Jean A. Saint-Cyr

A multicentre study on suicide outcomes following subthalamic stimulation for Parkinson's disease

Subthalamic nucleus deep brain stimulation improves motor symptoms and quality of life in advanced Parkinsons disease. As after other life-altering surgeries, suicides have been reported following deep brain stimulation for movement disorders. We sought to determine the suicide rate following subthalamic nucleus deep brain stimulation for Parkinsons disease by conducting an international multicentre retrospective survey of movement disorder and surgical centres. We further sought to determine factors associated with suicide attempts through a nested case-control study. In the survey of suicide rate, 55/75 centres participated. The completed suicide percentage was 0.45% (24/5311) and attempted suicide percentage was 0.90% (48/5311). Observed suicide rates in the first postoperative year (263/100,000/year) (0.26%) were higher than the lowest and the highest expected age-, gender- and country-adjusted World Health Organization suicide rates (Standardized Mortality Ratio for suicide: SMR 12.63-15.64; P < 0.001) and remained elevated at the fourth postoperative year (38/100,000/year) (0.04%) (SMR 1.81-2.31; P < 0.05). The excess number of deaths was 13 for the first postoperative year and one for the fourth postoperative year. In the case-control study of associated factors, 10 centres participated. Twenty-seven attempted suicides and nine completed suicides were compared with 70 controls. Postoperative depression (P < 0.001), being single (P = 0.007) and a previous history of impulse control disorders or compulsive medication use (P = 0.005) were independent associated factors accounting for 51% of the variance for attempted suicide risk. Attempted suicides were also associated (P < 0.05) with being younger, younger Parkinsons disease onset and a previous suicide attempt. Completed suicides were associated with postoperative depression (P < 0.001). Postoperative depression remained a significant factor associated with attempted and completed suicides after correction for multiple comparisons using the stringent Bonferroni correction. Mortality in the first year following subthalamic nucleus deep brain stimulation has been reported at 0.4%. Suicide is thus one of the most important potentially preventable risks for mortality following subthalamic nucleus deep brain stimulation for Parkinsons disease. Postoperative depression should be carefully assessed and treated. A multidisciplinary assessment and follow-up is recommended.

Memory and learning in early Parkinson's disease: evidence for a "frontal lobe syndrome".

Fifteen untreated patients in the earliest stages of Parkinsons disease were compared to fifteen age- and intellectually matched control subjects on a number of memory tasks assessing short- and long-term recall of both meaningful and unrelated material, semantic relations in the organization of memory, priming, and source forgetting, and the ability to form new stimulus-response associations under conditions of maximal task interference. While patients demonstrated considerable evidence of preserved function, impaired performance on a subgroup of tasks was consistent with selective frontostriatal system involvement. These findings are discussed with reference to the underlying pathological processes in Parkinsons disease.

Primary Dystonia Is More Responsive than Secondary Dystonia to Pallidal Interventions: Outcome after Pallidotomy or Pallidal Deep Brain Stimulation

OBJECTIVEThe response of patients with dystonia to pallidal procedures is not well understood. In this study, we assessed the postoperative outcome of patients with primary and secondary dystonia undergoing pallidotomy or pallidal deep brain stimulation. METHODSFifteen patients with dystonia had pallidal surgery (lesions or deep brain stimulation). These included nine patients with primary dystonia (generalized and cervical dystonias) and six with secondary dystonia (generalized, segmental, and hemidystonias). There were nine male patients and six female patients. The mean age at onset was 21 years for primary dystonia and 18 years for secondary dystonia. The primary outcome measure was a Global Outcome Scale score for dystonia at 6 months after surgery. Other outcome measures were the Burke-Fahn-Marsden Dystonia Rating Scale and Toronto Western Spasmodic Torticollis Rating Scale scores. RESULTSThe mean Global Outcome Scale score at 6 months for patients with primary dystonia was 3 (improvement in both movement disorder and function). In contrast, patients with secondary dystonia had a mean score of 0.83 (mild or no improvement in movement disorder with no functional improvement). All patients with primary dystonia had normal brains by magnetic resonance imaging, whereas five of six patients with secondary dystonia had basal ganglia abnormalities on their magnetic resonance imaging scans. CONCLUSIONThis study indicates that primary dystonia responds much better than secondary dystonia to pallidal procedures. We could not distinguish a difference in efficacy between pallidotomy and pallidal deep brain stimulation. The presence of basal ganglia abnormalities on the preoperative magnetic resonance imaging scan is an indicator of a lesser response to pallidal interventions for dystonia.

Deep brain stimulation for Parkinson's disease dissociates mood and motor circuits: A functional MRI case study

Behavioral disturbances have been reported with subthalamic (STN) deep brain stimulation (DBS) treatment in Parkinsons disease (PD). We report correlative functional imaging (fMRI) of mood and motor responses induced by successive right and left DBS. A 36‐year‐old woman with medically refractory PD and a history of clinically remitted depression underwent uncomplicated implantation of bilateral STN DBS. High‐frequency stimulation of the left electrode improved motor symptoms. Unexpectedly, right DBS alone elicited several reproducible episodes of acute depressive dysphoria. Structural and functional magnetic resonance imaging (fMRI) imaging was carried out with sequential individual electrode stimulation. The electrode on the left was within the inferior STN, whereas the right electrode was marginally superior and lateral to the intended STN target within the Fields of Forel/zona incerta. fMRI image analysis (Analysis of Functional NeuroImages, AFNI) contrasting OFF versus ON stimulation identified significant lateralized blood oxygen level‐dependent (BOLD) signal changes with DBS (P < 0.001). Left DBS primarily showed changes in motor regions: increases in premotor and motor cortex, ventrolateral thalamus, putamen, and cerebellum as well as decreases in sensorimotor/supplementary motor cortex. Right DBS showed similar but less extensive change in motor regions. More prominent were the unique increases in superior prefrontal cortex, anterior cingulate (Brodmanns area [BA] 24), anterior thalamus, caudate, and brainstem, and marked widespread decreases in medial prefrontal cortex (BA 9/10). The mood disturbance resolved spontaneously in 4 weeks despite identical stimulation parameters. Transient depressive mood induced by subcortical DBS stimulation was correlated with changes in mesolimbic cortical structures. This case provides new evidence supporting cortical segregation of motor and nonmotor cortico‐basal ganglionic systems that may converge in close proximity at the level of the STN and the adjacent white matter tracts (Fields of Forel/zona incerta).

Frontal-striatal circuit functions: Context, sequence, and consequence

The exact role of the basal ganglia in both the motor and non-motor domains has proven elusive since it is virtually impossible to refer to its function in isolation of cortical, and especially frontal cortical circuits. The result is that we often speak of frontal-striatal circuits and functions but this still leaves us in the dark when trying to specify basal ganglia information processing. A critical review of the data from both basic science and clinical studies suggests that we should break down processing along a temporal continuum, including the domains of context, sequential information processing, and feedback or reinforcement (i.e., the consequences of action). This analysis would cut across other theoretical constructs, such as attention, central executive, memory, and learning functions, traditionally employed in the neuropsychological literature. Under specified behavioral constraint, the basal ganglia can then be seen to be involved in fundamental aspects of attentional control (often covert), in the guidance of the early stages of learning (especially reinforcement-based, but also encoding strategies in explicit paradigms), and in the associative binding of reward to cue salience and response sequences via dopaminergic mechanisms. Parkinsons disease is considered to offer only a limited view of basal ganglia function due to partial striatal depletion of dopamine and the potential involvement of other structures and transmitters in its pathology. It is hoped that the present formulation will suggest new heuristic research strategies for basal ganglia research, permitting a closer link to be established between neurophysiological, functional imaging and neuropsychological paradigms.

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 Parkinsons 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.

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 Parkinsons 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 Parkinsons 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 Tamhanes 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.

Elevated Serotonin Transporter Binding in Depressed Patients with Parkinson's Disease : A Preliminary PET Study with [11C]DASB

This study investigated whether abnormalities in serotonin transporter binding occur in Parkinsons disease (PD) patients with concurrent depression. We estimated serotonin transporter levels in seven clinically depressed early‐stage PD patients and in seven healthy matched‐control subjects during a single positron emission tomography (PET) scan with the serotonin transporter radioligand, [11C]DASB. Depressed PD patients displayed a wide‐spread increase (8–68%) in [11C]DASB specific binding outside of the striatum, which was significant in dorsolateral (37%) and prefrontal (68%) cortices. Elevated [11C]DASB binding was positively correlated with depressive symptoms but not with disease severity or duration. Compatible with recent PET/[11C]DASB findings in major depression, the present preliminary data suggest that increased [11C]DASB binding, possibly reflecting greater serotonin transporter density (up‐regulation), might be a pathological feature of depression in Parkinsons disease—and possibly a characteristic of depressive illness in general.

Sources of descending afferents to the inferior olive from the upper brain stem in the cat as revealed by the retrograde transport of horseradish peroxidase

The retrograde transport of horseradish peroxidase (HRP) was employed in 35 cats to trace the sources of descending afferents to the inferior olivary nucleus. The majority of HRP‐labeled cells were located in the ipsilateral mesencephalon, from the rostral pole of the red nucleus to the caudomedial border of the thalamus. Among the heavily labeled nuclear groups were the parvocellular red nucleus, the interstitial nucleus of Cajal, the nucleus of Darkschewitsch, and the caudomedial extremity of the subparafascicular nucleus. Occasional cells were also labeled in the reticular formation lateral to the interstitial nucleus of Cajal, in the caudomedial parafascicular nucleus, in the nucleus of the fields of Forel, and in the centray gray. It was not possible to recognize a topographic distribution of the labeled cells corresponding to the loclization of the HRP deposits. Elsewhere in the midbrain, there were HRP‐labeled cells in the deep layers of the superior colliculus (IV and VI), predominantly on the side contralateral to the injection and in the nucleus of the optic tract, and in the anterior and posterior pretectal nuclei, ipsilaterally. These groups were best labeled after caudally located injections in the olive. Certain areas previously reported to project to the inferior olive were devoid of labeled cells; these included the basal ganglia, the rostral raphe nuclei, and the nucleus of Edinger‐Westphal. It appears that the mesecephalic nuclei bordering the central gray represent the major source of descending afferents to the olive.

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 Parkinsons 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.