Modulation of central thalamic oscillations during emotional-cognitive processing in chronic disorder of consciousness.

We report on thalamic recordings in a patient with chronic disorder of consciousness (DOC). Implantation of central thalamic deep brain stimulation (CT-DBS) electrodes was chosen, as this treatment has been reported to display beneficial effects with respect to behavioural responsiveness in DOC. Local field potential (LFP) oscillations were recorded from central thalamic electrodes and their changes elicited by speech stimuli consisting either of familiar voices addressing the patient or unfamiliar non-addressing phrases were studied. In response to familiar-addressing speech we observed modulation of oscillatory activity in the beta and theta band within the central thalamus accompanied by an increase in thalamocortical coherence in the theta band. Furthermore, the theta phase was coupled to the amplitude of gamma locally in the thalamus. These findings indicate a local and long-range cross-frequency response which is not only indicative of the principle involvement of the central thalamus in processing emotional and cognitive information, but also point towards intact physiological functions that may serve as a marker in diagnosing DOC patients and determining novel targets and parameters concerning therapeutic efforts.

Can we still dream when the mind is blank? Sleep and dream mentations in auto-activation deficit.

Bilateral damage to the basal ganglia causes auto-activation deficit, a neuropsychological syndrome characterized by striking apathy, with a loss of self-driven behaviour that is partially reversible with external stimulation. Some patients with auto-activation deficit also experience a mental emptiness, which is defined as an absence of any self-reported thoughts. We asked whether this deficit in spontaneous activation of mental processing may be reversed during REM sleep, when dreaming activity is potentially elicited by bottom-up brainstem stimulation on the cortex. Sleep and video monitoring over two nights and cognitive tests were performed on 13 patients with auto-activation deficit secondary to bilateral striato-pallidal lesions and 13 healthy subjects. Dream mentations were collected from home diaries and after forced awakenings in non-REM and REM sleep. The home diaries were blindly analysed for length, complexity and bizarreness. A mental blank during wakefulness was complete in six patients and partial in one patient. Four (31%) patients with auto-activation deficit (versus 92% of control subjects) reported mentations when awakened from REM sleep, even when they demonstrated a mental blank during the daytime (n = 2). However, the patients' dream reports were infrequent, short, devoid of any bizarre or emotional elements and tended to be less complex than the dream mentations of control subjects. The sleep duration, continuity and stages were similar between the groups, except for a striking absence of sleep spindles in 6 of 13 patients with auto-activation deficit, despite an intact thalamus. The presence of spontaneous dreams in REM sleep in the absence of thoughts during wakefulness in patients with auto-activation deficit supports the idea that simple dream imagery is generated by brainstem stimulation and is sent to the sensory cortex. However, the lack of complexity in these dream mentations suggests that the full dreaming process (scenario, emotions, etc.) require these sensations to be interpreted by higher-order cortical areas. The absence of sleep spindles in localized lesions in the basal ganglia highlights the role of the pallidum and striatum in spindling activity during non-REM sleep.

Effects of dopaminergic and subthalamic stimulation on musical performance.

Although subthalamic-deep brain stimulation (STN-DBS) is an efficient treatment for Parkinson's disease (PD), its effects on fine motor functions are not clear. We present the case of a professional violinist with PD treated with STN-DBS. DBS improved musical articulation, intonation and emotional expression and worsened timing relative to a timekeeper (metronome). The same effects were found for dopaminergic treatment. These results suggest that STN-DBS, mimicking the effects of dopaminergic stimulation, improves fine-tuned motor behaviour whilst impairing timing precision.

Thalamic stimulation for tremor: can target determination be improved?

High frequency stimulation of the ventral intermedius nucleus (Vim) of the thalamus is successfully used for the treatment of postural tremor. Target coordinates are most commonly calculated using a statistical method. Here, we compare a statistical and an individual targeting method, using an histology-based three-dimensional deformable brain atlas which allows localization of the Vim on individual patient's MR images by adaptation of the atlas onto the patient's brain. Twenty-nine consecutive patients had electrodes implanted in the Vim uni-or bilaterally for severe essential tremor. Thirty-five targets were determined by calculating the statistical target and then using the deformable atlas to compute the individual target. Pythagorean distance between these targets was calculated. Statistical and individual targets were compared by double blind evaluation of perioperative stimulation effects. For most cases (n = 24), the Pythagorean distance was higher than 1.5 mm. In 79% of these cases, the definitive electrode was implanted using the position of the individual target. For the remaining cases (n = 11, distance < 1.5 mm), the definitive electrode was implanted according to the statistical target location in 73% of the cases. As a whole, when individual target was used, it was located at least 2 mm more medial than the statistical one in 86% cases. These results suggest that Vim target determination based on a statistical method might be inaccurate. In particular, laterality might be overestimated, leading to nonoptimal clinical results. In clinical practice, this means that microelectrode exploration during Vim surgery should include at least one trajectory more medial than the statistical target.

External globus pallidus stimulation modulates brain connectivity in Huntington's disease.

Positron emission tomography with O-15-labeled water was used to study at rest the neurophysiological effects of bilateral external globus pallidus (GPe) deep brain stimulation in patients with Huntington's disease (HD). Five patients were compared with a control group in the on and off states of the stimulator. External globus pallidus stimulation decreased neuronal activity and modulated cerebral connectivity within the basal ganglia-thalamocortical circuitry, the sensorimotor, and the default-mode networks. These data indicate that GPe stimulation modulates functional integration in HD patients in accordance with the basal ganglia-thalamocortical circuit model.

Analysis of the striato-thalamo-cortical connectivity on the cortical surface to infer biomarkers of Huntington's disease.

The deep brain nuclei play an important role in many brain functions and particularly motor control. Damage to these structures result in movement disorders such as in Parkinson's disease or Huntington's disease, or behavioural disorders such as Tourette syndrome. In this paper, we propose to study the connectivity profile of the deep nuclei to the motor, associative or limbic areas and we introduce a novel tool to build a probabilistic atlas of these connections to the cortex directly on the surface of the cortical mantel, as it corresponds to the space of functional interest. The tool is then applied on two populations of healthy volunteers and patients suffering from severe Huntington's disease to produce two surface atlases of the connectivity of the basal ganglia to the cortical areas. Finally, robust statistics are used to characterize the differences of that connectivity between the two populations, providing new connectivity-based biomarkers of the pathology.

Gamma activity and reactivity in human thalamic local field potentials.

Depth recordings in patients with Parkinson's disease on dopaminergic therapy have revealed a tendency for oscillatory activity in the basal ganglia that is sharply tuned to frequencies of approximately 70 Hz and increases with voluntary movement. It is unclear whether this activity is essentially physiological and whether it might be involved in arousal processes. Here we demonstrate an oscillatory activity with similar spectral characteristics and motor reactivity in the human thalamus. Depth signals were recorded in 29 patients in whom the ventral intermediate or centromedian nucleus were surgically targeted for deep brain stimulation. Thirteen patients with four different pathologies showed sharply tuned activity centred at approximately 70 Hz in spectra of thalamic local field potential (LFP) recordings. This activity was modulated by movement and, critically, varied over the sleep-wake cycle, being suppressed during slow wave sleep and re-emergent during rapid eye movement sleep, which physiologically bears strong similarities with the waking state. It was enhanced by startle-eliciting stimuli, also consistent with modulation by arousal state. The link between this pattern of thalamic activity and that of similar frequency in the basal ganglia was strengthened by the finding that fast thalamic oscillations were lost in untreated parkinsonian patients, paralleling the behaviour of this activity in the basal ganglia. Furthermore, there was sharply tuned coherence between thalamic and pallidal LFP activity at approximately 70 Hz in eight out of the 11 patients in whom globus pallidus and thalamus were simultaneously implanted. Subcortical oscillatory activity at approximately 70 Hz may be involved in movement and arousal.

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.)

Internal pallidal and thalamic stimulation in patients with Tourette syndrome.

BACKGROUND: Tourette syndrome (TS) is thought to result from dysfunction of the associative-limbic territories of the basal ganglia, and patients with severe symptoms of TS respond poorly to medication. High-frequency stimulation has recently been applied to patients with TS in open studies using the centromedian-parafascicular complex (CM-Pf) of the thalamus, the internal globus pallidus (GPi), or the anterior limb of the internal capsule as the principal target. OBJECTIVE: To report the effect of high-frequency stimulation of the CM-Pf and/or the GPi, 2 associative-limbic relays of the basal ganglia, in patients with TS. DESIGN: Controlled, double-blind, randomized crossover study. SETTING: Medical research. PATIENTS: Three patients with severe and medically refractory TS. INTERVENTION: Bilateral placement of stimulating electrodes in the CM-Pf (associative-limbic part of the thalamus) and the GPi (ventromedial part). MAIN OUTCOME MEASURES: Effects of thalamic, pallidal, simultaneous thalamic and pallidal, and sham stimulation on neurologic, neuropsychological, and psychiatric symptoms. RESULTS: A dramatic improvement on the Yale Global Tic Severity Scale was obtained with bilateral stimulation of the GPi (reduction in tic severity of 65%, 96%, and 74% in patients 1, 2, and 3, respectively). Bilateral stimulation of the CM-Pf produced a 64%, 30%, and 40% reduction in tic severity, respectively. The association of thalamic and pallidal stimulation showed no further reduction in tic severity (60%, 43%, and 76%), whereas motor symptoms recurred during the sham condition. No neuropsychological, psychiatric, or other long-term adverse effect was observed. CONCLUSIONS: High-frequency stimulation of the associative-limbic relay within the basal ganglia circuitry may be an effective treatment of patients with TS, thus heightening the hypothesis of a dysfunction in these structures in the pathophysiologic mechanism of the disorder.

Stimulation of subterritories of the subthalamic nucleus reveals its role in the integration of the emotional and motor aspects of behavior.

Two parkinsonian patients who experienced transient hypomanic states when the subthalamic nucleus (STN) was stimulated during postoperative adjustment of the electrical parameters for antiparkinsonian therapy agreed to have the mood disorder reproduced, in conjunction with motor, cognitive, and behavioral evaluations and concomitant functional neuroimaging. During the experiment, STN stimulation again induced a hypomanic state concomitant with activation of cortical and thalamic regions known to process limbic and associative information. This observation suggests that the STN plays a role in the control of a complex behavior that includes emotional as well as cognitive and motor components. The localization of the four contacts of the quadripolar electrode was determined precisely with an interactive brain atlas. The results showed that (i) the hypomanic state was caused only by stimulation through one contact localized in the anteromedial STN; (ii) both this contact and the contact immediately dorsal to it improved the parkinsonian motor state; (iii) the most dorsal and ventral contacts, located at the boundaries of the STN, neither induced the behavioral disorder nor improved motor performance. Detailed analysis of these data led us to consider a model in which the three functional modalities, emotional, cognitive, and motor, are not processed in a segregated manner but can be subtly combined in the small volume of the STN. This nucleus would thus serve as a nexus that integrates the motor, cognitive, and emotional components of behavior and might consequently be an effective target for the treatment of behavioral disorders that combine emotional, cognitive, and motor impairment.

Localization of stimulating electrodes in patients with Parkinson disease by using a three-dimensional atlas-magnetic resonance imaging coregistration method.

OBJECT: The aim of this study was to correlate the clinical improvement in patients with Parkinson disease (PD) treated using deep brain stimulation (DBS) of the subthalamic nucleus (STN) with the precise anatomical localization of stimulating electrodes. METHODS: Localization was determined by superimposing figures from an anatomical atlas with postoperative magnetic resonance (MR) images obtained in each patient. This approach was validated by an analysis of experimental and clinical MR images of the electrode, and the development of a three-dimensional (3D) atlas-MR imaging coregistration method. The PD motor score was assessed through two contacts for each of two electrodes implanted in 10 patients: the "therapeutic contact" and the "distant contact" (that is, the next but one to the therapeutic contact). Seventeen therapeutic contacts were located within or on the border of the STN, most of which were associated with significant improvement of the four PD symptoms tested. Therapeutic contacts located in other structures (zona incerta, lenticular fasciculus, or midbrain reticular formation) were also linked to a significant positive effect. Stimulation applied through distant contacts located in the STN improved symptoms of PD, whereas that delivered through distant contacts in the remaining structures had variable effects ranging from worsening of symptoms to their improvement. CONCLUSIONS: The authors have demonstrated that 3D atlas-MR imaging coregistration is a reliable method for the precise localization of DBS electrodes on postoperative MR images. In addition, they have confirmed that although the STN is the main target during DBS treatment for PD, stimulation of surrounding regions, particularly the zona incerta or the lenticular fasciculus, can also improve symptoms of PD.

Compulsions, Parkinson's disease, and stimulation.

Pathophysiological models suggest that obsessive compulsive disorder (OCD) might be associated with dysfunctions in cortico-striato-pallido-thalamo-cortical neuronal circuits. We implanted subthalamic electrodes to alleviate parkinsonian symptoms in two patients who had Parkinson's disease and a history of severe OCD. Parkinsonian disability improved postoperatively in both patients, and 2 weeks after the procedure, their compulsions had disappeared and obsessive symptoms improved (58% improvement for patient 1 on the Yale-Brown obsessive compulsive scale, 64% for patient 2). The improvements in these two patients suggest that high-frequency stimulation could improve function in the subcortical-limbic circuitry in patients with severe OCD.

Distribution and morphology of nigral axons projecting to the thalamus in primates.

This study presents an analysis of the distribution and organization pattern of axons originating from the substantia nigra pars reticulata and projecting to the thalamus in monkeys. Biotin dextran amine was iontophoretically injected into different parts of the substantia nigra pars reticulata of monkeys (African green monkeys and macaques). In whatever part of the substantia nigra the injection was made, numerous axonal endings were found to be distributed within different thalamic regions: the ventral anterior nucleus and mainly its magnocellular part, the most ventromedial part of the ventral lateral nucleus, and the mediodorsal and parafascicular nuclei. Moreover, the nigrothalamic projection appeared to be topographically organized. Ten anterogradely labeled axons were reconstructed from serial sections. The axons terminated in three to six terminal fields per axon located in a relatively small portion of only one thalamic region. These terminal fields were variable in size and comprised 4-43 very thin, varicose branches. They consisted either of different axonal branches of the same axon or of different axons and covered 10-31 thalamic cell bodies. These findings demonstrate that the overall morphological organization of individual nigral axons is complex and allows single axons to influence thalamic neurons via a combination of divergent, convergent, and amplification processes.