuing study is teaching us more about the mechanism of deep-brain stimulation effect. New targets, which may treat the disease more successfully, are being examined. In this review, the history of deep-brain stimulation, the rationale for the known targets of stimulation; the clinical evidence demonstrating their benefit and, finally, future perspectives on new treatments that are being investigated and may have an impact on the field are discussed.
Brain↗
Cortical activation with deep brain stimulation of the anterior thalamus for epilepsy.
OBJECTIVE: We studied the relation between thalamic stimulation parameters and the morphology, topographic distribution and cortical sources of the cerebral responses in patients with intractable epilepsy undergoing deep brain stimulation (DBS) of the thalamus. METHODS: Bipolar and monopolar stimuli were delivered at a rate of 2 Hz to the anterior (AN, four patients), the dorsomedian (DM, four patients), and the centromedian nucleus (CM, one patient) using the programmable stimulation device (Medtronic ITREL II). Source modeling was carried out by using statistical non-parametric mapping of low-resolution electromagnetic tomography (LORETA) values. RESULTS: All patients demonstrated reproducible time-locked cortical responses (CRs) consisting of a sequence of components with latencies between 20 and 320 ms. The morphology of these CRs, however, was very heterogeneous, depending primarily on the site of stimulation. Following AN stimulation, cortical activation was most prominent in ipsilateral cingulate gyrus, insular cortex and lateral neocortical temporal structures. Stimulation of the DM mainly showed activation of the ipsilateral orbitofrontal and mesial and lateral frontal areas, but also involvement of mesial temporal structures. Stimulation of the CM showed a rather diffuse (though still mainly ipsilateral) increase of cortical activity. The magnitude of cortical activation was positively related to the strength of the stimulus and inversely related to the impedance of the electrode. CONCLUSIONS: The pattern of cortical activation corresponded with the hodology of the involved structures and may underscore the importance of optimal localization of DBS electrodes in patients with epilepsy. SIGNIFICANCE: The method of analyzing sources of CRs could potentially be a useful tool for titration of DBS parameters in patients with electrode contacts in clinically silent areas. Furthermore, the inverse relation of the cortical activation and the impedance of the electrode contacts might suggest that these impedance measurements should be taken into consideration when adjusting DBS parameters in patients with epilepsy.
Adult↗
Restating the importance of bipolar recording in subcortical nuclei.
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Brain↗
Human anterior cingulate cortex neurons encode cognitive and emotional demands.
The cortical mechanisms and substrates of cognitive and emotional demands are poorly understood. Lesion studies and functional imaging implicate the anterior cingulate cortex (ACC). The caudal ACC (cACC) has been implicated in cognitive processes such as attention, salience, interference, and response competition, mostly on the basis of neuroimaging results. To test the hypothesis that individual cACC neurons subserve these functions, we monitored neuronal activity from single cells in the cACC while subjects were engaged in a mental arithmetic task, the cognitively demanding counting Stroop task, and/or the emotional Stroop interference task. We now report the first direct measures of single neurons in humans identifying a population of cACC neurons that respond differentially or in a graded manner to cognitively demanding high- and low-conflict Stroop tasks, including those with emotional valence. These data indicate that cACC neurons may be acting as salience detectors when faced with conflict and difficult or emotional stimuli, consistent with neuroimaging results of cACC responses to abrupt sensory, novel, task-relevant, or painful stimuli.
Brain Mapping↗
Firing rates of pallidal neurons are similar in Huntington's and Parkinson's disease patients.
According to the now classical basal ganglia-thalamocortical circuitry model, the chorea of Huntington's disease (HD) and the hypokinesia in Parkinson's disease (PD) are explained by a decrease in the inhibitory output (reduced firing rates) from the globus pallidus internus (GPi) in HD and increased output in PD. Differences between firing patterns might also be a factor contributing to the different symptoms, however. To test the predictions of the model we examined neuronal firing rates and patterns in two HD patients and 14 PD patients. Single-cell, microelectrode recordings were obtained from awake patients undergoing stereotactic surgery for implantation of deep brain stimulating (DBS) electrodes in the GPi. The mean neuronal firing rate in the GPi of HD patients was 81.8+/-4.3 Hz (mean+/-SEM), which was not significantly different from that in PD patients (89.9+/-3.0 Hz). Firing pattern analyses using measurements of burst index, coefficient of variation, and percentage participation of spikes in bursts revealed, however, that GPi neurons in HD patients fired in a more regular pattern (fewer "bursts") than in PD patients. These results suggest that the rate-based model does not adequately explain the motor abnormalities present in the two HD patients studied. Furthermore, the findings did reveal a difference between firing patterns in the HD and PD groups, thereby supporting the role of altered firing patterns in the pathophysiology of these diseases.
Action Potentials↗
Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress.
Mutations of the DJ-1 (PARK7) gene are linked to familial Parkinson's disease. We used gene targeting to generate DJ-1-deficient mice that were viable, fertile, and showed no gross anatomical or neuronal abnormalities. Dopaminergic neuron numbers in the substantia nigra and fiber densities and dopamine levels in the striatum were normal. However, DJ-1-/- mice showed hypolocomotion when subjected to amphetamine challenge and increased striatal denervation and dopaminergic neuron loss induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine. DJ-1-/-embryonic cortical neurons showed increased sensitivity to oxidative, but not nonoxidative, insults. Restoration of DJ-1 expression to DJ-1-/- mice or cells via adenoviral vector delivery mitigated all phenotypes. WT mice that received adenoviral delivery of DJ-1 resisted 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine-induced striatal damage, and neurons overexpressing DJ-1 were protected from oxidative stress in vitro. Thus, DJ-1 protects against neuronal oxidative stress, and loss of DJ-1 may lead to Parkinson's disease by conferring hypersensitivity to dopaminergic insults.
Animals↗
Deep brain stimulation for treatment-resistant depression.
Treatment-resistant depression is a severely disabling disorder with no proven treatment options once multiple medications, psychotherapy, and electroconvulsive therapy have failed. Based on our preliminary observation that the subgenual cingulate region (Brodmann area 25) is metabolically overactive in treatment-resistant depression, we studied whether the application of chronic deep brain stimulation to modulate BA25 could reduce this elevated activity and produce clinical benefit in six patients with refractory depression. Chronic stimulation of white matter tracts adjacent to the subgenual cingulate gyrus was associated with a striking and sustained remission of depression in four of six patients. Antidepressant effects were associated with a marked reduction in local cerebral blood flow as well as changes in downstream limbic and cortical sites, measured using positron emission tomography. These results suggest that disrupting focal pathological activity in limbic-cortical circuits using electrical stimulation of the subgenual cingulate white matter can effectively reverse symptoms in otherwise treatment-resistant depression.
Adult↗
Pallidal deep brain stimulation influences both reflexive and voluntary saccades in Huntington's disease.
Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is being evaluated as a potential new therapy for patients with Huntington's disease (HD). In addition to skeletal movement disorders, HD patients have difficulty initiating voluntary saccades and have difficulty in suppressing rapid saccades toward newly appearing stimuli. We measured several saccade parameters in an HD patient who had marked improvement of clinical symptoms with bilateral GPi DBS to determine whether oculomotor performance improved in parallel with clinical scores. Oculomotor performance was assessed using three testing paradigms: pro-saccades, anti-saccades, and memory-guided saccades. The data from the HD patient was also compared to that of two healthy controls. Pallidal DBS decreased pro-saccade latency, total movement time, and the number of correctly executed trials, as well as increasing saccade gain. Memory-saccade performance was negatively affected with stimulation: saccade gain decreased, latency increased, and the patient's ability to suppress unwanted saccades decreased with stimulation. Our data demonstrate a task-specific improvement of oculomotor deficits in this HD patient with pallidal DBS, supporting a role of GPi in oculomotor control.
Adult↗
Comparison of 2-dimensional magnetic resonance imaging and 3-planar reconstruction methods for targeting the subthalamic nucleus in Parkinson disease.
OBJECTIVE: The study aims to compare 2-dimensional (2D) and 3-planar (3P) reconstruction magnetic resonance imaging (MRI) methods of targeting the optimal region of the subthalamic nucleus (STN) for chronic stimulation in patients with Parkinson disease. METHODS: We studied 14 patients with Parkinson disease treated with bilateral STN deep brain stimulation (DBS) (28 STN targets). Electrode implantation was based on direct and indirect targeting based upon the position of the anterior and posterior commissures using 2D MRI, with selection of the final target based on microelectrode recording. Optimal settings, including the contacts used, were determined during the clinical follow-up. The position of the best contact was defined with postoperative MRI. Optimal contact position was compared to targets calculated by the direct method from the preoperative 2D MRI and 3P reconstruction. Optimal contact position was also compared to the indirect targets calculated from the preoperative 2D MRI and 3P reconstruction. The distance between the targets and the position of the best contact were calculated. RESULTS: The mean improvement in OFF-period Unified Parkinson Disease Rating Scale III subscores with STN DBS was 52%. The mean distance between the optimal contact position and the direct target was 4.66 mm (SD = 1.33) using the 2D MRI and 3.49 mm (SD = 1.29) using the 3P reconstruction (t test, P < .001). The mean distance between the optimal contact and the indirect target was 3.42 mm (SD = 1.34) using the 2D MRI and 2.61 mm (SD = 0.97; t test, P = .001) using the 3P reconstruction. The variance of the direct target was less using the 3P reconstruction than using the 2D MRI (F test, P = .002), indicating greater precision. Similarly, the variance of the indirect target using the 3P reconstruction was less than using the 2D MRI (F test, P = .012). CONCLUSION: Indirect and direct targets chosen using 3P reconstruction more closely approximate the position of the clinically optimal contact than targets chosen using 2D MRI.
Deep Brain Stimulation↗
Correspondence of microelectrode mapping with magnetic resonance imaging for subthalamic nucleus procedures.
BACKGROUND: Magnetic resonance imaging (MRI) and microelectrode recording (MER) are commonly used to guide stereotactic procedures on the subthalamic nucleus (STN). Little is known about the correlation between the position of the STN as seen on MRI and that as determined by MER mapping. We compared these in 10 patients with Parkinson's disease. METHODS: The position of the STN was determined by intraoperative MER findings and stereotactic axial T2 magnetic resonance images with 2-mm slice thickness. Images were reconstructed in a 3-dimensional workstation. The anterior, posterior, medial, lateral, dorsal, and ventral borders of the STN defined with the MRI were measured relative to the midcommissural point. The location of STN activity during MER was reconstructed relative to the midcommissural point for comparison. RESULTS: Twenty-nine tracks recorded with microelectrodes provided clear spans of STN-like activity in 18 STN nuclei. The coordinates of MER were, in general, within the borders of the STN defined with the MRI. However, when analyzed individually, some of the tracks had STN-like activity outside the borders of the MRI-defined nucleus (mostly <1 mm). Three tracks had STN-like activity recorded between 2 and 3 mm more anterior than the anterior border of the nucleus defined with the MRI. CONCLUSIONS: There was a good correlation between MER and the borders of the STN defined in the MRI, except for the anterior-posterior axis, in which MER indicated that the STN extended more anteriorly than as suggested by MRI. This should be taken into account in STN surgery.
Action Potentials↗
Comparison of three methods of targeting the subthalamic nucleus for chronic stimulation in Parkinson's disease.
OBJECTIVE: The success of subthalamic nucleus (STN) surgery for Parkinson's disease depends on accuracy in target determination. The objective of this study was to determine which of the following techniques was most accurate and precise in identifying the location for stimulation in STN deep brain stimulation surgery that is most clinically effective: direct targeting, indirect targeting using the positions of the anterior and posterior commissures, or a technique using the red nucleus (RN) as an internal fiducial marker. METHODS: We reviewed 14 patients with Parkinson's disease treated with bilateral STN deep brain stimulation (28 STN targets). Electrode implantation was based on direct and indirect targeting using two-dimensional magnetic resonance imaging with refinement using microelectrode recording. Optimal settings, including the contacts used, were determined during the clinical follow-up. The position of the best contact was defined with postoperative magnetic resonance imaging. This location was compared with the modified direct, indirect, and RN-based targets. The mean distances between the targets and the final position of the optimal contact were calculated. The accuracy and variance of each target were analyzed. RESULTS: The mean position of the best contact was x = 12.12 (standard deviation [SD], 1.45 mm), y = -2.41 (SD, 1.63 mm), and z = -2.39 (SD, 1.49 mm) relative to the midcommissural point. The mean distance between the optimal contact position and the planned target was 3.19 mm (SD, 1.19 mm) using the RN-based method, 3.42 mm (SD, 1.34 mm) using indirect targeting, and 4.66 mm (SD, 1.33 mm) using a modified direct target. The mean distance between the optimal contact and the RN-based target was significantly smaller than the mean distance between the optimal contact and the direct target (post hoc with Tamhane's correction, P < 0.001) but not between the optimal contact and the indirect target. The RN-based target had the smallest variance (F test, P < 0.001), indicating greater precision. CONCLUSION: The use of the RN as an internal fiducial marker for targeting the optimal region of STN stimulation was reliable and closely approximates the position of the electrode contact that provides the optimal clinical results.
Deep Brain Stimulation↗
Bilateral subthalamic nucleus stimulation for Parkinson's disease: a systematic review of the clinical literature.
OBJECTIVE: To evaluate the benefits and adverse effects of bilateral subthalamic nucleus stimulation in the treatment of Parkinson's disease (PD) by systematically reviewing the published literature. METHODS: A search of the PubMed database using the key words subthalamic, nucleus, and stimulation yielded 624 articles published between 1966 and December 2003. Only articles that included original, nonduplicated descriptions of patients with PD treated with bilateral subthalamic nucleus stimulation were selected for further analysis. RESULTS: A total of 38 studies from 34 neurosurgical centers in 13 countries were identified for critical review. The outcomes for 471 patients with PD treated with bilateral subthalamic nucleus stimulation were assessed according to the Unified Parkinson's Disease Rating Scale in both on-medication and off-medication conditions. With stimulation, Unified Parkinson's Disease Rating Scale motor scores in the off-medication condition improved by 50% after 6 months, 56% after 12 months, 51% after 2 years, and 49% after 5 years compared with preoperative off-medication scores. At 12 months of subthalamic nucleus stimulation, the mean improvement in tremor was 81%, in rigidity was 63%, in bradykinesia was 52%, in gait was 64%, and in postural instability was 69% when compared with preoperative off-medication subscores. On-medication dyskinesias were reduced by 94%, as assessed 12 months after stimulation using the Unified Parkinson's Disease Rating Scale IV complications of therapy score. There was an overall 52% reduction in the l-dopa-equivalent dose intake after 12 months of stimulation. Most adverse effects were mild to moderate. There was a 1 to 2% incidence of severe adverse effects (death or permanent neurological deficits related to intracerebral hemorrhages). Nineteen percent of the patients had adverse effects related to stimulation that could be reversed by changing stimulation parameters. There was a 9% incidence of adverse effects related to the hardware (infections, lead and pulse generator problems). CONCLUSION: Bilateral subthalamic nucleus stimulation is effective in the treatment of PD. Further refinements in patient selection and surgical technique may lessen the incidence of complications associated with this procedure.
Electric Stimulation Therapy↗
Psychiatric symptoms in patients with Parkinson disease presenting for deep brain stimulation surgery.
OBJECT: Postoperative psychiatric symptoms have been associated with subthalamic deep brain stimulation (DBS) for Parkinson disease (PD), and preoperative psychiatric vulnerability, the effects of surgery, stimulation, medication changes, and psychosocial adjustment have been proposed as causative factors. The variables involved in whether preoperative psychiatric symptoms improve or worsen following surgery are not yet known. In the present study, preoperative psychiatric symptoms were systematically assessed in patients with PD presenting for routine preoperative psychiatric assessment. METHODS: Forty consecutive patients with PD presenting for DBS were interviewed using the Mini International Neuropsychiatric Inventory. Current depressive symptoms were quantified using clinician- and patient-rated depression scales. Seventy-eight percent of patients had at least one lifetime or current Axis I psychiatric diagnosis. The prevalence of depression was 60% (95% confidence interval [CI] 45-85), psychosis 35% (95% CI 25-50), and anxiety 40% (95% CI 25-55). These prevalence rates were comparable to or greater than those in the general population of patients with PD. Twenty-three percent of patients required psychiatric treatment for current symptoms prior to being considered eligible for DBS. CONCLUSIONS: As part of the selection process for surgery, members of the study population were chosen for their lack of overt dementia or other active disabling psychiatric symptomatology. The incidence rates of psychiatric disorders, including those diseases occurring in the general population affected with PD, were greater than expected. Data in the present study lead one to question the reliability of patient-rated depression scales as the sole instrument for assessing depression. The authors highlight the need for evidence-based guidelines in the management of these preoperative symptoms as well as the involvement of psychiatric personnel in the assessment and management of these symptoms.
Aged↗
Psychiatric symptoms following surgery for Parkinson's disease with an emphasis on subthalamic stimulation.
Bilateral subthalamic stimulation is a very effective neurosurgical treatment for advanced Parkinson's disease. Despite the range and frequency of psychiatric symptoms occurring in the postoperative state, most of these symptoms are transient and manageable. In clinical practice, preoperative psychiatric vulnerability, as with that of preoperative cognitive status, takes on an important role. Psychiatric assessment and active preoperative and postoperative intervention can potentially modify psychiatric outcomes. These psychiatric and psychological issues will take on greater importance, particularly with the rapid expansion of the number of neurosurgical sites and the need for adequate assessment and optimal management of patients. The paucity of the literature underscores the need for well-designed studies on psychiatric issues investigating both pathophysiology and clinical outcomes.
Anxiety↗
BAG5 inhibits parkin and enhances dopaminergic neuron degeneration.
Loss-of-function mutations in the parkin gene, which encodes an E3 ubiquitin ligase, are the major cause of early-onset Parkinson's disease (PD). Decreases in parkin activity may also contribute to neurodegeneration in sporadic forms of PD. Here, we show that bcl-2-associated athanogene 5 (BAG5), a BAG family member, directly interacts with parkin and the chaperone Hsp70. Within this complex, BAG5 inhibits both parkin E3 ubiquitin ligase activity and Hsp70-mediated refolding of misfolded proteins. BAG5 enhances parkin sequestration within protein aggregates and mitigates parkin-dependent preservation of proteasome function. Finally, BAG5 enhances dopamine neuron death in an in vivo model of PD, whereas a mutant that inhibits BAG5 activity attenuates dopaminergic neurodegeneration. This contrasts with the antideath functions ascribed to BAG family members and suggests a potential role for BAG5 in promoting neurodegeneration in sporadic PD through its functional interactions with parkin and Hsp70.
Adaptor Proteins, Signal Transducing↗