Simon Baudrexel

Resting state fMRI reveals increased subthalamic nucleus–motor cortex connectivity in Parkinson's disease

Parkinsons disease (PD) is associated with abnormal hypersynchronicity in basal ganglia-thalamo-cortical loops. The clinical effectiveness of subthalamic nucleus (STN) high frequency stimulation indicates a crucial role of this nucleus within the affected motor networks in PD. Here we investigate alterations in the functional connectivity (FC) profile of the STN using resting state BOLD correlations on a voxel-by-voxel basis in functional magnetic resonance imaging (fMRI). We compared early stage PD patients (n=31) during the medication-off state with healthy controls (n=44). The analysis revealed increased FC between the STN and cortical motor areas (BA 4 and 6) in PD patients in accordance with electrophysiological studies. Moreover, FC analysis of the primary motor cortex (M1) hand area revealed that the FC increase was primarily found in the STN area within the basal ganglia. These findings are in good agreement with recent experimental data, suggesting that an increased STN-motor cortex synchronicity mediated via the so called hyperdirect motor cortex-subthalamic pathway might play a fundamental role in the pathophysiology of PD. An additional subgroup analysis was performed according to the presence (n=16) or absence (n=15) of tremor in patients. Compared to healthy controls tremor patients showed increased STN FC specifically in the hand area of M1 and the primary sensory cortex. In non-tremor patients, increased FC values were also found between the STN and midline cortical motor areas including the SMA. Taken together our results underline the importance of the STN as a key node for the modulation of BG-cortical motor network activity in PD patients.

Quantitative mapping of T1 and T2* discloses nigral and brainstem pathology in early Parkinson's disease

Quantitative magnetic resonance imaging is a promising in vivo imaging technique revealing insights into different aspects of brain morphology in neurodegenerative diseases based on the determination of physical tissue parameters. Using combined T1- and T2*-mapping, we investigated changes of local relaxation times in the midbrain and lower brainstem of 20 patients with early Parkinsons disease (PD) compared to 20 healthy controls. Voxelwise statistical parametric mapping disclosed a widespread reduction of midbrain T1 values contralateral to the clinically more severely affected limbs. Within the SN, the T1 decrease matched the known pattern of selective neuronal loss as examined in various post-mortem studies, suggesting that T1 is a marker for PD related tissue pathology. However, the spatial extent of T1 reductions exceeded the SN and reached non-dopaminergic areas in the pontomesencephalic junction potentially involved in early non-motor symptoms of PD. In contrast, T2*-mapping revealed a bilateral decrease of T2* values restricted to the SN, indicating a local increase in total iron content. We conclude that, particularly in longitudinal studies, quantitative T1 may be a valuable marker for the monitoring of progressive neuronal loss in PD, whereas nigral T2* reductions might be more closely associated with an increased general vulnerability for the development of the disorder.

Diffusion tensor imaging of white matter involvement in essential tremor.

This study set out to determine whether there is white matter involvement in essential tremor (ET), the most common movement disorder. We collected diffusion MRI and analysed differences in fractional anisotropy (FA) and mean diffusivity (MD) between ET patients and control subjects as markers of white matter integrity. We used both classical ROI‐based statistics and whole‐brain analysis techniques, including voxel‐wise analysis with SPM5 and tract‐based spatial statistics (TBSS). Using region of interest (ROI) analysis, we found increased MD bilaterally in the inferior cerebellar peduncles (ICP) and reduced FA in the right‐sided ICP of ET patients. Whole‐brain analyses with TBSS detected increased MD distributed in both motor and nonmotor white matter fibers of ET patients predominantly in the left parietal white matter, while there were no significant FA differences in these areas between ET patients and controls. Voxel‐wise analysis with SPM detected significant increase of MD congruent with the highest probability of difference as detected by TBSS. VBM analysis of T1 images did not detect significant differences in either gray or white matter density between our study groups. In summary, we found evidence for changes in white matter MRI properties in ET. The circumscript pathology of the ICP corroborates the pathogenetic concept of the cerebellum and its projections as key structures for tremor generation in ET. Moreover, increased diffusivity in white matter structures of both hemispheres suggests widespread alterations of fiber integrity in motor and nonmotor networks in ET patients. The underlying cause of the DTI changes observed remains to be elucidated. Hum Brain Mapp, 2011.

Frontal FDG-PET activity correlates with cognitive outcome after STN-DBS in Parkinson disease

Background: Inconsistent changes of cognitive functioning have been reported in patients with Parkinson disease (PD) with deep brain stimulation (DBS) of the subthalamic nucleus (STN). To investigate the underlying pathomechanisms, we correlated alterations of cognitive test performance and changes of neuronal energy metabolism in frontal basal ganglia projection areas under bilateral STN stimulation. Methods: We conducted verbal fluency, learning, and memory tests and 18-fluorodeoxyglucose (FDG) PET in nine patients with PD with STN-DBS before and 6 months after surgery. Using coregistered MRI, postoperative changes of the normalized cerebral metabolic rates of glucose (nCMRGlc) in the dorsolateral prefrontal cortex (DLPFC), lateral orbitofrontal cortex (LOFC), ventral and dorsal cingulum (v/dACC), and in Broca area were determined and correlated with alterations of neuropsychological test results. Results: After surgery, highly variable changes of both cognitive test performance and frontal nCMRGlc values were found with significant correlations between verbal fluency and FDG uptake in the left DLPFC (Brodmann area [BA] 9, 46), left Broca area (BA 44/45), and the right dACC (BA 32). A decrease of nCMRGlc in the left OFC (BA 11/47) and dACC (BA 32) correlated with a decline of verbal learning. All patients showed reduced metabolic activity in the right anterior cingulate cortex after DBS. Baseline cognitive abilities did not predict verbal learning or fluency changes after surgery. Conclusions: These data show a significant linear relationship between changes in frontal 18-fluorodeoxyglucose PET activity and changes in cognitive outcome after deep brain stimulation of the subthalamic nucleus (STN) in advanced Parkinson disease. The best correlations were found in the left frontal lobe (dorsolateral prefrontal cortex and Broca area). Baseline performance on cognitive tests did not predict cognitive or metabolic changes after STN electrode implantation.

The tremor network targeted by successful VIM deep brain stimulation in humans

Objective: Deep brain stimulation (DBS) of the ventral intermediate nucleus of thalamus (VIM) is a treatment option in medically intractable tremor, such as essential tremor or tremor-dominant Parkinson disease (PD). Although functional studies demonstrated modulation of remote regions, the structural network supporting this is as yet unknown. In this observational study, we analyzed the network mediating clinical tremor modulation. Methods: We studied 12 patients undergoing VIM stimulation for debilitating tremor. We initiated noninvasive diffusion tractography from tremor-suppressive VIM electrode contacts. Moreover, we tested for the contribution of primary motor projections in this structural correlate of a functional tremor network, comparing the connectivity of effective DBS contacts with those of adjacent, but clinically ineffective, stimulation sites. Results: VIM stimulation resulted in decrease of tremor and improvement in quality of life. Tractography initiated from the effective stimulation site reconstructed a highly reproducible network of structural connectivity comprising motor cortical, subcortical, and cerebellar sites and the brainstem, forming the anatomic basis for remote effects of VIM stimulation. This network is congruent with functional imaging studies in humans and with thalamic projections found in the animal literature. Connectivity to the primary motor cortex seemed to play a key role in successful stimulation. Conclusions: Patients undergoing DBS provide a unique opportunity to assess an electrophysiologically defined seed region in human thalamus, a technique that is usually restricted to animal research. In the future, preoperative tractography could aid with stereotactic planning of individual subcortical target points for stimulation in tremor and in other disease entities.

Rapid single‐scan T 2*‐mapping using exponential excitation pulses and image‐based correction for linear background gradients

A method for fast quantitative T  2* mapping based on multiple gradient‐echo (multi‐GE) imaging with correction for static magnetic field inhomogeneities is described, using an exponential excitation pulse. Field gradient maps are obtained from the phase information and modulus data are subsequently corrected, allowing for simple monoexponential T  2* fitting. Echoes with long echo times suffering from major signal losses due to field inhomogeneities are excluded from the analysis. The acquisition time for a matrix size of 256 × 256, 1 mm in‐plane resolution, and 2 mm slice thickness amounts to 15 s per slice. An additional correction for in‐plane field gradients further improves accuracy. Phantom experiments show that the method provides accurate T  2* values for field gradients up to 200 μT/m; for gradients up to 300 μT/m errors do not exceed 15%. In vivo T  2* values acquired on healthy volunteers at 3T are in excellent agreement with results from the literature. Magn Reson Med, 2009.

STN-DBS activates the target area in Parkinson disease An FDG-PET study

Objective: The immediate effects of deep brain stimulation (DBS) on subcortical neurons of its target region are controversial. Methods: We measured the regional normalized resting cerebral metabolic rate of glucose (nCMRGlc) with 18-fluorodeoxyglucose (FDG) and PET in 12 patients with Parkinson disease (PD) and bilateral DBS of the subthalamic nucleus (STN) compared to 10 age-matched controls. PET was performed before surgery and 6 months after electrode implantation in DBS off- and on-conditions. Stereotactic coordinates of active STN electrode poles were determined with intraoperative skull x-ray and transferred to preoperative MR images. Subsequently, volumes of interest (VOIs) were placed around active electrode contacts, in the STN and in the globus pallidus. DBS induced changes of nCMRGlc values were determined in each VOI after PET and MRI coregistration. Results: Electrode placement without stimulation led to significant FDG uptake reduction in the electrode region and in the STN (microlesional effect). Under active DBS, the local nCMRGlc significantly increased in all VOIs under investigation. Conclusions: The data demonstrate that deep brain stimulation (DBS) induced metabolic activation of the subthalamic region and the directly connected globus pallidus which is in line with local and remote excitation of neurons by high frequency stimulation. These PET findings most likely reflect tonic driving of the DBS target area and its projection sites via ortho- and antidromic fiber conduction. We conclude that subthalamic nucleus DBS has predominant excitatory properties and does, therefore, fundamentally differ from lesional neurosurgery.

fMRI of the brainstem using dual-echo EPI

The brainstem is the part of the human brain that plays a pivotal role in the maintenance of many critical body functions. Due to the elevated level of cardiogenic noise, few fMRI studies have investigated the brainstem so far. Cardiac-gated echo-planar imaging with acquisition of two echoes per excitation (dual-echo EPI) is one method that significantly reduces cardiogenic noise and, thus, allows for fMRI measurements of the brainstem. As information on optimal preprocessing approaches for brainstem-fMRI data is still scarce, the goal of this study was to compare different combinations of normalization and smoothing procedures as implemented in standard fMRI software packages and to identify the combinations yielding optimal results for dual-echo EPI. 21 healthy subjects were measured while executing a simple motor paradigm to activate the facial and trigeminal motor nucleus in the brainstem. After motion correction and calculation of T(2)*-maps the data were preprocessed with 24 combinations of standard normalization (SPM classic, SPM unified, FSL, ABC) and smoothing procedures (pre-/post-smoothing with 3mm-, 4.5mm- and 6mm-kernel) before undergoing first- and second-level statistical analysis. Activation results were compared for first-level and second-level statistics using two anatomically defined regions of interest. Five methods were found to be sensitive for activation of both nuclei. These included FSL normalization with 3mm and 4.5mm pre-smoothing as well as 3mm post-smoothing, SPM unified normalization with 3mm pre-smoothing and ABC normalization with 4.5mm pre-smoothing. All these methods can be recommended for normalization and smoothing when analyzing fMRI data of the brainstem acquired by cardiac-gated dual-echo EPI.

The value of putaminal diffusion imaging versus 18-fluorodeoxyglucose positron emission tomography for the differential diagnosis of the Parkinson variant of multiple system atrophy.

Differentiating the Parkinson variant of multiple system atrophy (MSA‐P) from idiopathic Parkinsons disease (PD) and other forms of atypical parkinsonism can be difficult because symptoms overlap considerably. 18‐Fluorodeoxyglucose positron emission tomography (FDG‐PET) is a powerful imaging technique that can assist in the diagnosis of MSA‐P via detection of putaminal and cerebellar hypometabolism. Recent studies suggest that diffusion‐weighted imaging (DWI) might be of similar diagnostic value, as it can detect microstructural damage in the putamen by means of an increased mean diffusivity (MD). The aim of this study was a direct comparison of DWI and FDG‐PET by using both methods on the same subject cohort. To this end, combined DWI and FDG‐PET were employed in patients with MSA‐P (n = 11), PD (n = 13), progressive supranuclear palsy (n = 8), and in 6 control subjects. MD values and FDG uptake ratios were derived from volumetric parcellations of the putamen and subjected to further analysis of covariance (ANCOVA) and receiver operating characteristics analyses. MSA‐P was found to be associated with an increased posterior putaminal MD (P < 0.001 in all subgroup comparisons) that correlated strongly with local reductions in FDG uptake (r = −0.85, P = 0.002). DWI discriminated patients with MSA‐P from other subgroups nearly as accurately as FDG‐PET (area under the curve = 0.89 vs 0.95, P = 0.27 [pooled data]). Our data suggest a close association between the amount of putaminal microstructural damage and a reduced energy metabolism in patients with MSA‐P. The clinical use of DWI for the differential diagnosis of MSA‐P is encouraged.

Intraoperative microelectrode recording for the delineation of subthalamic nucleus topography in Parkinson's disease

BACKGROUND The subthalamic nucleus (STN) as an effective target for deep brain stimulation (DBS) in advanced Parkinsons disease is functionally divided into the dorsolateral sensorimotor and the ventromedial limbic and associative parts. To implant electrodes for DBS close to the sensorimotor region is considered crucial for optimal motor benefit and for avoidance of potential cognitive and behavioral side effects. OBJECTIVE The aim of this study was to determine whether the functional segregation of the STN is associated with distinct and region-specific neuronal activity patterns and action potential properties obtained by intraoperative microelectrode recordings. METHODS In 12 Parkinsons disease patients, stepwise intraoperative microelectrode recordings were performed using five concentrically configured electrodes starting 10 mm above the calculated target point until the dorsal border of the substantia nigra. RESULTS Based on autocorrelogram analysis of a total of 329 single units, we found a higher occurrence of oscillatory (P < 0.01) and bursty (P = 0.058) spike pattern in the dorsal versus the ventral STN. In contrast the ventral region was characterized by irregular firing neurons (P < 0.01). There were no significant differences in firing frequency, coefficient of variance, asymmetry index as well as spike form, duration, and amplitude. CONCLUSIONS Among all parameters analyzed in the study, spike pattern is the only convenient electrophysiologic parameter for the differentiation of STN subregions in patients with Parkinsons disease. The autocorrelogram-based analysis of spike activity seems to be of certain value for the delineation of the dorsolateral STN and might therefore facilitate the precise electrode implantation for DBS.