Movement disorders after hypoxic brain injury following cardiac arrest in adults.

BACKGROUND AND PURPOSE: Post-hypoxic movement disorders and chronic post-hypoxic myoclonus are rare complications after cardiac arrest in adults. Our study investigates the clinical spectrum, neuroimaging results, therapy and prognosis of these debilitating post-hypoxic sequelae. METHODS: This retrospective study included 72 patients from the neurological intensive care unit at a university hospital, who were diagnosed with hypoxic-ischaemic encephalopathy after cardiac arrest between January 2007 and September 2018. Clinical records were screened for occurrence of post-hypoxic movement disorders and chronic post-hypoxic myoclonus. Affected patients were further analysed for applied neuroprognostic tests, administered therapy and treatment response, and the outcome of these movement disorders and neurological function. RESULTS: Nineteen out of 72 screened patients exhibited post-hypoxic motor symptoms. Basal ganglia injury was the most likely neuroanatomical correlate of movement disorders as indicated by T1 hyperintensities and hypometabolism of this region in magnetic resonance imaging and positron emission tomography computed tomography. Levomepromazine and intrathecal baclofen showed first promising and mostly prompt responses to control these post-hypoxic movement disorders and even hyperkinetic storms. In contrast, chronic post-hypoxic myoclonus best responded to co-application of clonazepam, levetiracetam and primidone. Remission rates of post-hypoxic movement disorders and chronic post-hypoxic myoclonus were 58% and 50%, respectively. Affected patients seemed to present a rather good recovery of cognitive functions in contrast to the often more severe physical deficits. CONCLUSIONS: Post-hypoxic movement disorders associated with pronounced basal ganglia dysfunction might be efficiently controlled by levomepromazine or intrathecal baclofen. Their occurrence might be an indicator for a more unfavourable, but often not devastating, neurological outcome.

Different patterns of local field potentials from limbic DBS targets in patients with major depressive and obsessive compulsive disorder.

The role of distinct limbic areas in emotion regulation has been largely inferred from neuroimaging studies. Recently, the opportunity for intracranial recordings from limbic areas has arisen in patients undergoing deep brain stimulation (DBS) for neuropsychiatric disorders including major depressive disorder (MDD) and obsessive compulsive disorder (OCD). Here we test the hypothesis that distinct temporal patterns of local field potential (LFP) activity in the human limbic system reflect disease state and symptom severity in MDD and OCD patients. To this end, we recorded LFPs via implanted DBS electrodes from the bed nucleus of stria terminalis (BNST area) in 12 patients (5 OCD, 7 MDD) and from the subgenual cingulate cortex in 7 MDD patients (CG25 area). We found a distinct pattern of oscillatory activity with significantly higher α-power in MDD compared with OCD in the BNST area (broad α-band 8-14 Hz; P<0.01) and a similar level of α-activity in the CG25 area as in the BNST area in MDD patients. The mean α-power correlated with severity of depressive symptoms as assessed by the Beck depression inventory in MDD (n=14, r=0.55, P=0.042) but not with severity of obsessive compulsive symptoms in OCD. Here we show larger α-band activity in MDD patients compared with OCD recorded from intracranial DBS targets. Our results suggest that α-activity in the limbic system may be a signature of symptom severity in MDD and may serve as a potential state biomarker for closed loop DBS in MDD.

Interhemispheric functional interactions between the subthalamic nuclei of patients with Parkinson's disease.

Parkinson's disease (PD) is characterized by widespread neural interactions in cortico-basal-ganglia networks primarily in beta oscillations (approx. 10-30 Hz), as suggested by previous findings of levodopa-modulated interhemispheric coherence between the bilateral subthalamic nuclei (STN) in local field potential recordings (LFPs). However, due to confounding effects of volume conduction the existence of 'genuine' interhemispheric subcortical coherence remains an open question. To address this issue we utilized the imaginary part of coherency (iCOH) which, in contrast to the standard coherence, is not susceptible to volume conduction. LFPs were recorded from eight patients with PD during wakeful rest before and after levodopa administration. We demonstrated genuine coherence between the bilateral STN in both 10-20 and 21-30 Hz oscillations, as revealed by a non-zero iCOH. Crucially, increased iCOH in 10-20 Hz oscillations positively correlated with the worsening of motor symptoms in the OFF medication condition across patients, which was not the case for standard coherence. Furthermore, across patients iCOH was increased after levodopa administration in 21-30 Hz oscillations. These results suggest a functional distinction between low and high beta oscillations in STN-LFP in line with previous studies. Furthermore, the observed functional coupling between the bilateral STN might contribute to the understanding of bilateral effects of unilateral deep brain stimulation. In conclusion, the present results imply a significant contribution of time-delayed neural interactions to interhemispheric coherence, and the clinical relevance of long-distance neural interactions between bilateral STN for motor symptoms in PD.

Quadruple deep brain stimulation in Huntington's disease, targeting pallidum and subthalamic nucleus: case report and review of the literature.

Deep brain stimulation (DBS) represents an established treatment option in a growing number of movement disorders. Recent case reports suggest beneficial effect of globus pallidus internus (GPi)-DBS in selected patients suffering from Huntington's disease with marked disabling chorea. We present a 41-year-old man with genetically confirmed HD following quadruple GPi- and subthalamic nucleus (STN)-DBS. Motor function was assessed by Abnormal Involuntary Movement Scale (AIMS) and by Unified Huntington Disease Rating Scale (UHDRS) presurgery and postsurgery for up to 4 years. Furthermore, cognitive, neuropsychiatric state and quality of life (QoL) including life satisfaction (QLS) were annually evaluated. Chorea assessed by AIMS and UHDRS subscores improved by 52 and 55 %, 45 and 60 %, 35 and 45 % and 55-66 % at 1-4 years, respectively, compared to presurgical state following GPi-STN-DBS. During these time periods bradykinesia did not increase following separate STN- and combined GPi-STN-DBS compared to presurgical state. Mood, QoL and QLS were ameliorated. However, dysexecutive symptoms increased at 4 years postsurgery. The present case report suggests that bilateral GPi- and STN-DBS may represent a new treatment avenue in selected HD patients. Clinically, GPi-DBS attenuated chorea and was associated with a larger effect-adverse effect window compared to STN-DBS. However, GPi-DBS-induced bradykinesia may emerge as one main limitation of GPi-DBS in HD. Thus, quadruple GPi-STN-DBS may be indicated, if separate GPi-DBS does not result in sufficient control of motor symptoms. Future controlled studies need to confirm if the present anecdotal observation of additive beneficial effects of GPi- and STN-DBS in a HD patient with severe generalized chorea and relatively intact cognitive and affective functions indeed represents a new therapeutic option.

[Deep brain stimulation. New target areas and new indications]. / Tiefe Hirnstimulation. Neue Zielgebiete und neue Indikationen.

Many patients with neurological movement disorders and psychiatric diseases cannot yet be adequately treated with conventional methods. Deep brain stimulation represents an important extension of therapeutic options by which invasive electrodes are implanted in various subcortical brain areas in order to achieve an improvement in motor and psychiatric symptoms by high frequency stimulation. Up to 2012 approximately 100,000 patients had been treated with deep brain stimulation worldwide. The indications for deep brain stimulation were essentially already established indications, such as idiopathic Parkinson's syndrome, dystonia and tremors. The newer indications which include in particular psychiatric symptoms, such as depression, obsessive diseases, addiction and Tourette syndrome, are as yet limited to approximately 5 % of treated patients. An increasingly better understanding of the system physiology of neurological and psychiatric diseases has promoted the search for new target areas and indications for treatment by neuromodulation. This article gives an overview of the latest developments in the established and also the developing application areas of deep brain stimulation.

Long-range temporal correlations in the subthalamic nucleus of patients with Parkinson's disease.

Neuronal activity in the subthalamic nucleus (STN) of patients with Parkinson's disease (PD) is characterised by excessive neuronal synchronization, particularly in the beta frequency range. However, less is known about the temporal dynamics of neuronal oscillations in PD. In this respect long-range temporal correlations (LRTC) are of special interest as they quantify the neuronal dynamics on different timescales and have been shown to be relevant for optimal information processing in the brain. While the presence of LRTC has been demonstrated in cortical data, their existence in deep brain structures remains an open question. We investigated (i) whether LRTC are present in local field potentials (LFP) recorded bilaterally from the STN at wakeful rest in ten patients with PD after overnight withdrawal of levodopa (OFF) and (ii) whether LRTC can be modulated by levodopa treatment (ON). Detrended fluctuation analysis was utilised in order to quantify the temporal dynamics in the amplitude fluctuations of LFP oscillations. We demonstrated for the first time the presence of LRTC (extending up to 50 s) in the STN. Importantly, the ON state was characterised by significantly stronger LRTC than the OFF state, both in beta (13-35 Hz) and high-frequency (> 200 Hz) oscillations. The existence of LRTC in subcortical structures such as STN provides further evidence for their ubiquitous nature in the brain. The weaker LRTC in the OFF state might indicate limited information processing in the dopamine-depleted basal ganglia. The present results implicate LRTC as a potential biomarker of pathological neuronal processes in PD.

Randomized double-blind sham-controlled trial of thalamic versus GPi stimulation in patients with severe medically refractory Gilles de la Tourette syndrome.

BACKGROUND: There are still no sufficient data regarding the use of deep brain stimulation (DBS) in Gilles de la Tourette syndrome (GTS) and no agreement on optimal target. OBJECTIVE: To compare efficacy and safety of bilateral DBS of thalamus (centromedian-ventro-oral internus, CM-Voi) versus posteroventral lateral globus pallidus internus (pvl GPi)) versus sham stimulation, and baseline in severe medically refractory GTS. METHODS: In this randomized double-blind sham stimulation-controlled trial (RCT), 10 patients (3 women, mean age = 29.4 ± 10.2 SD, range 18-47) underwent three blinded periods each lasting three months including (i) sham, (ii) pvl GPi (on-GPi), and (iii) thalamic stimulation (on-thal) followed by an open uncontrolled long-term follow-up (up to 9 years) with individually determined target and stimulation settings. RESULTS: Nine patients completed the RCT. At group level, on-GPi - but not on-thal - resulted in a significant tic reduction compared to baseline, but had no effect on premonitory urges and psychiatric comorbidities. Direct comparisons of targets resulted in inconsistent or negative (compared to sham) findings. During follow-up, we found no improvement of tics, comorbidities, and quality of life at group level, however, single patients benefitted continuously from thalamic DBS. At last follow-up 89.9 months (mean) after surgery, 50% of patients had discontinued DBS. Hardware infections occurred in 3/10 patients. CONCLUSION: Our data suggest that the initial effect of pvl GPi DBS is superior to thalamic (CM-Voi) DBS. While half of the patients discontinued treatment, single patients benefitted from thalamic DBS even after years. It is likely that outcome is influenced by various factors beyond the mere change in tic severity.

Adverse events associated with deep brain stimulation in patients with childhood-onset dystonia.

BACKGROUND: Data on pediatric DBS is still limited because of small numbers in single center series and lack of systematic multi-center trials. OBJECTIVES: We evaluate short- and long-term adverse events (AEs) of patients undergoing deep brain stimulation (DBS) during childhood and adolescence. METHODS: Data collected by the German registry on pediatric DBS (GEPESTIM) were analyzed according to reversible and irreversible AEs and time of occurrence with relation to DBS-surgery: Intraoperative, perioperative (<4 weeks), postoperative (4 weeks < 6 months) and long term AEs (>6 months). RESULTS: 72 patients with childhood-onset dystonia from 10 DBS-centers, who received 173 DBS electrodes and 141 implantable pulse generators (IPG), were included in the registry. Mean time of postoperative follow-up was 4.6 ±â€¯4 years. In total, 184 AEs were documented in 53 patients (73.6%). 52 DBS-related AEs in 26 patients (36.1%) required 45 subsequent surgical interventions 4.7 ±â€¯4.1 years (range 3 months-15 years) after initial implantation. The total risk of an AE requiring surgical intervention was 7.9% per electrode-year. Hardware-related AEs were the most common reason for surgery. There was a tendency of a higher rate of AEs in patients aged 7-9 years beyond 6 months after implantation. DISCUSSION: The intraoperative risk of AEs in pediatric patients with dystonia undergoing DBS is very low, whereas the rate of postoperative hardware-related AEs is a prominent feature with a higher occurrence compared to adults, especially on long-term follow-up. CONCLUSION: Factors leading to such AEs must be identified and patient management has to be focused on risk minimization strategies in order to improve DBS therapy and maximize outcome in pediatric patients.

Suppression of beta oscillations in the subthalamic nucleus following cortical stimulation in humans.

It is unclear how subthalamic nucleus activity is modulated by the cerebral cortex. Here we investigate the effect of transcranial magnetic stimulation (TMS) of the cortex on oscillatory subthalamic local field potential activity in the 8-35 Hz (alpha/beta) band, as exaggerated synchronization in this band is implicated in the pathophysiology of parkinsonism. We studied nine patients with Parkinson's disease (PD) to test whether cortical stimulation can modulate synchronized oscillations in the human subthalamic nucleus. With patients at rest, single-pulse TMS was delivered every 5 s over each primary motor area and supplementary motor area at intensities of 85-115% resting motor threshold. Subthalamic local field potentials were recorded from deep brain stimulation electrodes implanted into this nucleus for the treatment of PD. Motor cortical stimulation suppressed beta activity in the subthalamic nucleus from approximately 0.2 to 0.6 s after TMS (repeated measures anova; main effect of time, P < 0.01; main effect of side, P = 0.03), regardless of intensity. TMS over the supplementary motor area also reduced subthalamic beta activity at 95% (P = 0.05) and 115% resting motor threshold (P = 0.01). The oscillatory activity decreased to 80 +/- 26% of baseline (averaged across sites and stimulation intensities). Suppression with subthreshold stimuli confirmed that these changes were centrally driven and not due to peripheral afference. The results may have implications for mechanisms underlying the reported therapeutic benefits of cortical stimulation.

Neural correlates of lexical decisions in Parkinson's disease revealed with multivariate extraction of cortico-subthalamic interactions.

OBJECTIVE: Neural interactions between cortex and basal ganglia are pivotal for sensorimotor processing. Specifically, coherency between cortex and subthalamic structures is a frequently studied phenomenon in patients with Parkinson's disease. However, it is unknown whether cortico-subthalamic coherency might also relate to cognitive aspects of task performance, e.g., language processing. Furthermore, standard coherency studies are challenged by how to efficiently handle multi-channel recordings. METHODS: In eight patients with Parkinson's disease treated with deep brain stimulation, simultaneous recordings of surface electroencephalography and deep local field potentials were obtained from bilateral subthalamic nuclei, during performing a lexical decision task. A recent multivariate coherency measure (maximized imaginary part of coherency, MIC) was applied, simultaneously accounting for multi-channel recordings. RESULTS: Cortico-subthalamic synchronization (MIC) in 14-35Hz oscillations positively correlated with accuracy in lexical decisions across patients, but not in 7-13Hz oscillations. In contrast to multivariate MIC, no significant correlation was obtained when extracting cortico-subthalamic synchronization by "standard" bivariate coherency. CONCLUSIONS: Cortico-subthalamic synchronization may relate to non-motor aspects of task performance, here reflected in lexical accuracy. SIGNIFICANCE: The results tentatively suggest the relevance of cortico-subthalamic interactions for lexical decisions. Multivariate coherency might be effective to extract neural synchronization from multi-channel recordings.

German registry of paediatric deep brain stimulation in patients with childhood-onset dystonia (GEPESTIM).

BACKGROUND: Data on paediatric deep brain stimulation (DBS) is limited, especially for long-term outcomes, because of small numbers in single center series and lack of systematic multi-center trials. OBJECTIVES: We seek to systematically evaluate the clinical outcome of paediatric patients undergoing DBS. METHODS: A German registry on paediatric DBS (GEPESTIM) was created to collect data of patients with dystonia undergoing DBS up to the age of 18 years. Patients were divided into three groups according to etiology (group 1 inherited, group 2 acquired, and group 3 idiopathic dystonia). RESULTS: Data of 44 patients with a mean age of 12.8 years at time of operation provided by 6 German centers could be documented in the registry so far (group 1 n = 18, group 2 n = 16, group 3 n = 10). Average absolute improvement after implantation was 15.5 ± 18.0 for 27 patients with pre- and postoperative Burke-Fahn-Marsden Dystonia Rating scale movement scores available (p < 0.001) (group 1: 19.6 ± 19.7, n = 12; group 2: 7.0 ± 8.9, n = 8; group 3: 19.2 ± 20.7, n = 7). Infection was the main reason for hardware removal (n = 6). 20 IPG replacements due to battery expiry were necessary in 15 patients at 3.7 ± 1.8 years after last implantation. DISCUSSION: Pre- and postoperative data on paediatric DBS are very heterogeneous and incomplete but corroborate the positive effects of DBS on inherited and acquired dystonia. Adverse events including relatively frequent IPG replacements due to battery expiry seem to be a prominent feature of children with dystonia undergoing DBS. The registry enables collaborative research on DBS treatment in the paediatric population and to create standardized management algorithms in the future.

Long-term results of deep brain stimulation in a cohort of eight children with isolated dystonia.

Pallidal deep brain stimulation (DBS) is an established treatment for patients with severe isolated dystonia. However, clinical evidence for the long-term use of DBS in children is limited and controlled trials have not yet been conducted. Here, we provide the long-term results of up to 13 years of pallidal DBS in eight pediatric patients with generalized idiopathic or hereditary isolated dystonia (five males, mean age at surgery 12.5 ± 3.5 years), as assessed by retrospective video rating. Video rating was performed at three time points: pre-operative, 1-year short-term follow-up (1y-FU) and long-term last FU (LT-FU, up to 13 years). Symptom severity and disability were assessed using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). Disability scores were obtained from clinical charts and during the last FU. The mean improvement in BFMDRS motor score was 54.4 ± 8.9 % at 1y-FU and 42.9 ± 11.6 % at LT-FU; the disability scores improved by 59.8 ± 10.3 and 63.3 ± 7.8 %, respectively. Electrode dislocation was noted in one patient and implantable pulse generator dislocation in another, both requiring surgical intervention; no further serious adverse events occurred. Our study presents the first blinded video rating assessment of the short- and long-term effects of pallidal DBS in children with idiopathic or hereditary isolated dystonia. Results confirm that pallidal DBS is a safe and efficacious long-term treatment in children, with overall motor improvement similar to that described in controlled trials in adults.

Correlation between cortical and subcortical neural dynamics on multiple time scales in Parkinson's disease.

Complex amplitude dynamics of dominant alpha oscillations (8-13 Hz) in the cortex can be captured with long-range temporal correlations (LRTC) in healthy subjects and in various diseases. In patients with Parkinson's disease (PD), intra-nuclear coherence was demonstrated in dominant beta rhythms (10-30 Hz) in the basal ganglia. However, so far the relation between cortical LRTC (across tens of seconds) and subcortical coherence (millisecond scale) is unknown. We addressed these "multiscale interactions" by simultaneous recordings of surface electroencephalography (EEG) and deep local field potentials (LFP) from the bilateral subthalamic nucleus (STN) in eight patients with severe PD eligible for deep brain stimulation, who performed a lexical decision task on medication. In the continuous data set LRTC up to 20s were calculated in the amplitude envelope of 8-13-Hz EEG oscillations (across whole scalp), and subcortical coherence was assessed with measures being insensitive to volume conduction artifacts (imaginary part of coherency; iCOH) in 10-20 and 21-30-Hz oscillations in STN-LFP. We showed a significant positive correlation across patients between cortical LRTC (8-13Hz) and subcortical iCOH selectively in 10-20-Hz oscillations in the left STN. Our results suggest a relation between neural dynamics in the most dominant rhythms in the cortex and basal ganglia in PD, extending across multiple time scales (milliseconds vs. tens of seconds). Furthermore, the investigation of multiscale interactions might contribute to our understanding of cortical-subcortical neural coupling in PD.

The effects of frequency in pallidal deep brain stimulation for primary dystonia.

The effect of stimulation frequency for pallidal deep brain stimulation in five patients with either generalized or segmental dystonia was evaluated three to twelve months postoperatively via a randomized, double-blind paradigm. The quality of life and the severity of dystonic symptoms improved by approximately 60% and 43% respectively using a frequency of 130 Hz. Compared with 130 Hz a significant further clinical improvement was observed at frequencies of 180 and 250 Hz, which contrasted with a significant deterioration at lower frequencies (5, 50 Hz) compared to 130 Hz.

Pseudo-bilateral hand motor responses evoked by transcranial magnetic stimulation in patients with deep brain stimulators.

OBJECTIVES: In 3 of 5 patients with dystonia and bilaterally implanted deep brain stimulating electrodes, focal transcranial magnetic stimulation (TMS) of one motor cortex elicited bilateral hand motor responses. The aim of this study was to clarify the origin of these ipsilateral responses. METHODS: TMS and electrical stimulation of corticospinal fibres by the implanted electrodes were performed and the evoked hand motor potentials were analysed. RESULTS: In comparison with responses elicited by contralateral motor cortex stimulation, ipsilateral responses were smaller in amplitude (3.0+/-1.4 versus 5.8+/-1.5 mV), had shorter peak latencies (first negative peak: 20.9+/-0.8 versus 25.1+/-0.4 ms) and were followed by a shorter-lasting silent period (46+/-4 versus 195+/-35 ms). Ipsilateral responses following TMS had similar peak latencies to responses elicited subcortically by deep brain stimulation (DBS) (20.4+/-0.9 ms). CONCLUSIONS: Hand motor responses ipsilateral to TMS result from a subcortical activation of corticospinal fibres, via the implanted electrode in the other hemisphere, secondary to currents induced by TMS in subcutaneous wire loops that underlie the magnetic coil. Studies of TMS in patients with DBS have to take this potential source of confounding into account.

Patterns of abnormal motor cortex excitability in atypical parkinsonian syndromes.

OBJECTIVE: Multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal-ganglionic degeneration (CBGD) are all clinically characterized by an akinetic-rigid syndrome together with a variety of additional signs. We hypothesised that these atypical parkinsonian syndromes (APS) will show distinctive patterns in their motor output upon transcranial magnetic stimulation (TMS) due to their different underlying anatomico-functional deficits. METHODS: We performed single and paired-pulse TMS and assessed inhibitory and excitatory response parameters from the first dorsal interosseus muscles in 13 patients with MSA, 18 with PSP, 13 with CBGD, 15 patients with Parkinson's disease and 17 healthy subjects. RESULTS: PSP and MSA patients had significantly enlarged response amplitudes at rest, reduced intracortical inhibition (ICI) and prolonged ipsi- and contralateral silent periods, whereas CBGD patients showed significantly increased motor thresholds, smaller response amplitudes at rest, shortened contralateral silent period, reduced transcallosal inhibition and a reduced ICI. In 22% of APS patients ipsilateral motor responses occurred in upper limb muscles irrespective of the underlying disease. CONCLUSIONS: Our results indicate that motor cortex disinhibition is predominant in patients with PSP and MSA. In CBGD more severe neuronal cell loss in the motor cortex itself may lead to hypoexcitability of corticospinal and transcallosal pathways.

Functional and effective connectivity in subthalamic local field potential recordings of patients with Parkinson's disease.

In Parkinson's disease (PD) levodopa-associated changes in the power and long-range temporal correlations of beta oscillations have been demonstrated, yet the presence and modulation of genuine connectivity in local field potentials (LFP) recorded from the subthalamic nucleus (STN) remains an open question. The present study investigated LFP recorded bilaterally from the STN at wakeful rest in ten patients with PD after overnight withdrawal of levodopa (OFF) and after a single dose levodopa administration (ON). We utilized connectivity measures being insensitive to volume conduction (functional connectivity: non-zero imaginary part of coherency; effective connectivity: phase-slope index). We demonstrated the presence of neuronal interactions in the frequency range of 10-30 Hz in STN-LFP without a preferential directionality of interactions between different contacts along the electrode tracks. While the direction of neuronal interactions per se was preserved after levodopa administration, functional connectivity and the ventral-dorsal information flow were modulated by medication. The OFF-ON differences in functional connectivity were correlated with the levodopa-induced improvement in clinical Unified Parkinson's Disease Rating Scale scores. We hypothesize that regional neuronal interactions, as reflected in STN-LFP connectivity, might represent a basis for the intra-nuclear spatial specificity of deep brain stimulation. Moreover, our results suggest the potential use of volume conduction-insensitive measures of connectivity in STN-LFP as a marker of clinical motor symptoms in PD.

ß band stability over time correlates with Parkinsonian rigidity and bradykinesia.

Abnormal oscillatory activity in the basal ganglia is increasingly implicated in the pathophysiology of Parkinson's disease. Such activity is recorded in patients in the form of oscillations in the local field potential (LFP) picked up in the subthalamic nucleus. Previous studies have focused on correlations between features of the time averaged power or amplitude spectrum of the LFP and the clinical state, either off medication or in response to levodopa. However, average spectral densities do not take account of time variant spectral properties and we hypothesised that these dynamic properties of the spectrum of the LFP would contain additional information about clinical state. Here we assess the variability in LFP amplitude over time using the coefficient of variation (CV), evaluating this with regard to clinical state off medication and in response to levodopa in two datasets. The CV of activity in the high beta frequency band was found to be correlated with clinical state off levodopa (rho=-0.59, p<0.001) and this was shown to be complementary, rather than redundant, to spectral amplitude in a multiple regression analysis, selective for rigidity-bradykinesia and highly focal. Similarly, a strong correlation was found between change in clinical scores and change in high beta CV following levodopa (rho=-0.66, p=0.004). This too was selective for rigidity-bradykinesia and non-redundant to spectral power in a multiple regression model. Our results indicate that temporal stability in the beta band is correlated with rigidity-bradykinesia. It is suggested that loss of beta reactivity is deleterious to basal ganglia function over and above any concomitant change in absolute level of beta synchrony. The CV of LFP beta band amplitude may potentially provide an additional index of clinical state suitable for feedback control in closed loop stimulation therapy.

Automated optimization of subcortical cerebral MR imaging-atlas coregistration for improved postoperative electrode localization in deep brain stimulation.

BACKGROUND AND PURPOSE: The efficacy of deep brain stimulation in treating movement disorders depends critically on electrode localization, which is conventionally described by using coordinates relative to the midcommissural point. This approach requires manual measurement and lacks spatial normalization of anatomic variances. Normalization is based on intersubject spatial alignment (coregistration) of corresponding brain structures by using different geometric transformations. Here, we have devised and evaluated a scheme for automated subcortical optimization of coregistration (ASOC), which maximizes patient-to-atlas normalization accuracy of postoperative structural MR imaging into the standard Montreal Neurologic Institute (MNI) space for the basal ganglia. MATERIALS AND METHODS: Postoperative T2-weighted MR imaging data from 39 patients with Parkinson disease and 32 patients with dystonia were globally normalized, representing the standard registration (control). The global transformations were regionally refined by 2 successive linear registration stages (RSs) (ASOC-1 and 2), focusing progressively on the basal ganglia with 2 anatomically selective brain masks, which specify the reference volume (weighted cost function). Accuracy of the RSs was quantified by spatial dispersion of 16 anatomic landmarks and their root-mean-square errors (RMSEs) with respect to predefined MNI-based reference points. The effects of CSF volume, age, and sex on RMSEs were calculated. RESULTS: Mean RMSEs differed significantly (P < .001) between the global control (4.2 +/- 2.0 mm), ASOC-1 (1.92 +/- 1.02 mm), and ASOC-2 (1.29 +/- 0.78 mm). CONCLUSIONS: The present method improves the registration accuracy of postoperative structural MR imaging data into MNI space within the basal ganglia, allowing automated normalization with increased precision at stereotactic targets, and enables lead-contact localization in MNI coordinates for quantitative group analysis.

Long-term effects of pallidal deep brain stimulation in tardive dystonia.

OBJECTIVE: High-frequency stimulation of the globus pallidus internus (GPi) is a highly effective therapy in primary dystonia. Recent reports have also demonstrated almost immediate improvement of motor symptoms in patients with tardive dystonia after pallidal deep brain stimulation (DBS). Here, we show the long-term effect of continuous bilateral GPi DBS in tardive dystonia on motor function, quality of life (QoL), and mood. METHODS: Nine consecutive patients undergoing DBS for tardive dystonia were assessed during continuous DBS at 3 time points: 1 week, 3 to 6 months, and last follow-up at the mean of 41 (range 18-80) months after surgery using established and validated movement disorder and neuropsychological scales. Clinical assessment was performed by a neurologist not blinded to the stimulation settings. RESULTS: One week and 3 to 6 months after pallidal DBS, Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) motor scores were ameliorated by 56.4 +/- 26.7% and 74.1 +/- 15.8%, BFMDRS disability scores by 62.5 +/- 21.0% and 88.9 +/- 10.3%, and Abnormal Involuntary Movement Scale (AIMS) scores by 52.3 +/- 24.1% and 69.5 +/- 27.6%, respectively. At last follow-up, this improvement compared with the presurgical assessment was maintained as reflected by a reduction of BFMDRS motor scores by 83.0 +/- 12.2%, BFMDRS disability scores by 67.7 +/- 28.0%, and AIMS scores by 78.7 +/- 19.9%. QoL improved significantly in physical components, and there was a significant improvement in affective state. Furthermore, cognitive functions remained unchanged compared with presurgical status in the long-term follow-up. No permanent adverse effects were observed. CONCLUSION: Pallidal deep brain stimulation is a safe and effective long-term treatment in patients with medically refractory tardive dystonia.