Brain serotonin transporter binding in non-depressed patients with Parkinson's disease.

Early post-mortem data suggest that damage to brain serotonin neurones might play a role in some features (e.g., depression) of Parkinson's disease (PD). However, it is not known whether such damage is a typical characteristic of living patients with PD or whether the changes are regionally widespread. To address this question we measured, by positron emission tomography imaging, levels of the brain serotonin transporter (SERT), a marker for serotonin neurones, as inferred from binding of [11C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB), a second generation SERT radioligand, in subcortical and cerebral cortical brain areas of clinically advanced non-depressed (confirmed by structured psychiatric interview) patients with PD. SERT binding levels in PD were lower than those in controls in all examined brain areas, with the changes statistically significant in orbitofrontal cortex (-22%), caudate (-30%), putamen (-26%), and midbrain (-29%). However, only a slight non-significant reduction (-7%) was observed in dorsolateral pre-frontal cortex, an area implicated in major depression. Our imaging data suggests that a modest, regionally widespread loss of brain serotonergic innervation might be a common feature of advanced PD. Further investigation will be required to establish whether SERT binding is more or less decreased in those patients with PD who also have major depressive disorder.

Involvement of the human subthalamic nucleus in movement preparation.

BACKGROUND: Although it has long been recognized that the basal ganglia play a major role in motor control, their precise functions remain unclear. As patients with Parkinson's disease (PD) have difficulties initiating movement, the basal ganglia may be involved in movement preparation. The subthalamic nucleus (STN) is particularly suited to play a role in movement preparation because it receives direct input from the supplementary motor area through the corticosubthalamic pathway. METHODS: Taking advantage of the electrodes surgically implanted in the STN for deep brain stimulation (DBS) treatment in 13 PD patients, we recorded from the DBS electrodes and the scalp simultaneously while the patients were performing self-paced wrist extension movements. RESULTS: Scalp recordings showed a slow, negative movement-related potential (MRP) in all patients studied (onset 1,690 +/- 336 milliseconds before electromyography onset). STN recordings showed premovement MRP in 11 of 13 patients. The STN activity occurred with both ipsilateral and contralateral hand movement. The onset time for STN MRP (contralateral 2,095 +/- 1,005 milliseconds, ipsilateral 2,020 +/- 920 milliseconds) was not significantly different from that for cortical MRP. CONCLUSION: The STN or nearby structures are active before self-paced movement in humans.

Potentials recorded at the scalp by stimulation near the human subthalamic nucleus.

OBJECTIVE: To record the potentials evoked at the scalp by stimulation through electrodes targeted at the human subthalamic nucleus (STN) and to determine whether the responsible pathways continue to be excited or become blocked with high frequency stimulation. METHODS: We recorded the potentials evoked at the scalp in response to single and multiple stimuli delivered through STN contacts in 6 patients with Parkinson's disease. RESULTS: On 9/11 sides tested, single stimuli elicited a negative potential with latency of approximately 3 ms which was largest over the frontal region. Its short chronaxie (50 micros) and refractory period imply that it arose from the activation of low threshold neural elements, possibly myelinated axons. This potential could follow at 100 Hz. This early potential was sometimes followed by later negative potentials at approximately 5 ms (6/11 sides) and approximately 8 ms (8/11 sides). The responsible neural elements had the same short chronaxie. These potentials were augmented by paired stimuli at separations of 2-7 ms and by trains of stimuli at 200 Hz. CONCLUSIONS: Trains of stimuli delivered to the STN may excite low threshold neural elements which can transmit impulses at frequencies >100 Hz without blocking and which may produce postsynaptic facilitation at the cortex.

Neuropsychologic assessment of patients for movement disorder surgery.

The neuropsychologic evaluation of patients under consideration for movement disorder surgery is recognized as being an essential component of the preoperative process. Patients with early-stage concomitant dementia must be identified and the relative risk of postoperative cognitive decline evaluated. Knowledge of the patterns of an individual's strengths and weaknesses might also be a factor in deciding on a neurosurgical procedure. Although the advent of pallidal deep brain stimulation (DBS) has possibly resulted in reduced risk of induced cognitive impairment, even this procedure has been associated with negative sequelae. DBS within the subthalamic nucleus is becoming the method of choice and this may lead to cognitive and behavioral compromise, especially in the elderly patient. The team considering the establishment of neurosurgical treatment is often at a loss to decide how much neuropsychologic testing is required to determine relative risks of cognitive or behavioral morbidity as a consequence of the procedure. A brief summary of expected outcome and of pertinent family process and psychodynamic issues are addressed. This article is intended to serve as a guide to permit clinicians to choose the appropriate length and depth of neuropsychologic assessment, but also to highlight the confounding factors often present in these patients.

Neuropsychological consequences of chronic bilateral stimulation of the subthalamic nucleus in Parkinson's disease.

The aim of this study was to examine possible neuropsychological changes in patients with advanced idiopathic Parkinson's disease treated with bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN). Eleven patients (age = 67 +/- 8 years, years with Parkinson's disease = 15 +/- 3, verbal IQ = 114 +/- 12) were evaluated (in their best 'on state') with tests assessing processes reliant on the functional integrity of frontal striatal circuitry, prior to the procedure (n = 11), at 3-6 months (n = 11) and at 9-12 months (n =10) post-operatively. Six of these patients were older than 69 years. Despite clinical motor benefits at 3-6 months post-operative, significant declines were noted in working memory, speed of mental processing, bimanual motor speed and co-ordination, set switching, phonemic fluency, long-term consolidation of verbal material and the encoding of visuospatial material. Declines were more consistently observed in patients who were older than 69 years, leading to a mental state comparable with progressive supranuclear palsy. 'Frontal' behavioural dyscontrol without the benefit of insight was also reported by half (three of six) of the caregivers of the elderly subgroup. At 9-12 months postoperative, only learning based on multiple trials had recovered. Tasks reliant on the integrity of frontal striatal circuitry either did not recover or gradually worsened over time. Bilateral STN DBS can have a negative impact on various aspects of frontal executive functioning, especially in patients older than 69 years. Future studies will evaluate a larger group of patients and examine the possible reversibility of these effects by turning the DBS off.

Neuropsychological outcome of GPi pallidotomy and GPi or STN deep brain stimulation in Parkinson's disease.

This paper highlights the neuropsychological sequelae of posteroventral pallidotomy (PVP) and deep brain stimulation (DBS) of the subthalamic nucleus (STN) and the internal segment of the globus pallidus (GPi) at 3/6 months postoperatively. Results are based on our extensive experience with PVP and our preliminary observations with DBS. Patients with borderline cognitive or psychiatric functioning risk postoperative decompensation. Nonlateralizing attentional and hemisphere-specific impairments of frontostriatal cognitive functions followed unilateral PVP. "Frontal" behavioral dyscontrol was observed in approximately 25% of patients. Three cases of staged bilateral PVP suggest that premorbid factors may predict outcome, although lesion size and location are also critical. Older patients are at risk for significant cognitive and behavioral decline after bilateral STN DBS, while GPi DBS may be safer.

Relationship of lesion location to cognitive outcome following microelectrode-guided pallidotomy for Parkinson's disease: support for the existence of cognitive circuits in the human pallidum.

Current models of basal ganglia anatomy posit the existence of multiple parallel, anatomically segregated circuits. Anatomical data from non-human primates suggest that the circuits subserving motor functions are segregated from those subserving cognitive functions. Here we present data that demonstrate that, in humans, motor and cognitive frontosubcortical circuits are segregated. We studied a group of patients with Parkinson's disease undergoing surgical lesioning of the globus pallidus internus for relief of their symptoms. Lesion location along an anteromedial-to-posterolateral axis was found to be related to postsurgical outcome on both cognitive and motor measures. Performance on several neuropsychological measures, including the generation of category exemplars and continuous mental addition, was linearly related to distance along this axis, with anteromedial lesions leading to postsurgical impairment, intermediate lesions having little effect and posterolateral lesions leading to an improvement on several measures. The same relationship was found between memory performance under conditions of proactive interference and lesion location within the globus pallidus internus. In contrast, bradykinesia, assessed as the speed of finger-tapping, had a non-linear relationship to lesion location, intermediate lesions leading to greater postsurgical improvement than lesions in more extreme anteromedial or posterolateral locations. These data demonstrate that the cognitive effects of pallidotomy can be dissociated from the motor effects. These effects depend upon the placement of the lesions within the globus pallidus internus, supporting the segregation of functionally distinct circuits in the human pallidum.

Posteroventral medial pallidotomy in Parkinson's disease.

There has been a resurgence in the use of functional neurosurgery for Parkinson's disease. An important factor that has played a role in this development is the recent understanding of the functional anatomy of the basal ganglia including a knowledge of the changes in the activities of neurons in the internal segment of the globus pallidus (Gpi) and the subthalamic nucleus (STN) in Parkinson's disease as well as the knowledge of the presence of segregated functional loops within the basal ganglia which include a sensory-motor loop that involves the posteromedial globus pallidus rather than the anterior GPi where earlier pallidotomy lesions had been made. Laitinen reintroduced the modern posteroventral medial pallidotomy (PVMP) in 1992. Since then it has become clear that this treatment has major effects on levodopa-induced dyskinesias and, unlike Vim thalamotomy, improves bradykinesia and rigidity as well as tremor. In this report, we review a number of topics related to PVMP including the clinical results of pallidotomy available in the literature as well as an update of our own 2 year follow-up data, studies evaluating factors that might predict the subsequent response to pallidotomy, the neuropsychological effects of the procedure, results of imaging studies including the correlation of clinical effects with lesion location, the question of bilateral pallidotomy and pallidotomy combined with deep brain stimulation and finally whether PVMP is effective in other parkinsonian disorders.

Relationship of lesion location to clinical outcome following microelectrode-guided pallidotomy for Parkinson's disease.

The purpose of this study was to examine the relationship between lesion location and clinical outcome following globus pallidus internus (GPi) pallidotomy for advanced Parkinson's disease. Thirty-three patients were prospectively studied with extensive neurological examinations before and at 6 and 12 months following microelectrode-guided pallidotomy. Lesion location was characterized using volumetric MRI. The position of lesions within the posteroventral region of the GPi was measured, from anteromedial to posterolateral along an axis parallel to the internal capsule. To relate lesion position to clinical outcome, hierarchical multiple regression analysis was used. The variance in outcome measures that was related to preoperative scores and lesion volume was first calculated, and then the remaining variance attributable to lesion location was determined. Lesion location along the anteromedial-to-posterolateral axis within the GPi influenced the variance in total score on the Unified Parkinson's Disease Rating Scale in the postoperative 'off' period, and in 'on' period dyskinesia scores. Within the posteroventral GPi, anteromedial lesions were associated with greater improvement in 'off' period contralateral rigidity and 'on' period dyskinesia, whereas more centrally located lesions correlated with better postoperative scores of contralateral akinesia and postural instability/gait disturbance. Improvement in contralateral tremor was weakly related to lesion location, being greater with posterolateral lesions. We conclude that improvement in specific motor signs in Parkinson's disease following pallidotomy is related to lesion position within the posteroventral GPi. These findings are consistent with the known segregated but parallel organization of specific motor circuits in the basal ganglia, and may explain the variability in clinical outcome after pallidotomy and therefore have important therapeutic implications.

Variability in lesion location after microelectrode-guided pallidotomy for Parkinson's disease: anatomical, physiological, and technical factors that determine lesion distribution.

OBJECT: To understand the factors that determine the distribution of lesions after microelectrode-guided pallidotomy for Parkinson's disease, the authors quantitatively characterized lesion location in a cohort of patients who were prospectively followed to determine the effects of pallidotomy on clinical outcome. METHODS: Thirty-three patients underwent volumetric magnetic resonance (MR) imaging after surgery to allow quantitative lesion localization in relation to conventional intraventricular landmarks and, alternatively, more anatomically relevant landmarks. The validity of the method was verified in a cohort of postpallidotomy patients who underwent concurrent volumetric and stereotactic MR imaging in an external head frame. Lesions were distributed over a considerable distance in the anteroposterior (8.8 mm) and mediolateral (8.7 mm) dimensions in relation to the anterior commissure and wall of the third ventricle, respectively. Less variation was seen in lesion location in the dorsoventral dimension (4.8 mm) in relation to the intercommissural plane. CONCLUSIONS: Lesion distribution was not random: lesion locations in the anteroposterior and mediolateral dimensions were highly correlated, such that lesions were distributed from anteromedial to posterolateral, parallel to the border of the globus pallidus internus with the obliquely oriented internal capsule. The factors that led to variability in lesion location were variation in third ventricle width and the oblique anteromedial-to-posterolateral course of the internal capsule. This demonstration of variability of lesion location in a cohort of patients who experienced excellent clinical benefits and minimal postoperative complications emphasizes the importance of anatomical variations in determining lesion position and the need for physiological corroboration for correct lesion placement.

The differential effects of cueing on recall in Parkinson's disease and normal subjects.

Patients with Parkinson's disease (PD) are known to be impaired in supraspan verbal learning due to reduced availability of internal encoding capacity. PD patients may suffer from poor semantic, source and sequential processing capacity. Thirty-three patients with idiopathic PD and 42 matched normal control subjects (NC) were administered the California Verbal Learning Test under 3 conditions of graded cueing. While the PD patients benefited significantly and progressively from increasingly explicit cueing, the NC group did not since their performance was optimal even without cueing. Results are discussed in relation to frontal executive control of attentional resources and the establishment of encoding strategies.

Temporal horn enlargement is present in schizophrenia and bipolar disorder.

BACKGROUND: Ventricular enlargement and temporal lobe volume deficits have been demonstrated in patients with affective disorder as well as those with schizophrenia. This study compares quantitative measures of temporal lobe, hemispheric, and ventricular volumes in a group of patients with chronic schizophrenia and bipolar disorder and seeks to determine if the groups can be differentiated on the basis of measured brain abnormalities. METHODS: A series of coronal magnetic resonance imaging sections were acquired and analyzed for each of 22 patients with chronic schizophrenia, 14 patients with bipolar disorder, and 15 community volunteers. Eleven regions of interest for each brain were defined, which included temporal lobe, superior temporal gyrus, hemisphere, lateral ventricle, third ventricle, and temporal horn measures. Tissue measures were obtained by tracing, and cerebrospinal fluid measures were obtained by fluid-tissue thresholding using specialized computer software. RESULTS: Both patient groups had significantly larger temporal horn volumes in comparison with the control group both before and after correction for intracranial volume. The two patient groups did not differ from each other or controls on any other tissue or fluid measure. CONCLUSIONS: This study confirms the findings of increased temporal horn volume in patients with schizophrenia and suggests that this structural abnormality does not differentiate the structural neuropathology of schizophrenia from that of bipolar disorder.

Neuropsychological consequences of posteroventral pallidotomy for the treatment of Parkinson's disease.

OBJECTIVE: Neuropsychological changes were assessed in patients who had idiopathic PD after unilateral posteroventral pallidotomy. METHODS: Posteroventral stereotactic pallidotomies were performed on 42 PD patients (24 right and 18 left hemisphere). All patients were evaluated in the "on state" before the procedure (n = 42) and at intervals of 3 (n = 26), 6 (n = 27), and 12+ (n = 24) months after surgery. RESULTS: Modest improvement in sustained attention and decline in working memory was observed by 6 months after surgery. Left hemisphere lesions led to a loss of verbal learning (-2.2 SD) and verbal fluency (-1.6 SD) in 60% of patients at their first evaluation at 3 or 6 months. No patients returned to baseline on the verbal fluency task and most (71%) did not recover verbal-learning ability by 12 months after surgery. Right hemisphere lesions led to a loss of visuospatial constructional abilities (-3.5 SD), which fully resolved by 12 months for all but one patient. Evidence of further decline of frontal-executive functioning was noted within other tasks but not on a "direct" test (i.e., Conditional Associative Learning). Lastly, behavioral changes of a "frontal nature" were reported in 25% to 30% of patients. These cognitive and emotional costs increased dependence in these domains and negatively affected some patients' relations with caregivers and restricted their ability to function properly at work or in social settings. Caregivers, particularly, and patients who were aware of their resulting changes had difficulty adjusting after surgery. CONCLUSIONS: Although patients and caregivers were generally pleased with the clinical neurologic outcome of the procedure, the neurologic benefits of unilateral pallidotomy must be weighed against modest cognitive and behavioral risks.

The neuropsychology of Parkinson's disease.

This article discusses the neuropsychological profile of Parkinson's disease from the perspective of cognitive theory, anatomical organization, and unit recording data. Despite the point of origin, methodologically controlled studies are converging to support the position that patients with this disorder suffer selective impairment in the acquisition of novel tasks which rely on internal (subjective) processing for the efficient establishment of new cognitive "habits." The roles of attention and learning as well as of unit activity within the relevant networks are considered. Also included are recent but important concepts from personality theory which potentially enhance understanding of the neuropsychology of Parkinson's disease.

Behavior and the basal ganglia.

When viewed as a whole, these basal ganglia-thalamo-cortical circuits appear to play a modulating role in a wide range of behaviors. At the cortical level, given convergence upon specified regions within the frontal lobes, the behaviors in question would be those dependent upon SMA, premotor, frontal eye fields, dorsolateral, and orbitofrontal outflow targets. Broadly speaking, processes such as the generation, maintenance, switching, and blending of motor, mental, or emotional sets would be involved. Accordingly, in basal ganglia disease, the planning and the execution of the above behavioral domains can be affected. Given the diversity and complexity of activity within the basal ganglia, the consequences of disruption depend largely upon lesion site and the associated interplay of neurochemical factors. For example, in the motor domain, damage to various striatal circuitry levels can result in either hypo- or hyperkinetic disorders of movement. Following this analogy, it might also be said that diverse lesions, depending on site, can result in problems with the development and maintenance of behavioral sets ("hypophrenic") versus problems in relinquishing preferential sets ("hyperphrenic"). These contrasting patterns are best represented in PD and OCD, respectively. In the latter case, however, the "hyperphrenic" pattern would only apply to those behaviors which are part of the obsessional rituals. This suggests that procedural system "overdrive" remains domain-specific as is the case for most operations within the procedural system. To return to the broad principle of habituation, a process first described in the context of the visual system and its connections with the tail of the caudate nucleus, it would be tempting to view PD and OCD as disorders of "under" and "over" habituation to behavioral routines. Unfortunately, the situation has proven to be more complex in view of recent neuropsychological findings (Nicholson et al., in preparation). Using a variety of problem-solving and other cognitive tasks, both PD and OCD patients were found to require more practice and/or the provision of external guidelines to facilitate habit formation. Thus, in both cases, as in other disorders of the basal ganglia, the establishment of useful heuristics by which to direct adaptive behavior suffers. OCD patients therefore appear to have at least two compartmentalized types of basal ganglia dysfunction: the ritualistic compulsions and obsessions as well as the heuristic inefficiency (i.e., poor procedural mobilization). PD patients would also suffer a similar fate as it is known that the degrees of motor versus nonmotor (i.e., procedural) deficit are poorly correlated (42).(ABSTRACT TRUNCATED AT 400 WORDS)

Differential neuronal activity in segments of globus pallidus in Parkinson's disease patients.

Microelectrode trajectories through the globus pallidus of 6 Parkinson's disease (PD) patients yielded neurophysiological 'landmarks' which enabled the identification of neurones located in the external segment (GPe) and internal segments, exterior (GPi,e) and interior (GPi,i) of globus pallidus and the surrounding borders (Bor). Firing rate histograms and inter-spike interval time histograms were constructed for neurones in each region. The neuronal activity in GPi,i was higher than in the other segments, and a high degree of bursting was found in GPe and GPi neurones. This profile of neuronal activity is similar to that observed in monkeys treated with MPTP, suggesting that the observed level of activity of neurones in GPi,i is excessive, and contributes to the bradykinesia and rigidity of PD patients.

Neuropsychological and psychiatric side effects in the treatment of Parkinson's disease.

All medications currently used to treat Parkinson's disease carry some risk of causing confusion, hallucinations, or disruption of such higher-order mental operations as problem-solving and learning. Although the elderly demented patient is at greatest risk, such complications have also been noted during treatment of younger patients. Treatment with anticholinergics may lead to a confusional state and decreased memory function in some patients, especially the elderly and those with preexisting dementia. Monoamine oxidase inhibition is considered quite benign when used alone, but may potentiate certain side effects when used in combination with other compounds. Ergot alkaloid medication, which is usually combined with levodopa, often induces severe psychiatric complications. Typical findings with levodopa treatment indicate little or no positive impact on cognition, apart from nonspecific arousal and alleviation of concomitant depressive affect. Guidelines for the management of neuropsychological and psychiatric side effects are suggested.

Cognitive processes in idiopathic dystonia treated with high-dose anticholinergic therapy: implications for treatment strategies.

Studies utilizing single doses of scopolamine have suggested a role for the cholinergic system in memory. Results are consistent in identifying a selective effect on the early encoding stage of information processing. In terms of long-term administration of anticholinergics, patients with Parkinson's disease often display memory deficits. However, underlying pathology within the forebrain cholinergic system complicates the study of treatment effects in this disorder. We therefore assessed multiple memory routines in 20 cognitively intact patients with dystonia where no such pathology has been identified. Patients were tested before and after 2-4 months of 15-74 mg of trihexyphenidyl daily. Twelve tolerated this regime. Compared to control subjects, matched for age and I.Q., only tests with a single presentation of the material to be remembered were affected at follow-up. The speed of information processing was also significantly reduced. Age was strongly related to memory performance in the patient group alone and interacted with dose and duration of treatment. Results suggest that drug-induced slowing of mentation was responsible for impaired encoding, particularly in older patients. These findings affect treatment strategies, especially now that injections of botulinum toxin have proved to be highly effective for certain forms of focal dystonia.