Postoperative MRI localisation of electrodes and clinical efficacy of pallidal deep brain stimulation in cervical dystonia.

INTRODUCTION: Pallidal deep brain stimulation (DBS) has been shown to be effective in cervical dystonia (CD) with an improvement of about 50-60% in the Toronto Western Spasmodic Torticollis Rating (TWSTR) Scale. However, predictive factors for the efficacy of DBS in CD are missing with the anatomical location of the electrodes being one of the most important potential predictive factors. METHODS: In the present blinded observational study we correlated the anatomical localisation of DBS contacts with the relative clinical improvement (CI %) in the TWSTR as achieved by DBS at different pallidal contacts in 20 patients with CD. Localisations of DBS contacts were derived from postoperative MRI-data following anatomical normalisation into the standard Montreal Neurological Institute stereotactic space. The CIs following 76 bilateral test stimulations of 24 h were mapped to stereotactic coordinates of the corresponding bilateral 152 active contacts and were allocated to low CI (<30%; n=74), intermediate CI (≥30%; <60%; n=52) or high CI (≥60%; n=26). RESULTS: Euclidean distances between contacts and the centroid differed between the three clusters (p<0.001) indicating different anatomical variances between clusters. The Euclidean distances between contacts and the centroid of the cluster with high CIs correlated with the individual level of CIs (r=-0.61; p<0.0001). This relationship was best fitted with an exponential regression curve (r(2)=0.41). DISCUSSION: Our data show that the clinical effect of pallidal DBS on CD displays an exponential decay over anatomical distance from an optimised target localisation within a subregion of the internal pallidum. The results will allow a comparison of future DBS studies with postoperative MRI by verifying optimised (for instance pallidal) targeting in DBS-treated patients.

Encoding of sequence boundaries in the subthalamic nucleus of patients with Parkinson's disease.

Sequential behaviour is widespread not only in humans but also in animals, ranging in different degrees of complexity from locomotion to birdsong or music performance. The capacity to learn new motor sequences relies on the integrity of basal ganglia-cortical loops. In Parkinson's disease the execution of habitual action sequences as well as the acquisition of novel sequences is impaired partly due to a deficiency in being able to generate internal cues to trigger movement sequences. In addition, patients suffering from Parkinson's disease have difficulty initiating or terminating a self-paced sequence of actions. Direct recordings from the basal ganglia in these patients show an increased level of beta (14-30 Hz) band oscillatory activity associated with impairment in movement initiation. In this framework, the current study aims to evaluate in patients with Parkinson's disease the neuronal activity in the subthalamic nucleus related to the encoding of sequence boundaries during the explicit learning of sensorimotor sequences. We recorded local field potential activity from the subthalamic nucleus of 12 patients who underwent deep brain stimulation for the treatment of advanced Parkinson's disease, while the patients in their usual medicated state practiced sequences of finger movements on a digital piano with corresponding auditory feedback. Our results demonstrate that variability in performance during an early phase of sequence acquisition correlates across patients with changes in the pattern of subthalamic beta-band oscillations; specifically, an anticipatory suppression of beta-band activity at sequence boundaries is linked to better performance. By contrast, a more compromised performance is related to attenuation of beta-band activity before within-sequence elements. Moreover, multivariate pattern classification analysis reveals that differential information about boundaries and within-sequence elements can be decoded at least 100 ms before the keystroke from the amplitude of oscillations of subthalamic nucleus activity across different frequency bands, not just from the beta-band. Additional analysis was performed to assess the strength of how much the putative signal encoding class of ordinal position (boundaries, within-sequence elements) is reflected in each frequency band. This analysis demonstrates that suppression of power in the beta-band contains the most class-related information, whereas enhancement of gamma band (31-100 Hz) activity is the second main contributor to the encoding. Our findings support the hypothesis that subthalamic nucleus-mediated gating of salient boundary elements during sequence encoding may be a prerequisite for the adequate acquisition of action sequences and the transition to habitual behaviour.

Oscillatory subthalamic nucleus activity is modulated by dopamine during emotional processing in Parkinson's disease.

Dopaminergic denervation in Parkinson's disease (PD) leads to motor deficits but also depression, lack of motivation and apathy. These symptoms can be reversed by dopaminergic treatment, which may even lead to an increased hedonic tone in some patients with PD. Here, we tested the effects of dopamine on emotional processing as indexed by changes in local field potential (LFP) activity of the subthalamic nucleus (STN) in 28 PD patients undergoing deep brain stimulation. LFP activity from the STN was recorded after the administration of levodopa (ON group) or after overnight withdrawal of medication (OFF group) during presentation of an emotional picture-viewing task. Neutral and emotionally arousing pleasant and unpleasant stimuli were chosen from the International Affective Picture System. We found a double dissociation of the alpha band response depending on dopamine state and stimulus valence: dopamine enhanced the processing of pleasant stimuli, while activation during unpleasant stimuli was reduced, as indexed by the degree of desynchronization in the alpha frequency band. This pattern was reversed in the OFF state and more pronounced in the subgroup of non-depressed PD patients. Further, we found an early gamma band increase with unpleasant stimuli that occurred when ON but not OFF medication and was correlated with stimulus arousal. The late STN alpha band decrease is thought to represent active processing of sensory information. Our findings support the idea that dopamine enhances approach-related processes during late stimulus evaluation in PD. The early gamma band response may represent local encoding of increased attention, which varies as a function of stimulus arousal.

Involvement of human internal globus pallidus in the early modulation of cortical error-related activity.

The detection and assessment of errors are a prerequisite to adapt behavior and improve future performance. Error monitoring is afforded by the interplay between cortical and subcortical neural systems. Ample evidence has pointed to a specific cortical error-related evoked potential, the error-related negativity (ERN), during the detection and evaluation of response errors. Recent models of reinforcement learning implicate the basal ganglia (BG) in early error detection following the learning of stimulus-response associations and in the modulation of the cortical ERN. To investigate the influence of the human BG motor output activity on the cortical ERN during response errors, we recorded local field potentials from the sensorimotor area of the internal globus pallidus and scalp electroencephalogram representing activity from the posterior medial frontal cortex in patients with idiopathic dystonia (hands not affected) during a flanker task. In error trials, a specific pallidal error-related potential arose 60 ms prior to the cortical ERN. The error-related changes in pallidal activity-characterized by theta oscillations-were predictive of the cortical error-related activity as assessed by Granger causality analysis. Our findings show an early modulation of error-related activity in the human pallidum, suggesting that pallidal output influences the cortex at an early stage of error detection.

Antidepressant effects after short-term and chronic stimulation of the subgenual cingulate gyrus in treatment-resistant depression.

BACKGROUND: Deep brain stimulation (DBS) of the subcallosal cingulate gyrus (SCG) is an experimental approach in treatment-resistant depression (TRD). Apart from its potential long-term antidepressant effects acute stimulation effects have been described. We investigated putative neuroanatomical clusters in which such acute effects accumulate and followed patients over the long-term. METHODS: We assessed safety and efficacy of DBS in six patients with TRD receiving bilateral DBS with electrodes implanted in the SCG. First, high intensity 130 Hz stimulation was applied on five consecutive days after surgery for 24 h comprising a sham condition in a double-blind, randomized design. Acute stimulation was conducted at all four homologous electrode contacts on both sides. Afterwards, chronic stimulation was initiated and the clinical effect was evaluated at 24-36 weeks compared to baseline (50% reduction in HAMD scores). The primary outcome criterion was depression severity as assessed with the Hamilton Depression Rating Scale (HAMD-24); secondary outcome parameters were the Montgomery-Åsberg Rating-Scale and Beck Depression Inventory following DBS. The clinical effect over the three scores was compared to sham stimulation and was correlated to the anatomical localization of active contacts by stereotactically delimiting the cluster of most effective contacts in responding patients. RESULTS: Acute 24 h of stimulation showed only moderate reductions in mean HAMD-24, MADRS and BDI scores. At the last observation (24-36 weeks), two patients were remitters (HAMD-24 < 10) and the four other patients were non-responders. CONCLUSIONS: Our results confirm that stimulation of the SCG is capable of exerting moderate acute and chronic antidepressant effects. The predictive value of these findings needs to be addressed in future studies.

Thalamic gamma oscillations correlate with reaction time in a Go/noGo task in patients with essential tremor.

Intracerebral recordings of neuronal activity in patients undergoing deep brain stimulation have revealed characteristic movement-related desynchronization at frequencies <30 Hz and increased activity in the gamma band (~30-100 Hz) in the basal ganglia and thalamus. Thalamic gamma activity is also found during arousal. Here, we explore oscillatory gamma band activity recorded from the ventralis intermedius nucleus of the thalamus during motor performance in a Go/noGo task in 10 patients with essential tremor after implantation of deep brain stimulation electrodes. We show that movement-related gamma activity is lateralized to the nucleus contralateral to the moved side similar to previous findings in the globus pallidus internus and the subthalamic nucleus. The onset of contralateral gamma band synchronization following imperative Go cues is positively correlated with reaction time. Remarkably, baseline levels of gamma activity shortly before the Go cue correlated with the reaction times. Here, faster responses occurred in patients with higher levels of pre-cue gamma activity. Our findings support the role of gamma activity as a physiological prokinetic activity in the motor system. Moreover, we suggest that subtle fluctuations in pre-cue gamma band activity may have an impact on task performance and may index arousal-related states.

Scaling of movement is related to pallidal γ oscillations in patients with dystonia.

Neuronal synchronization in the gamma (γ) band is considered important for information processing through functional integration of neuronal assemblies across different brain areas. Movement-related γ synchronization occurs in the human basal ganglia where it is centered at ~70 Hz and more pronounced contralateral to the moved hand. However, its functional significance in motor performance is not yet well understood. Here, we assessed whether event-related γ synchronization (ERS) recorded from the globus pallidus internus in patients undergoing deep brain stimulation for medically intractable primary focal and segmental dystonia might code specific motor parameters. Pallidal local field potentials were recorded in 22 patients during performance of a choice-reaction-time task. Movement amplitude of the forearm pronation-supination movements was parametrically modulated with an angular degree of 30°, 60°, and 90°. Only patients with limbs not affected by dystonia were tested. A broad contralateral γ band (35-105 Hz) ERS occurred at movement onset with a maximum reached at peak velocity of the movement. The pallidal oscillatory γ activity correlated with movement parameters: the larger and faster the movement, the stronger was the synchronization in the γ band. In contrast, the event-related decrease in beta band activity was similar for all movements. Gamma band activity did not change with movement direction and did not occur during passive movements. The stepwise increase of γ activity with movement size and velocity suggests a role of neuronal synchronization in this frequency range in basal ganglia control of the scaling of ongoing movements.

Factors predicting protracted improvement after pallidal DBS for primary dystonia: the role of age and disease duration.

In many patients, optimal results after pallidal deep brain stimulation (DBS) for primary dystonia may appear over several months, possibly beyond 1 year after implant. In order to elucidate the factors predicting such protracted clinical effect, we retrospectively reviewed the clinical records of 44 patients with primary dystonia and bilateral pallidal DBS implants. Patients with fixed skeletal deformities, as well as those with a history of prior ablative procedures, were excluded. The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) scores at baseline, 1 and 3 years after DBS were used to evaluate clinical outcome. All subjects showed a significant improvement after DBS implants (mean BFMDRS improvement of 74.9% at 1 year and 82.6% at 3 years). Disease duration (DD, median 15 years, range 2-42) and age at surgery (AS, median 31 years, range 10-59) showed a significant negative correlation with DBS outcome at 1 and 3 years. A partition analysis, using DD and AS, clustered subjects into three groups: (1) younger subjects with shorter DD (n = 19, AS < 27, DD ≤ 17); (2) older subjects with shorter DD (n = 8, DD ≤ 17, AS ≥ 27); (3) older subjects with longer DD (n = 17, DD > 17, AS ≥ 27). Younger patients with short DD benefitted more and faster than older patients, who however continued to improve 10% on average 1 year after DBS implants. Our data suggest that subjects with short DD may expect to achieve a better general outcome than those with longer DD and that AS may influence the time necessary to achieve maximal clinical response.