Filip Růžička

Subthalamic Nucleus Stimulation Affects Incentive Salience Attribution in Parkinson's Disease

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) can induce nonmotor side effects such as behavioral and mood disturbances or body weight gain in Parkinsons disease (PD) patients. We hypothesized that some of these problems could be related to an altered attribution of incentive salience (ie, emotional relevance) to rewarding and aversive stimuli. Twenty PD patients (all men; mean age ± SD, 58.3 ± 6 years) in bilateral STN DBS switched ON and OFF conditions and 18 matched controls rated pictures selected from the International Affective Picture System according to emotional valence (unpleasantness/pleasantness) and arousal on 2 independent visual scales ranging from 1 to 9. Eighty‐four pictures depicting primary rewarding (erotica and food) and aversive fearful (victims and threat) and neutral stimuli were selected for this study. In the STN DBS ON condition, the PD patients attributed lower valence scores to the aversive pictures compared with the OFF condition (P < .01) and compared with controls (P < .01). The difference between the OFF condition and controls was less pronounced (P < .05). Furthermore, postoperative weight gain correlated with arousal ratings from the food pictures in the STN DBS ON condition (P < .05 compensated for OFF condition). Our results suggest that STN DBS increases activation of the aversive motivational system so that more relevance is attributed to aversive fearful stimuli. In addition, STN DBS–related sensitivity to food reward stimuli cues might drive DBS‐treated patients to higher food intake and subsequent weight gain.

The Subthalamic Microlesion Story in Parkinson's Disease: Electrode Insertion-Related Motor Improvement with Relative Cortico-Subcortical Hypoactivation in fMRI

Electrode implantation into the subthalamic nucleus for deep brain stimulation in Parkinsons disease (PD) is associated with a temporary motor improvement occurring prior to neurostimulation. We studied this phenomenon by functional magnetic resonance imaging (fMRI) when considering the Unified Parkinsons Disease Rating Scale (UPDRS-III) and collateral oedema. Twelve patients with PD (age 55.9± (SD)6.8 years, PD duration 9–15 years) underwent bilateral electrode implantation into the subthalamic nucleus. The fMRI was carried out after an overnight withdrawal of levodopa (OFF condition): (i) before and (ii) within three days after surgery in absence of neurostimulation. The motor task involved visually triggered finger tapping. The OFF/UPDRS-III score dropped from 33.8±8.7 before to 23.3±4.8 after the surgery (p<0.001), correlating with the postoperative oedema score (p<0.05). During the motor task, bilateral activation of the thalamus and basal ganglia, motor cortex and insula were preoperatively higher than after surgery (p<0.001). The results became more enhanced after compensation for the oedema and UPDRS-III scores. In addition, the rigidity and axial symptoms score correlated inversely with activation of the putamen and globus pallidus (p<0.0001). One month later, the OFF/UPDRS-III score had returned to the preoperative level (35.8±7.0, p = 0.4). In conclusion, motor improvement induced by insertion of an inactive electrode into the subthalamic nucleus caused an acute microlesion which was at least partially related to the collateral oedema and associated with extensive impact on the motor network. This was postoperatively manifested as lowered movement-related activation at the cortical and subcortical levels and differed from the known effects of neurostimulation or levodopa. The motor system finally adapted to the microlesion within one month as suggested by loss of motor improvement and good efficacy of deep brain stimulation.

Weight Gain Is Associated with Medial Contact Site of Subthalamic Stimulation in Parkinson's Disease

The aim of our study was to assess changes in body-weight in relation to active electrode contact position in the subthalamic nucleus. Regular body weight measurements were done in 20 patients with advanced Parkinsons disease within a period of 18 months after implantation. T1-weighted (1.5T) magnetic resonance images were used to determine electrode position in the subthalamic nucleus and the Unified Parkinsons disease rating scale (UPDRS-III) was used for motor assessment. The distance of the contacts from the wall of the third ventricle in the mediolateral direction inversely correlated with weight gain (r = −0.55, p<0.01) and with neurostimulation-related motor condition expressed as the contralateral hemi-body UPDRS-III (r = −0.42, p<0.01). Patients with at least one contact within 9.3 mm of the wall experienced significantly greater weight gain (9.4±(SD)4.4 kg, N = 11) than those with both contacts located laterally (3.9±2.7 kg, N = 9) (p<0.001). The position of the active contact is critical not only for motor outcome but is also associated with weight gain, suggesting a regional effect of subthalamic stimulation on adjacent structures involved in the central regulation of energy balance, food intake or reward.

Distinct populations of neurons respond to emotional valence and arousal in the human subthalamic nucleus

Significance The involvement of the subthalamic nucleus (STN) in affective processing has been suggested with the appearance of neuropsychiatric side effects of deep brain stimulation in Parkinson’s disease (PD), but direct evidence has been lacking. In our study, we recorded single-neuron activity from the STN during affective picture presentation to PD patients intraoperatively. We discovered two spatially distinct populations of “affective” neurons responding to the emotional dimensions of the stimuli: valence (pleasantness-unpleasantness) and arousal (intensity). As previously believed, neural circuits underlying these two affective dimensions are functionally segregated. Here we observed separated emotional processing even at the single neuron level. These results extend our knowledge regarding the emotional role of the STN and the neural basis of emotions. Both animal studies and studies using deep brain stimulation in humans have demonstrated the involvement of the subthalamic nucleus (STN) in motivational and emotional processes; however, participation of this nucleus in processing human emotion has not been investigated directly at the single-neuron level. We analyzed the relationship between the neuronal firing from intraoperative microrecordings from the STN during affective picture presentation in patients with Parkinson’s disease (PD) and the affective ratings of emotional valence and arousal performed subsequently. We observed that 17% of neurons responded to emotional valence and arousal of visual stimuli according to individual ratings. The activity of some neurons was related to emotional valence, whereas different neurons responded to arousal. In addition, 14% of neurons responded to visual stimuli. Our results suggest the existence of neurons involved in processing or transmission of visual and emotional information in the human STN, and provide evidence of separate processing of the affective dimensions of valence and arousal at the level of single neurons as well.

Sex, Food and Threat: Startling Changes after Subthalamic Stimulation in Parkinson's Disease

BACKGROUND Changes in motivational processing may play a role in weight gain and other non-motor side effects in Parkinsons disease (PD) patients treated with deep brain stimulation of the subthalamic nucleus. OBJECTIVE/HYPOTHESIS We aimed to assess changes in aversive and appetitive motivational activation using modulation of the acoustic blink reflex (ABR) by rewarding and aversive stimuli. METHODS ABR elicited during the viewing of erotic, food, aversive and neutral pictures was recorded in 11 off-medicated patients with the subthalamic stimulation switched ON and OFF, and in 11 control subjects. RESULTS ABR to erotic stimuli was larger in patients in the ON compared to the OFF condition and controls (P < 0.01). Aversive stimuli caused a larger increase in the ABR in patients with the ON condition than in controls (P < 0.05). Additionally, we found a negative correlation of the ABR magnitude to food pictures in the ON condition with weight gain following subthalamic stimulation (P < 0.01, after adjustment to OFF condition). CONCLUSIONS Our results suggest that subthalamic stimulation affects motivational processing. Subthalamic stimulation may disturb appetitive engagement by erotic cues and increase aversive activation in PD patients. Additionally, postoperative weight gain may be related to changes in the processing of food cues due to subthalamic stimulation.

Basal ganglia neuronal activity during scanning eye movements in Parkinson's disease.

The oculomotor role of the basal ganglia has been supported by extensive evidence, although their role in scanning eye movements is poorly understood. Nineteen Parkinsońs disease patients, which underwent implantation of deep brain stimulation electrodes, were investigated with simultaneous intraoperative microelectrode recordings and single channel electrooculography in a scanning eye movement task by viewing a series of colored pictures selected from the International Affective Picture System. Four patients additionally underwent a visually guided saccade task. Microelectrode recordings were analyzed selectively from the subthalamic nucleus, substantia nigra pars reticulata and from the globus pallidus by the WaveClus program which allowed for detection and sorting of individual neurons. The relationship between neuronal firing rate and eye movements was studied by crosscorrelation analysis. Out of 183 neurons that were detected, 130 were found in the subthalamic nucleus, 30 in the substantia nigra and 23 in the globus pallidus. Twenty percent of the neurons in each of these structures showed eye movement-related activity. Neurons related to scanning eye movements were mostly unrelated to the visually guided saccades. We conclude that a relatively large number of basal ganglia neurons are involved in eye motion control. Surprisingly, neurons related to scanning eye movements differed from neurons activated during saccades suggesting functional specialization and segregation of both systems for eye movement control.

The Diagnostic Accuracy of Parkinson's Disease Mild Cognitive Impairment Battery Using the Movement Disorder Society Task Force Criteria

The aim of the present study was to provide empirical evidence regarding the classification accuracy of the International Parkinson and Movement Disorder Society (MDS) neuropsychological battery (NB) in the determination of Parkinsons disease mild cognitive impairment (PD‐MCI).

Decrease in blood cortisol corresponds to weight gain following deep brain stimulation of the subthalamic nucleus in Parkinson's disease.

months (p = 0.001). WG was associated with changes of ghrelin and leptin levels at 3 and 6 months. The authors concluded that STN DBS may temporarily dysregulate the hypothalamic secretion of NPY and ghrelin, whereas the WG may be related to an increased production of ghrelin and leptin. These observations bear remarkable similarities to our earlier study, in which we assessed anthropometric and hormonal profiles in 27 PD patients on the day of surgery and at 2, 4, 6 and 12 months on STN DBS [5] . Our patients’ weight continuously increased throughout the study, with the mean body weight change with regard to baseline being +4.16 8 3.5 kg (p ! 0.001) at 6 months and +5.18 8 5.8 kg (p ! 0.001) at 12 months. Furthermore, in both studies, leptin and ghrelin levels correlated with body WG, corresponding to the known roles of the adipocytederived leptin and the orexigenic hormone ghrelin. Curiously enough, Markaki et al. [4] do not pay much attention to their own finding of markedly decreased cortisol levels following STN DBS. Nevertheless, this result is in surprisingly precise agreement with our observation, probably shedding more light on the mechanisms of WG in PD following STN DBS ( table 1 ). At 3 months after STN DBS, Markaki et al. [4] noticed a significant decrease in blood cortisol (–23.8%, p = 0.027). In our study, cortisol levels decreased at 2 months, (–23.9%, p ! 0.002), still remaining significantly reduced compared to baseline at 12 months after DBS implantation (–22.9%, p = 0.008) [5] . These results seem to indicate the involvement of hypothalamic-pituitaryadrenal axis in the mechanisms of WG after STN DBS. It can be hypothesized that STN DBS acts on adjacent nerve fibers and structures including hypothalamic nuclei, where it suppresses secretion of corticotropin-releasing factor with a subsequent decrease in the production of cortisol. Since the level of corticotropin-releasing factor is low, its catabolic effect is mitigated; therefore, the homeostatic balance shifts towards predominance in It has repeatedly been shown that patients with Parkinson’s disease (PD) gain body weight under treatment with deep brain stimulation of the subthalamic nucleus (STN DBS) [1–3] . However, the mechanisms underlying this weight gain (WG) remain unclear. We, therefore, read with great interest the recently published article ‘The role of ghrelin, neuropeptide Y and leptin peptides in weight gain after deep brain stimulation for Parkinson’s disease’ by Markaki et al. [4] . The authors performed body composition measurements and blood sampling before, and 3 and 6 months after STN DBS in 23 PD patients, looking for relations between WG and changes in blood levels of the metabolic hormones ghrelin, neuropeptide Y (NPY) and leptin. A significant WG (3.09 8 5 kg, mean 8 SD, p = 0.007) was observed 3 months after surgery, with no further increase at 6 months. Also the circulating levels of NPY increased significantly (p = 0.05) at 3 months, while the increase of ghrelin was significant only at 6 Received: April 27, 2012 Accepted: July 5, 2012 Published online: October 17, 2012

Separate neural representations of depression, anxiety and apathy in Parkinson’s disease

Depression, anxiety and apathy are distinct neuropsychiatric symptoms that highly overlap in Parkinson’s disease (PD). It remains unknown whether each symptom is uniquely associated with a functional network dysfunction. Here, we examined whether individual differences in each neuropsychiatric symptom predict functional connectivity patterns in PD patients while controlling for all other symptoms and motor function. Resting-state functional connectivity MRI were acquired from 27 PD patients and 29 healthy controls. Widespread reduced functional connectivity was identified in PD patients and explained by either the neuropsychiatric or motor symptoms. Depression in PD predicted increased functional connectivity between the orbitofrontal, hippocampal complex, cingulate, caudate and thalamus. Apathy in PD predicted decreased caudate-thalamus and orbitofrontal-parahippocampal connectivity. Anxiety in PD predicted three distinct types of functional connectivity not described before: (i) increased limbic-orbitofrontal cortex; (ii) decreased limbic-dorsolateral prefrontal cortex and orbitofrontal-dorsolateral prefrontal cortices and (iii) decreased sensorimotor-orbitofrontal cortices. The first two types of functional connectivity suggest less voluntary and more automatic emotion regulation. The last type is argued to be specific to PD and reflect an impaired ability of the orbitofrontal cortex to guide goal-directed motor actions in anxious PD patients.

Automated Atlas Fitting for Deep Brain Stimulation Surgery Based on Microelectrode Neuronal Recordings

Introduction: The deep brain stimulation (DBS) is a treatment technique for late-stage Parkinson’s disease (PD), based on chronic electrical stimulation of neural tissue through implanted electrodes. To achieve high level of symptom suppression with low side effects, precise electrode placement is necessary, although difficult due to small size of the target nucleus and various sources of inaccuracy, especially brain shift and electrode bending. To increase accuracy of electrode placement, electrophysiological recording using several parallel microelectrodes (MER) is used intraoperatively in most centers. Location of the target nucleus is identified from manual expert evaluation of characteristic neuronal activity. Existing studies have presented several models to classify individual recordings or trajectories automatically. In this study, we extend this approach by fitting a 3D anatomical atlas to the recorded electrophysiological activity, thus adding topological information. Methods: We developed a probabilistic model of neuronal activity in the vicinity the subthalamic nucleus (STN), based on normalized signal energy. The model is used to find a maximum-likelihood transformation of an anatomical surface-based atlas to the recorded activity. The resulting atlas fit is compared to atlas position estimated from pre-operative MRI scans. Accuracy of STN classification is then evaluated in a leave-one-subject-out scenario using expert MER annotation. Results: In an evaluation on a set of 27 multi-electrode trajectories from 15 PD patients, the proposed method showed higher accuracy in STN-nonSTN classification (88.1%) compared to the reference methods (78.7%) with an even more pronounced advantage in sensitivity (69.0% vs 44.6%). Conclusion: The proposed method allows electrophysiology-based refinement of atlas position of the STN and represents a promising direction in refining accuracy of MER localization in clinical DBS setting, as well as in research of DBS mechanisms.