Usefulness of thalamic beta activity for closed-loop therapy in essential tremor.

A partial loss of effectiveness of deep brain stimulation of the ventral intermediate nucleus of the thalamus (VIM) has been reported in some patients with essential tremor (ET), possibly due to habituation to permanent stimulation. This study focused on the evolution of VIM local-field potentials (LFPs) data over time to assess the long-term feasibility of closed-loop therapy based on thalamic activity. We performed recordings of thalamic LFPs in 10 patients with severe ET using the ACTIVA™ PC + S (Medtronic plc.) allowing both recordings and stimulation in the same region. Particular attention was paid to describing the evolution of LFPs over time from 3 to 24 months after surgery when the stimulation was Off. We demonstrated a significant decrease in high-beta LFPs amplitude during movements inducing tremor in comparison to the rest condition 3 months after surgery (1.91 ± 0.89 at rest vs. 1.27 ± 1.37 µV2/Hz during posture/action for N = 8/10 patients; p = 0.010), 12 months after surgery (2.92 ± 1.75 at rest vs. 2.12 ± 1.78 µV2/Hz during posture/action for N = 7/10 patients; p = 0.014) and 24 months after surgery (2.32 ± 0.35 at rest vs 0.75 ± 0.78 µV2/Hz during posture/action for 4/6 patients; p = 0.017). Among the patients who exhibited a significant decrease of high-beta LFP amplitude when stimulation was Off, this phenomenon was observed at least twice during the follow-up. Although the extent of this decrease in high-beta LFPs amplitude during movements inducing tremor may vary over time, this thalamic biomarker of movement could potentially be usable for closed-loop therapy in the long term.

Anticholinergic drugs rescue synaptic plasticity in DYT1 dystonia: role of M1 muscarinic receptors.

Broad-spectrum muscarinic receptor antagonists have represented the first available treatment for different movement disorders such as dystonia. However, the specificity of these drugs and their mechanism of action is not entirely clear. We performed a systematic analysis of the effects of anticholinergic drugs on short- and long-term plasticity recorded from striatal medium spiny neurons from DYT1 dystonia knock-in (Tor1a(+/Δgag) ) mice heterozygous for ΔE-torsinA and their controls (Tor1a(+/+) mice). Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, trihexyphenydil, biperiden, orphenadrine, and a novel selective M1 antagonist, VU0255035. Tor1a(+/Δgag) mice exhibited a significant impairment of corticostriatal synaptic plasticity. Anticholinergics had no significant effects on intrinsic membrane properties and on short-term plasticity of striatal neurons. However, they exhibited a differential ability to restore the corticostriatal plasticity deficits. A complete rescue of both long-term depression (LTD) and synaptic depotentiation (SD) was obtained by applying the M1 -preferring antagonists pirenzepine and trihexyphenidyl as well as VU0255035. Conversely, the nonselective antagonist orphenadrine produced only a partial rescue of synaptic plasticity, whereas biperiden and ethopropazine failed to restore plasticity. The selectivity for M1 receptors was further demonstrated by their ability to counteract the M1 -dependent potentiation of N-methyl-d-aspartate (NMDA) current recorded from striatal neurons. Our study demonstrates that selective M1 muscarinic receptor antagonism offsets synaptic plasticity deficits in the striatum of mice with the DYT1 dystonia mutation, providing a potential mechanistic rationale for the development of improved antimuscarinic therapies for this movement disorder.

Motor cortex stimulation does not improve dystonia secondary to a focal basal ganglia lesion.

OBJECTIVE: To assess the efficacy of epidural motor cortex stimulation (MCS) on dystonia, spasticity, pain, and quality of life in patients with dystonia secondary to a focal basal ganglia (BG) lesion. METHODS: In this double-blind, crossover, multicenter study, 5 patients with dystonia secondary to a focal BG lesion were included. Two quadripolar leads were implanted epidurally over the primary motor (M1) and premotor cortices, contralateral to the most dystonic side. The leads were placed parallel to the central sulcus. Only the posterior lead over M1 was activated in this study. The most lateral or medial contact of the lead (depending on whether the dystonia predominated in the upper or lower limb) was selected as the anode, and the other 3 as cathodes. One month postoperatively, patients were randomly assigned to on- or off-stimulation for 3 months each, with a 1-month washout between the 2 conditions. Voltage, frequency, and pulse width were fixed at 3.8 V, 40 Hz, and 60 µs, respectively. Evaluations of dystonia (Burke-Fahn-Marsden Scale), spasticity (Ashworth score), pain intensity (visual analog scale), and quality of life (36-Item Short Form Health Survey) were performed before surgery and after each period of stimulation. RESULTS: Burke-Fahn-Marsden Scale, Ashworth score, pain intensity, and quality of life were not statistically significantly modified by MCS. CONCLUSIONS: Bipolar epidural MCS failed to improve any clinical feature in dystonia secondary to a focal BG lesion. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that bipolar epidural MCS with the anode placed over the motor representation of the most affected limb failed to improve any clinical feature in dystonia secondary to a focal BG lesion.

Inverse relationship between thalamic and orbitofrontal volumes in obsessive-compulsive disorder.

Volumetric magnetic resonance imaging (MRI) studies in obsessive-compulsive disorder (OCD) have reported a smaller volume of the orbitofrontal cortex (OFC) and a larger volume of the thalamus compared with healthy controls. Both of these brain regions are strongly connected; therefore, it may be hypothesized that cortical and thalamic alterations are related. Here, we investigated the relationship between thalamic and orbitofrontal volumes in OCD patients relative to healthy controls. MRI volumetric measurements of the thalamus and the OFC were obtained in 16 OCD patients without comorbidity and 16 comparison subjects matched for age, sex and educational level. Partial correlation analyses that controlled for intracranial volume (ICV) were performed to explore relationships between thalamic and OFC volumes in each group. In order to assess the specificity of this relationship, we conducted similar analyses of the anterior cingulate cortex (ACC) as a non-OFC cortical volume. Finally, by using data from previously published volumetric MRI studies, we conducted a meta-regression to explore the relationships between volume changes in these regions of interest. Results showed that thalamic volumes were significantly negatively correlated with OFC volumes in OCD patients (r=-0.83, p<0.001), but not in healthy subjects (r=-0.15, p=0.59). A significant relationship between thalamic and ACC volumes was found neither in the OCD patients (r=0.03, p=0.91) nor in the comparison subjects (r=-0.23, p=0.40). Furthermore, meta-regression analyses showed that previously reported volume changes in the thalamus were significantly correlated with OFC volume changes (r=-0.71, p<0.05), but not with ACC volume changes (r=0.07, p=0.86). Although our results do not allow for any causal relationship to be established, they suggest that structural alterations of both the thalamus and the OFC are inversely and specifically related in OCD.

Meta-analysis of brain volume changes in obsessive-compulsive disorder.

BACKGROUND: Many neuroimaging studies exploring the volumes of brain structures in obsessive-compulsive disorder (OCD) have been published in the past 2 decades. In this study, we attempted to provide a complete overview of structural alterations in OCD by meta-analyzing magnetic resonance imaging (MRI) data. METHODS: We conducted a systematic search of MRI studies that reported volumetric measurements in both OCD patients and healthy subjects. Data were entered into the meta-analysis through calculation of the standardized mean differences (SMDs) between the volumes of cerebral regions in OCD patients and the corresponding volumes in control subjects. We then performed a meta-regression to explore the influence of clinical covariates on effect sizes. RESULTS: Although no volumetric differences were found for the whole brain, intracranial region, gray matter, or prefrontal cortex, OCD patients did show a reduced volume of the left anterior cingulate cortex (ACC) and the left and right orbitofrontal cortex (OFC). No significant volumetric differences within the basal ganglia were observed, although the left and right thalamic volumes were significantly increased in OCD patients. The severity of obsessive or compulsive symptoms correlated significantly with the effect sizes for the left and right thalamus. CONCLUSIONS: Our findings indicate volumetric differences between OCD patients and control subjects in the cortical and thalamic regions, suggesting that structural alteration of the thalamocortical pathways may contribute to the functional disruptions of frontosubcortical circuits observed in OCD.

Subthalamic nucleus stimulation in severe obsessive-compulsive disorder.

BACKGROUND: Severe, refractory obsessive-compulsive disorder (OCD) is a disabling condition. Stimulation of the subthalamic nucleus, a procedure that is already validated for the treatment of movement disorders, has been proposed as a therapeutic option. METHODS: In this 10-month, crossover, double-blind, multicenter study assessing the efficacy and safety of stimulation of the subthalamic nucleus, we randomly assigned eight patients with highly refractory OCD to undergo active stimulation of the subthalamic nucleus followed by sham stimulation and eight to undergo sham stimulation followed by active stimulation. The primary outcome measure was the severity of OCD, as assessed by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), at the end of two 3-month periods. General psychopathologic findings, functioning, and tolerance were assessed with the use of standardized psychiatric scales, the Global Assessment of Functioning (GAF) scale, and neuropsychological tests. RESULTS: After active stimulation of the subthalamic nucleus, the Y-BOCS score (on a scale from 0 to 40, with lower scores indicating less severe symptoms) was significantly lower than the score after sham stimulation (mean [+/-SD], 19+/-8 vs. 28+/-7; P=0.01), and the GAF score (on a scale from 1 to 90, with higher scores indicating higher levels of functioning) was significantly higher (56+/-14 vs. 43+/-8, P=0.005). The ratings of neuropsychological measures, depression, and anxiety were not modified by stimulation. There were 15 serious adverse events overall, including 1 intracerebral hemorrhage and 2 infections; there were also 23 nonserious adverse events. CONCLUSIONS: These preliminary findings suggest that stimulation of the subthalamic nucleus may reduce the symptoms of severe forms of OCD but is associated with a substantial risk of serious adverse events. (ClinicalTrials.gov number, NCT00169377.)

Auditory temporal processing in Parkinson's disease.

Previous research has suggested that Parkinson's disease (PD) impairs perceptual acuity in the temporal domain. In the present study, psychophysical tests assessing several aspects of auditory temporal processing were administered to a group of PD patients treated with bilateral subthalamic nucleus (STN) stimulation and to a normal control group. Each patient was tested in three clinical conditions: without treatment, with levodopa therapy, and during STN stimulation. In all three conditions, the patients showed a significant deficit in the detection of very short temporal gaps within noise bursts and in the discrimination between the durations of two well-detectable time intervals (circa 50ms) bounded by two temporally non-contiguous pairs of clicks. However, the patients showed no deficit in the detection of a temporal break produced by a local interval change in an otherwise isochronous sequence of 10 clicks spaced by 50-ms intervals. The latter result contradicts previous suggestions that PD slows down an internal clock or pacemaker involved in the perception of short durations. In this regard, we reinterpret previous evidence. Remarkably, the patients' deficits were not diminished by levodopa therapy; in contrast, STN stimulation slightly improved performance, overall. We tentatively ascribe the deficit observed in the gap-detection test to a dysfunctioning of the auditory cortex, impairing its ability to track rapid fluctuations in sound intensity. We argue that the deficit in the duration-discrimination test is the consequence of an impairment in memory and/or attention rather than in the perception of time per se.

Deep brain stimulation of the ventral caudate nucleus in the treatment of obsessive-compulsive disorder and major depression. Case report.

Obsessive-compulsive disorder (OCD) is an anxiety disorder associated with recurrent intrusive thoughts and repetitive behaviors. Although conventional pharmacological and/or psychological treatments are well established and effective in treating OCD, symptoms remain unchanged in up to 30% of patients. Deep brain stimulation (DBS) of the anterior limb of the internal capsule has recently been proposed as a possible therapeutic alternative in treatment-resistant OCD. In the present study, the authors tested the hypothesis that DBS of the ventral caudate nucleus might be effective in a patient with intractable severe OCD and concomitant major depression. Psychiatric assessment included the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), the Hamilton Depression Rating Scale (HDRS), the Hamilton Anxiety Rating Scale (HARS), and the Global Assessment of Functioning (GAF) Scale for determining the symptom severity of OCD, depression, and anxiety as well as the quality of pychosocial and occupational functioning, respectively. Neuropsychological assessment consisted of a wide range of tests primarily exploring memory and executive functions. Deep brain stimulation of the ventral caudate nucleus markedly improved symptoms of depression and anxiety until their remission, which was achieved at 6 months after the start of stimulation (HDRS < or = 7 and HARS < or = 10). Remission of OCD (Y-BOCS < 16) was also delayed after 12 or 15 months of DBS. The level of functioning pursuant to the GAF scale progressively increased during the 15-month follow-up period. No neuropsychological deterioration was observed, indicating that DBS of the ventral caudate nucleus could be a promising strategy in the treatment of refractory cases of both OCD and major depression.

Risus sardonicus after thalamic haemorrhage.

We describe an uncommon movement disorder after stroke. A 70-year-old man was admitted for a right thalamic haemorrhage and 1 week later developed bilateral contractions of the face. Electromyographic study revealed a bilateral facial dystonia. The association of this bilateral facial dystonia and vertical gaze palsy produced the aspect of a "risus sardonicus."

Pathophysiology of obsessive-compulsive disorder: a necessary link between phenomenology, neuropsychology, imagery and physiology.

Obsessive-compulsive disorder (OCD) is characterized by repetitive intrusive thoughts and compulsive time-consuming behaviors classified into three to five distinct symptom dimensions including: (1) aggressive/somatic obsessions with checking compulsions; (2) contamination concerns with washing compulsions; (3) symmetry obsessions with counting/ordering compulsions; (4) hoarding obsessions with collecting compulsions; and (5) sexual/religious concerns. Phenomenologically, OCD could be thought of as the irruption of internal signals centered on the erroneous perception that "something is wrong" in a specific situation. This generates severe anxiety, leading to recurrent behaviors aimed at reducing the emotional tension. In this paper, we examine how the abnormalities in brain activity reported in OCD can be interpreted in the light of physiology after consideration of various approaches (phenomenology, neuropsychology, neuroimmunology and neuroimagery) that contribute to proposing the central role of several cortical and subcortical regions, especially the orbitofrontal cortex (OFC), the anterior cingulate cortex (ACC), the dorsolateral prefrontal cortex (DLPC), the head of the caudate nucleus and the thalamus. The OFC is involved in the significance attributed to the consequences of action, thereby subserving decision-making, whereas the ACC is particularly activated in situations in which there are conflicting options and a high likelihood of making an error. The DLPC plays a critical part in the cognitive processing of relevant information. This cortical information is then integrated by the caudate nucleus, which controls behavioral programs. A dysfunction of these networks at one or several stages will result in the emergence and maintenance of repetitive thoughts and characteristic OCD behavior.

Parkinson's disease patients with bilateral subthalamic deep brain stimulation gain weight.

Weight, body mass index (BMI) and energy expenditure/energy intake (EE/EI) was studied in 19 Parkinson's disease (PD) patients after subthalamic deep brain stimulation (STN-DBS) versus 14 nonoperated ones. Operated patients had a significant weight gain (WG, + 9.7 +/- 7 kg) and BMI increase (+ 4.7 kg/m2). The fat mass was higher after STN-DBS. Resting EE (REE; offdrug/ON stimulation) was significantly decreased in STN-DBS patients, while their daily energy expenditure (DEI) was not significantly different. A significant correlation was found among WG, BMI increase, and pre-operative levodopa-equivalent daily dose, their reduction after STN-DBS, and the differential REE related to stimulation and the REE in the offdrug/OFF stimulation condition. In conclusion, STN-DBS in PD induces a significant WG associated with a reduction in REE without DEI adjustment.

Lack of agreement between direct magnetic resonance imaging and statistical determination of a subthalamic target: the role of electrophysiological guidance.

OBJECT: The goal of this study was to determine the most suitable procedure(s) to localize the optimal site for high-frequency stimulation of the subthalamic nucleus (STN) for the treatment of advanced Parkinson disease. METHODS: Stereotactic coordinates of the STN were determined in 14 patients by using three different methods: direct identification of the STN on coronal and axial T2-weighted magnetic resonance (MR) images and indirect targeting in which the STN coordinates are referred to the anterior commissure-posterior commissure (AC-PC) line, which, itself, is determined either by using stereotactic ventriculography or reconstruction from three-dimensional (3D) MR images. During the surgical procedure, electrode implantation was guided by single-unit microrecordings on multiple parallel trajectories and by clinical assessment of stimulations. The site where the optimal functional response was obtained was considered to be the best target. Computerized tomography scanning was performed 3 days later and the scans were combined with preoperative 3D MR images to transfer the position of the best target to the same system of stereotactic coordinates. An algorithm was designed to convert individual stereotactic coordinates into an all-purpose PC-referenced system for comparing the respective accuracy of each method of targeting, according to the position of the best target. CONCLUSIONS: The target that is directly identified by MR imaging is more remote (mainly in the lateral axis) from the site of the optimal functional response than targets obtained using other procedures, and the variability of this method in the lateral and superoinferior axes is greater. In contrast, the target defined by 3D MR imaging is closest to the target of optimal functional response and the variability of this method is the least great. Thus, 3D reconstruction adjusted to the AC-PC line is the most accurate technique for STN targeting, whereas direct visualization of the STN on MR images is the least effective. Electrophysiological guidance makes it possible to correct the inherent inaccuracy of the imaging and surgical techniques and is not designed to modify the initial targeting.

Improvement of severe trunk spasms by bilateral high-frequency stimulation of the motor thalamus in a patient with chorea-acanthocytosis.

We report on a patient with a severe form of chorea-acanthocytosis, intractable to medical treatment, who benefited from bilateral high-frequency stimulation (HFS) of the posterior ventral oral nucleus of the thalamus. The frequency of trunk spasms dramatically decreased after surgery and the clinical benefit remained stable 1 year later. However, no clear effect was observed on dysarthria nor on hypotonia, which always impaired gait. We propose that HFS of the motor thalamus is a potential treatment for choreic or truncal dystonic symptoms whenever hypotonia is not the main feature of the syndrome.