Cortical hemodynamic mapping of subthalamic nucleus deep brain stimulation in Parkinsonian patients, using high-density functional near-infrared spectroscopy.

Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment for idiopathic Parkinson's disease. Despite recent progress, the mechanisms responsible for the technique's effectiveness have yet to be fully elucidated. The purpose of the present study was to gain new insights into the interactions between STN-DBS and cortical network activity. We therefore combined high-resolution functional near-infrared spectroscopy with low-resolution electroencephalography in seven Parkinsonian patients on STN-DBS, and measured cortical haemodynamic changes at rest and during hand movement in the presence and absence of stimulation (the ON-stim and OFF-stim conditions, respectively) in the off-drug condition. The relative changes in oxyhaemoglobin [HbO], deoxyhaemoglobin [HbR], and total haemoglobin [HbT] levels were analyzed continuously. At rest, the [HbO], [HbR], and [HbT] over the bilateral sensorimotor (SM), premotor (PM) and dorsolateral prefrontal (DLPF) cortices decreased steadily throughout the duration of stimulation, relative to the OFF-stim condition. During hand movement in the OFF-stim condition, [HbO] increased and [HbR] decreased concomitantly over the contralateral SM cortex (as a result of neurovascular coupling), and [HbO], [HbR], and [HbT] increased concomitantly in the dorsolateral prefrontal cortex (DLPFC)-suggesting an increase in blood volume in this brain area. During hand movement with STN-DBS, the increase in [HbO] was over the contralateral SM and PM cortices was significantly lower than in the OFF-stim condition, as was the decrease in [HbO] and [HbT] in the DLPFC. Our results indicate that STN-DBS is associated with a reduction in blood volume over the SM, PM and DLPF cortices, regardless of whether or not the patient is performing a task. This particular effect on cortical networks might explain not only STN-DBS's clinical effectiveness but also some of the associated adverse effects.

Vascularization of the Subthalamic Nucleus: Highlighting the Significance of the Premamillary Artery.

BACKGROUND: The need for a better understanding of the subthalamic nucleus (STN)'s vascular anatomy is still evident because revealing its vascular supply may increase insight in the pathogenesis of related disorders, such as STN ischemia. The mechanisms under motor, behavioral, and cognitive changes following deep brain stimulation treatment may also be explained by its pattern of vascularization. The primary goal of this study was to delineate the vascularization of the STN and highlight the predominant perforating arteries supplying its territory. METHODS: Fiber dissections were performed with the modified Klingler technique under 6-40× magnification by preserving all vascular structures. RESULTS: The thalamic and subthalamic regions were dissected from medial to lateral in silicone-injected cadavers. The STN was revealed as a biconvex-shaped structure surrounded by dense inferolateral bundles of myelinated fibers, the zona incerta, bordering the superolateral portion of the red nucleus. The ventral limit of the STN was the substantia nigra, and the internal capsule traversed from its inferior to anterolateral side. The premamillary artery, a large perforator arising from the posterior communicating artery, constantly supplied the STN and was followed proximally along the anterior third ventricular floor toward its origin. The premamillary artery was found to be one of the posterior perforators of the posterior communicating artery in all hemispheres. CONCLUSIONS: The 3-dimensional microsurgical anatomy of the deep-seated STN region is complex, and the additional knowledge on its vascularization should improve our understanding of its surgical anatomy.

Significance of N-isopropyl-[123I] p-iodoamphetamine single-photon emission computed tomography in detection of responsible hypoperfusion in hemichorea.

Hemichorea is relatively an uncommon clinical presentation while its known etiology are vascular, metabolic, neoplastic, infectious, autoimmune, and inherited disorders. In the acquired case of hemichorea, the most common cause is the cerebrovascular insult, which is often diagnosed by the magnetic resonance (MR) imaging. An 84-year-old woman reported a one-week history of involuntary movements in the left side of her face and left limbs. Blood tests were normal and brain MR imaging showed no responsible hyperintense lesion on T1-, FLAIR, and diffusion-weighted imaging. N-isopropyl-[123I] p-iodoamphetamine single-photon emission computed tomography (SPECT) detected hypoperfusion in the right thalamus. Further three-dimensional tomography clearly detected the hypoperfusion in the right subthalamic nucleus. The hypoperfused lesion was MR-negative and remained unchanged in SPECT one year after the onset. After the treatment with 0.35 mg of oral haloperidol was initiated, the hemichorea was gradually decreased and completely disappeared in 9 months. Because the three-dimensional analysis performs voxel-by-voxel analysis, it possibly detects the precise hypoperfusion in a specific region. In conclusion, evaluation of cerebral blood flow using SPECT on patients presenting with acute hemichorea can lead to the detection of responsible lesion when the routine examinations are negative.

Resting-state functional magnetic resonance imaging of the subthalamic microlesion and stimulation effects in Parkinson's disease: Indications of a principal role of the brainstem.

During implantation of deep-brain stimulation (DBS) electrodes in the target structure, neurosurgeons and neurologists commonly observe a "microlesion effect" (MLE), which occurs well before initiating subthalamic DBS. This phenomenon typically leads to a transitory improvement of motor symptoms of patients suffering from Parkinson's disease (PD). Mechanisms behind MLE remain poorly understood. In this work, we exploited the notion of ranking to assess spontaneous brain activity in PD patients examined by resting-state functional magnetic resonance imaging in response to penetration of DBS electrodes in the subthalamic nucleus. In particular, we employed a hypothesis-free method, eigenvector centrality (EC), to reveal motor-communication-hubs of the highest rank and their reorganization following the surgery; providing a unique opportunity to evaluate the direct impact of disrupting the PD motor circuitry in vivo without prior assumptions. Penetration of electrodes was associated with increased EC of functional connectivity in the brainstem. Changes in connectivity were quantitatively related to motor improvement, which further emphasizes the clinical importance of the functional integrity of the brainstem. Surprisingly, MLE and DBS were associated with anatomically different EC maps despite their similar clinical benefit on motor functions. The DBS solely caused an increase in connectivity of the left premotor region suggesting separate pathophysiological mechanisms of both interventions. While the DBS acts at the cortical level suggesting compensatory activation of less affected motor regions, the MLE affects more fundamental circuitry as the dysfunctional brainstem predominates in the beginning of PD. These findings invigorate the overlooked brainstem perspective in the understanding of PD and support the current trend towards its early diagnosis.

Deep-brain stimulation associates with improved microvascular integrity in the subthalamic nucleus in Parkinson's disease.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become an accepted treatment for motor symptoms in a subset of Parkinson's disease (PD) patients. The mechanisms why DBS is effective are incompletely understood, but previous studies show that DBS targeted in brain structures other than the STN may modify the microvasculature. However, this has not been studied in PD subjects who have received STN-DBS. Here we investigated the extent and nature of microvascular changes in post-mortem STN samples from STN-DBS PD patients, compared to aged controls and PD patients who had not been treated with STN-DBS. We used immunohistochemical and immunofluorescent methods to assess serial STN-containing brain sections from PD and STN-DBS PD cases, compared to similar age controls using specific antibodies to detect capillaries, an adherens junction and tight junction-associated proteins as well as activated microglia. Cellular features in stained sections were quantified by confocal fluorescence microscopy and stereological methods in conjunction with in vitro imaging tools. We found significant upregulation of microvessel endothelial cell thickness, length and density but lowered activated microglia density and striking upregulation of all analysed adherens junction and tight junction-associated proteins in STN-DBS PD patients compared to non-DBS PD patients and controls. Moreover, in STN-DBS PD samples, expression of an angiogenic factor, vascular endothelial growth factor (VEGF), was significantly upregulated compared to the other groups. Our findings suggest that overexpressed VEGF and downregulation of inflammatory processes may be critical mechanisms underlying the DBS-induced microvascular changes.

Differences in regional cerebral blood flow response to a 5HT3 antagonist in early- and late-onset cocaine-dependent subjects.

5-hydroxytryptamine 3 (5HT3) receptors are important modulators of mesostriatal dopaminergic transmission and have been implicated in the pathophysiology of cocaine reward, withdrawal and self-administration. In addition, the 5HT3 antagonist ondansetron is effective in treating early-onset, but not late-onset, alcohol-dependent subjects. To explore the role of 5HT3 receptor systems in cocaine addiction using functioning imaging, we administered ondansetron to 23 abstinent, treatment-seeking cocaine-addicted and 22 sex-, age- and race-matched healthy control participants. Differences between early- (first use before 20 years, n = 10) and late-onset (first use after 20 years, n = 10) cocaine-addicted subjects were also assessed. On two separate days, subjects were administered ondansetron (0.15 mg/kg intravenously over 15 minutes) or saline. Regional cerebral blood flow (rCBF) was measured following each infusion with single photon emission computed tomography. No significant rCBF differences between the cocaine-addicted and control participants were observed following ondansetron relative to saline. Early-onset subjects, however, showed increased (P < 0.001) right posterior parahippocampal rCBF following ondansetron. In contrast, late-onset subjects showed decreased rCBF following ondansetron in an overlapping region of the right parahippocampal/hippocampal gyrus. Early-onset subjects also displayed increased rCBF in the left anterior insula and subthalamic nucleus following ondansetron; late-onset subjects showed decreased rCBF in the right anterior insula. These findings suggest that the age of drug use onset is associated with serotonergic biosignatures in cocaine-addicted subjects. Further clarification of these alterations may guide targeted treatment with serotonergic medications similar to those successfully used in alcohol-dependent patients.

Modulation of local field potential power of the subthalamic nucleus during isometric force generation in patients with Parkinson's disease.

Investigations of local field potentials of the subthalamic nucleus of patients with Parkinson's disease have provided evidence for pathologically exaggerated oscillatory beta-band activity (13-30 Hz) which is amenable to physiological modulation by, e.g., voluntary movement. Previous functional magnetic resonance imaging studies in healthy controls have provided evidence for an increase of subthalamic nucleus blood-oxygenation-level-dependant signal in incremental force generation tasks. However, the modulation of neuronal activity by force generation and its relationship to peripheral feedback remain to be elucidated. We hypothesised that beta-band activity in the subthalamic nucleus is modulated by incremental force generation. Subthalamic nucleus local field potentials were recorded intraoperatively in 13 patients with Parkinson's disease (37 recording sites) during rest and five incremental isometric force generation conditions of the arm with applied loads of 0-400 g (in 100-g increments). Repeated measures analysis of variance (ANOVA) revealed a modulation of local field potential (LFP) power in the upper beta-band (in 24-30 Hz; F(3.042)=4.693, p=0.036) and the gamma-band (in 70-76 Hz; F(4)=4.116, p=0.036). Granger-causality was computed with the squared partial directed coherence and showed no significant modulation during incremental isometric force generation. Our findings indicate that the upper beta- and gamma-band power of subthalamic nucleus local field potentials are modulated by the physiological task of force generation in patients with Parkinson's disease. This modulation seems to be not an effect of a modulation of peripheral feedback.

Preoperative regional cerebral blood flow and postoperative clinical improvement in patients with Parkinson's disease undergoing subthalamic nucleus deep brain stimulation.

Preoperative regional cerebral blood flow (rCBF) was measured in 92 patients with Parkinson's disease (PD) by iodine-123 N-isopropyl-p-iodoamphetamine single-photon emission computed tomography. Quantitative mapping of rCBF was performed using the stereotactic extraction estimation method. The clinical features of the patients were assessed according to the Unified Parkinson Disease Rating Scale (UPDRS). The correlation between rCBF and improvement in the UPDRS score following surgery was examined. rCBF in the fusiform gyrus, superior and inferior parietal gyri, middle occipital gyrus, superior frontal gyrus, and middle temporal gyrus of the Talairach Daemon Level 3 was significantly correlated with UPDRS part II (off stage) and III (on stage) scores (p < 0.05). rCBF in the middle temporal gyrus (p = 0.00147), medial frontal gyrus (p = 0.00713), and cerebellum (p = 0.048) of the Talairach Daemon Level 3 was significantly greater in 47 patients with >60% improvement of UPDRS part III (off stage) score than in 37 patients with 40-60% improvement. The cutoff value of rCBF, which indicated that >40% improvement in the surgical outcome could be expected, was 38.8 ± 6.2 ml/100 g/min in the frontal lobe. This study indicated that rCBF in patients with PD might be related to their clinical features, suggesting that quantitative mapping of rCBF may be useful for predicting surgical outcome.

High frequency deep brain stimulation: what are the therapeutic mechanisms?

High frequency deep brain stimulation (HFS) used to treat the symptoms of Parkinson's disease (PD) was first assumed to act by reducing an excessive tonic GABAergic inhibitory output from the internal globus pallidus (GPi). Stimulation in GPi might produce this directly by mechanisms such as depolarization block or activation of presynaptic inhibitory fibers, and the same mechanisms evoked by HFS in the subthalamic nucleus (STN) could reduce the excitatory action of STN on GPi neurons. Although somatic recordings from neurons near the stimulation site may appear to support this potential mechanism, the action downstream from the site of stimulation often is not consistent with this interpretation. A more parsimonious explanation for the similar effects of HFS in STN or GPi and a lesion of either of these structures is that both HFS and pallidotomy interrupt an abnormal pattern of firing in cortico-basal ganglia-thalamocortical loops that is responsible for the symptoms of PD.

Role of individual basal ganglia nuclei in force amplitude generation.

The basal ganglia-thalamo-cortical loop is an important neural circuit that regulates motor control. A key parameter that the nervous system regulates is the level of force to exert against an object during tasks such as grasping. Previous studies indicate that the basal ganglia do not exhibit increased activity with increasing amplitude of force, although these conclusions are based mainly on the putamen. The present study used functional magnetic resonance imaging to investigate which regions in the basal ganglia, thalamus, and motor cortex display increased activity when producing pinch-grip contractions of increasing force amplitude. We found that the internal portion of the globus pallidus (GPi) and subthalamic nucleus (STN) had a positive increase in percent signal change with increasing force, whereas the external portion of the globus pallidus, anterior putamen, posterior putamen, and caudate did not. In the thalamus we found that the ventral thalamic regions increase in percent signal change and activation volume with increasing force amplitude. The contralateral and ipsilateral primary motor/somatosensory (M1/S1) cortices had a positive increase in percent signal change and activation volume with increasing force amplitude, and the contralateral M1/S1 had a greater increase in percent signal change and activation volume than the ipsilateral side. We also found that deactivation did not change across force in the motor cortex and basal ganglia, but that the ipsilateral M1/S1 had greater deactivation than the contralateral M1/S1. Our findings provide direct evidence that GPi and STN regulate the amplitude of force output. These findings emphasize the heterogeneous role of individual nuclei of the basal ganglia in regulating specific parameters of motor output.

Are there adaptive changes in the human brain of patients with Parkinson's disease treated with long-term deep brain stimulation of the subthalamic nucleus? A 4-year follow-up study with regional cerebral blood flow SPECT.

PURPOSE: The aim of this follow-up study was to assess persistent motor and regional cerebral blood flow (rCBF) changes in patients with Parkinson's disease (PD) treated with high-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN). METHODS: Ten PD patients with STN-DBS underwent three rCBF SPECT studies at rest, once preoperatively in the off-drug condition (T(0)), and twice postoperatively in the off-drug/off-stimulation conditions at 5 +/- 2 (T(1)) and 42 +/- 7 months (T(2)). Patients were assessed using the UPDRS, H&Y and S&E scales. SPM was used to investigate baseline rCBF changes from the preoperative condition to the postoperative conditions and the relationship between rCBF and UPDRS scores used as covariate of interest. RESULTS: Parkinsonian patients showed a clinical improvement which was significant only on follow-up at 42 months. The main effect of treatment from T(0) to T(1) was to produce baseline rCBF increases in the pre-supplementary motor area (pre-SMA), premotor cortex and somatosensory association cortex. From T(1) to T(2) a further baseline rCBF increase was detected in the pre-SMA (p < 0.0001). A correlation was detected between the slight improvement in motor scores and the rCBF increase in the pre-SMA (p < 0.0001), which is known to play a crucial role in clinical progression. CONCLUSION: Our study suggests the presence of adaptive functional changes in the human brain of PD patients treated with long-term STN-DBS. Such adaptive processes seem to occur in the pre-SMA and to play only a slightly beneficial role in terms of functional compensation of motor impairment.

Normalizing motor-related brain activity: subthalamic nucleus stimulation in Parkinson disease.

OBJECTIVE: To test whether therapeutic unilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) in patients with Parkinson disease (PD) leads to normalization in the pattern of brain activation during movement execution and control of movement extent. METHODS: Six patients with PD were imaged off medication by PET during performance of a visually guided tracking task with the DBS voltage programmed for therapeutic (effective) or subtherapeutic (ineffective) stimulation. Data from patients with PD during ineffective stimulation were compared with a group of 13 age-matched control subjects to identify sites with abnormal patterns of activation. Conjunction analysis was used to identify those areas in patients with PD where activity normalized when they were treated with effective stimulation. RESULTS: For movement execution, effective DBS caused an increase of activation in the supplementary motor area (SMA), superior parietal cortex, and cerebellum toward a more normal pattern. At rest, effective stimulation reduced overactivity of SMA. Therapeutic stimulation also induced reductions of movement related "overactivity" compared with healthy subjects in prefrontal, temporal lobe, and basal ganglia circuits, consistent with the notion that many areas are recruited to compensate for ineffective motor initiation. Normalization of activity related to the control of movement extent was associated with reductions of activity in primary motor cortex, SMA, and basal ganglia. CONCLUSIONS: Effective subthalamic nucleus stimulation leads to task-specific modifications with appropriate recruitment of motor areas as well as widespread, nonspecific reductions of compensatory or competing cortical activity.

Cortical and subcortical contributions to Stop signal response inhibition: role of the subthalamic nucleus.

Suppressing an already initiated manual response depends critically on the right inferior frontal cortex (IFC), yet it is unclear how this inhibitory function is implemented in the motor system. It has been suggested that the subthalamic nucleus (STN), which is a part of the basal ganglia, may play a role because it is well placed to suppress the "direct" fronto-striatal pathway that is activated by response initiation. In two experiments, we investigated this hypothesis with functional magnetic resonance imaging and a Stop-signal task. Subjects responded to Go signals and attempted to inhibit the initiated response to occasional Stop signals. In experiment 1, Going significantly activated frontal, striatal, pallidal, and motor cortical regions, consistent with the direct pathway, whereas Stopping significantly activated right IFC and STN. In addition, Stopping-related activation was significantly greater for fast inhibitors than slow ones in both IFC and STN, and activity in these regions was correlated across subjects. In experiment 2, high-resolution functional and structural imaging confirmed the location of Stopping activation within the vicinity of the STN. We propose that the role of the STN is to suppress thalamocortical output, thereby blocking Go response execution. These results provide convergent data for a role for the STN in Stop-signal response inhibition. They also suggest that the speed of Go and Stop processes could relate to the relative activation of different neural pathways. Future research is required to establish whether Stop-signal inhibition could be implemented via a direct functional neuroanatomic projection between IFC and STN (a "hyperdirect" pathway).

Focal changes of oxygen consumption in cerebral cortex of patients with Parkinson's disease during subthalamic stimulation.

Motor symptoms of Parkinson's disease (PD) are substantially improved by bilateral high-frequency electrical stimulation of the subthalamic nucleus (STN). Altered cerebral blood flow (CBF) in a network of frontal cortical and subcortical structures has been reported in numerous studies of patients undergoing subthalamic stimulation. However, CBF is a controversial indicator of brain activation because measures of blood flow bear a variable relation to measures of brain work and energy metabolism. We hypothesized that STN stimulation would alter the rate of oxygen consumption (CMRO(2)) in cerebral cortical areas in proportion to previously reported changes in CBF in patients undergoing stimulation at rest. We used quantitative PET to map CMRO(2) in brain of seven patients with Parkinson's disease, first in a baseline condition with pause of stimulation and medication for a period of 12 h, and again after 4 h of stimulation. Comparison of these two conditions revealed activation of CMRO(2) in the cerebellum, and in specific posterior neocortical regions, most notably in the left lingual gyrus and in the right lateral occipitotemporal gyrus, both of which latter regions are linked to higher-order visual processing. CMRO(2) was unaffected in the frontal cortex. Thus, the present findings do not support the original hypothesis, but suggest that STN stimulation increases energy metabolism in the posterior cerebral cortex, especially in regions involved in perception of movement and the direction of movement to visual cues.

Arm chorea secondary to an unruptured giant aneurysm.

We describe the case of a 20-year-old male who developed right-arm choreic movements secondary to a giant unruptured aneurysm impinging upon the left thalamus, putamen, globus pallidus, cerebral peduncle, midbrain, and subthalamic nucleus. The aneurysm was treated successfully with coils and a supraclinoid balloon. Abnormal movements initially failed to ameliorate, but within a few months, it was possible to discontinue symptomatic haloperidol therapy, with only mild residual abnormal movements.

Effects of subthalamic nucleus stimulation on actual and imagined movement in Parkinson's disease : a PET study.

BACKGROUND: PET studies in moderately affected Parkinson's disease (PD) patients reveal abnormal cerebral activation during motor execution and imagery, but the effects of subthalamic nucleus (STN) stimulation are not well established. OBJECTIVES: to assess the effect of STN stimulation on cerebral activation during actual and imagined movement in patients with advanced PD. METHODS: seven severely affected PD patients treated with bilateral STN stimulation were studied with PET and H(2)(15)O. The following conditions were investigated: (1). rest; (2). motor execution of a sequential predefined joystick movement with the right hand and (3). motor imagery of the same task. Patients were studied with and without left STN stimulation while right stimulator remained off. RESULTS: Without STN stimulation, the primary motor cortex was activated only during motor execution whereas the dorsolateral prefrontal cortex (DLPFC) was activated only during motor imagery. An activation of the supplementary motor area (SMA) was seen during both motor execution and motor imagery. Left STN stimulation during motor execution increased the regional cerebral blood flow (rCBF) bilaterally in the prefrontal cortex including DLPFC, in the left thalamus and putamen. In addition, a reduction of rCBF was noted in the right primary motor cortex, inferior parietal lobe and SMA. Under left STN stimulation, during motor imagery, rCBF increased bilaterally in the DLPFC and in the left thalamus and putamen and decreased in the left SMA and primary motor cortex. CONCLUSION: STN stimulation during both motor execution and imagery tends to improve the functioning of the frontal-striatal-thalamic pathway and to reduce the recruitment of compensatory motor circuits notably in motor, premotor and parietal cortical areas.

Relationship between nicotinamide adenine dinucleotide phosphate-diaphorase-reactive neurons and blood vessels in basal ganglia.

The relationship between nicotinamide adenine dinucleotide phosphate-diaphorase-positive neurons and blood vessels was investigated within the rat basal ganglia. Nicotinamide adenine dinucleotide phosphate-diaphorase-positive cell bodies, dendrites or axon-like processes surrounding many but not all blood vessels were observed in the caudate-putamen, ventral pallidum, medial part of the globus pallidus, substantia nigra and subthalamic nucleus. It is concluded that this close relationship contributes to the local vasodilator effect of nitric oxide in the regulation of blood flow in cerebral blood vessels.