Manuela Rosa

Progression of multiple system atrophy (MSA): A prospective natural history study by the European MSA study group (EMSA SG)

The disease‐specific Unified Multiple System Atrophy Rating Scale (UMSARS) has been developed recently and validated for assessing disease severity in multiple system atrophy (MSA). Here, we aimed at (1) assessing rates of disease progression in MSA and (2) validating UMSARS for sensitivity to change over time. Impairment was assessed at two time points 12 months apart using UMSARS Part I (historical review), UMSARS Part II (motor examination), as well as measures of global disease severity, including UMSARS Part IV, Hoehn and Yahr (HY) Parkinsons disease staging, Schwab England Activities of Daily Living (SE ADL), and a three‐point global Severity Scale (SS3). Fifty patients (male:female ratio, 1:0.9; possible MSA, 16%; probable MSA, 84%; MSA‐parkinsonian, 58%; MSA‐cerebellar, 42%) were assessed twice with an interval of 12.3 months. UMSARS II scores progressed by 57.3% (P < 0.0001) and UMSARS I scores by 35.6% (P < 0.0001) in relation to the respective baseline scores with no differences between motor subtypes, diagnostic categories and gender. Significant inverse correlations between (1) UMSARS I or UMSARS II progression and (2) baseline disability measures (i.e., the respective UMSARS or SS3 scores) and disease duration were found. Furthermore, the increases in HY staging, SE ADL and SS3 correlated significantly with UMSARS I, UMSARS II, and UMSARS IV progression. This report is the first prospective study showing rapid annual UMSARS rates of decline in MSA. Our data contribute to the ongoing validation process of UMSARS, and they facilitate the planning and implementation of future neuroprotective intervention trials.

Cerebellum and processing of negative facial emotions: Cerebellar transcranial DC stimulation specifically enhances the emotional recognition of facial anger and sadness

Some evidence suggests that the cerebellum participates in the complex network processing emotional facial expression. To evaluate the role of the cerebellum in recognising facial expressions we delivered transcranial direct current stimulation (tDCS) over the cerebellum and prefrontal cortex. A facial emotion recognition task was administered to 21 healthy subjects before and after cerebellar tDCS; we also tested subjects with a visual attention task and a visual analogue scale (VAS) for mood. Anodal and cathodal cerebellar tDCS both significantly enhanced sensory processing in response to negative facial expressions (anodal tDCS, p=.0021; cathodal tDCS, p=.018), but left positive emotion and neutral facial expressions unchanged (p>.05). tDCS over the right prefrontal cortex left facial expressions of both negative and positive emotion unchanged. These findings suggest that the cerebellum is specifically involved in processing facial expressions of negative emotion.

The European Multiple System Atrophy-Study Group (EMSA-SG)

Summary.Introduction. The European Multiple System Atrophy-Study Group (EMSA-SG) is an academic network comprising 23 centers across Europe and Israel that has constituted itself already in January 1999. This international forum of established experts under the guidance of the University Hospital of Innsbruck as coordinating center is supported by the 5th framework program of the European Union since March 2001 (QLK6-CT-2000-00661). Objectives. Primary goals of the network include (1) a central Registry for European multiple system atrophy (MSA) patients, (2) a decentralized DNA Bank, (3) the development and validation of the novel Unified MSA Rating Scale (UMSARS), (4) the conduction of a Natural History Study (NHS), and (5) the planning or implementation of interventional therapeutic trials. Methods. The EMSA-SG Registry is a computerized data bank localized at the coordinating centre in Innsbruck collecting diagnostic and therapeutic data of MSA patients. Blood samples of patients and controls are recruited into the DNA Bank. The UMSARS is a novel specific rating instrument that has been developed and validated by the EMSA-SG. The NHS comprises assessments of basic anthropometric data as well as a range of scales including the UMSARS, Unified Parkinson’s Disease Rating Scale (UPDRS), measures of global disability, Red Flag list, MMSE (Mini Mental State Examination), quality of live measures, i.e. EuroQoL 5D (EQ-5D) and Medical Outcome Study Short Form (SF-36) as well as the Beck Depression Inventory (BDI). In a subgroup of patients dysautonomic features are recorded in detail using the Queen Square Cardiovascular Autonomic Function Test Battery, the Composite Autonomic Symptom Scale (COMPASS) and measurements of residual urinary volume. Most of these measures are repeated at 6-monthly follow up visits for a total study period of 24 months. Surrogate markers of the disease progression are identified by the EMSA-SG using magnetic resonance and diffusion weighted imaging (MRI and DWI, respectively). Results. 412 patients have been recruited into the Registry so far. Probable MSA-P was the most common diagnosis (49% of cases). 507 patients donated DNA for research. 131 patients have been recruited into the NHS. There was a rapid deterioration of the motor disorder (in particular akinesia) by 26.1% of the UMSARS II, and – to a lesser degree – of activities of daily living by 16.8% of the UMSARS I in relation to the respective baseline scores. Motor progression was associated with low motor or global disability as well as low akinesia or cerebellar subscores at baseline. Mental function did not deteriorate during this short follow up period. Conclusion. For the first time, prospective data concerning disease progression are available. Such data about the natural history and prognosis of MSA as well as surrogate markers of disease process allow planning and implementation of multi-centre phase II/III neuroprotective intervention trials within the next years more effectively. Indeed, a trial on growth hormone in MSA has just been completed, and another on minocycline will be completed by the end of this year.

Subthalamic Local Field Beta Oscillations during Ongoing Deep Brain Stimulation in Parkinson's Disease in Hyperacute and Chronic Phases

In the past years, local field potential (LFP) signals recorded from the subthalamic nucleus (STN) in patients undergoing deep brain stimulation (DBS) for Parkinson’s disease (PD) disclosed that DBS has a controversial effect on STN beta oscillations recorded 2–7 days after surgery for macroelectrode implantation. Nothing is known about these DBS-induced oscillatory changes 30 days after surgery. We recorded STN LFPs during ongoing DBS in 7 patients with PD, immediately (hyperacute phase) and 30 days (chronic phase) after surgery. STN LFP recordings showed stationary intranuclear STN beta LFP activity in hyperacute and chronic phases, confirming that beta peaks were also present in chronic recordings. Power spectra of nuclei with significant beta activity (54% of the sample) showed that it decreased significantly during DBS (p = 0.021) under both recording conditions. The time course of beta activity showed more evident DBS-induced changes in the chronic than in the hyperacute phase (p = 0.014). DBS-induced changes in STN beta LFPs in patients undergoing DBS in chronic phase provide useful information for developing a new neurosignal-controlled adaptive DBS system.

Conflict-dependent dynamic of subthalamic nucleus oscillations during moral decisions.

Although lesional, neuroimaging, and brain stimulation studies have provided an insight into the neural mechanisms of judgement and decision-making, all these works focused on the cerebral cortex, without investigating the role of subcortical structures such as the basal ganglia. Besides being an effective therapeutic tool, deep brain stimulation (DBS) allows local field potential (LFP) recordings through the stimulation electrodes thus providing a physiological “window” on human subcortical structures. In this study we assessed whether subthalamic nucleus LFP oscillations are modulated by processing of moral conflictual, moral nonconflictual, and neutral statements. To do so, in 16 patients with Parkinsons disease (8 men) bilaterally implanted with subthalamic nucleus (STN) electrodes for DBS, we recorded STN LFPs 4 days after surgery during a moral decision task. During the task, recordings from the STN showed changes in LFP oscillations. Whereas the 14–30 Hz band (beta) changed during the movement executed to perform the task, the 5–13 Hz band (low-frequency) changed when subjects evaluated the content of statements. Low-frequency band power increased significantly more during conflictual than during nonconflictual or neutral sentences. We conclude that STN responds specifically to conflictual moral stimuli, and could be involved in conflictual decisions of all kinds, not only those for moral judgment. LFP oscillations provide novel direct evidence that the neural processing of conflictual decision-making spreads beyond the cortex to the basal ganglia and encompasses a specific subcortical conflict-dependent component.

Subthalamic local field potentials after seven-year deep brain stimulation in Parkinson's disease.

Studies describing subthalamic (STN) local field potentials (LFPs) recorded during deep brain stimulation (DBS) in patients with Parkinsons disease (PD), within the first month after DBS electrode implant, show that DBS modulates specific STN oscillations: whereas low-frequency (LF) oscillations (2-7 Hz) increase, beta oscillations (8-30 Hz) variably decrease. No data show whether LFPs remain stable for longer than one month after DBS surgery. Having long-term information is essential especially for use as a long-term feedback control signal for adaptive DBS systems. To evaluate how STN activity behaves years after prolonged chronic stimulation in PD we studied STN LFPs at rest without DBS and during ongoing DBS, in 11 parkinsonian patients 7 years (7.54±1.04) after STN electrode implantation for DBS (hyperchronic group) and in 16 patients 3 days after STN electrode implantation (acute group). STN LF and beta-band LFPs recorded at rest at 7 years contained almost the same information as those recorded at 3 days. STN recordings showed similar LFP responses to DBS in the acute and hyperchronic stages: whereas during ongoing DBS the LF power band increased for the whole population, beta activity decreased only in nuclei with significant beta activity at baseline. The LF/beta power ratio in all nuclei changed in both study groups, suggesting that this variable might be an even more informative marker of PD than the single LF and beta bands. Because STN LFP activity patterns and STN LFP responses to DBS stay almost unchanged for years after DBS electrode implantation they should provide a consistent feedback control signal for adaptive DBS.

Neurophysiology of deep brain stimulation.

We review the data concerning the neurophysiology of deep brain stimulation (DBS) in humans, especially in reference to Parkinsons disease. The electric field generated by DBS interacts with the brain in complex ways, and several variables could influence the DBS-induced biophysical and clinical effects. The neurophysiology of DBS comprises the DBS-induced effects per se as well as neurophysiological studies designed to record electrical activity directly from the basal ganglia (single-unit or local field potential) through the electrodes implanted for DBS. In the subthalamic nucleus, DBS locally excites and concurrently inhibits at single-unit level, synchronizes low-frequency activity, and desynchronizes beta activity and also induces neurochemical changes in cyclic guanosine monophosphate (cGMP) and GABA concentrations. DBS-induced effects at system level can be studied through evoked potentials, autonomic tests, spinal cord segmental system, motor cortical and brainstem excitability, gait, and decision-making tasks. All these variables are influenced by DBS, suggesting also distant effects on nonmotor structures of the brain. Last, advances in understanding the neurophysiological mechanisms underlying DBS led researchers to develop a new adaptive DBS technology designed to adapt stimulation settings to the individual patients clinical condition through a closed-loop system controlled by signals from the basal ganglia.

Pathological gambling in Parkinson's disease: Subthalamic oscillations during economics decisions

Pathological gambling develops in up to 8% of patients with Parkinsons disease. Although the pathophysiology of gambling remains unclear, several findings argue for a dysfunction in the basal ganglia circuits. To clarify the role of the subthalamic nucleus in pathological gambling, we studied its activity during economics decisions. We analyzed local field potentials recorded from deep brain stimulation electrodes in the subthalamic nucleus while parkinsonian patients with (n = 8) and without (n = 9) pathological gambling engaged in an economics decision‐making task comprising conflictual trials (involving possible risk‐taking) and non conflictual trials. In all parkinsonian patients, subthalamic low frequencies (2–12 Hz) increased during economics decisions. Whereas, in patients without gambling, low‐frequency oscillations exhibited a similar pattern during conflictual and non conflictual stimuli, in those with gambling, low‐frequency activity increased significantly more during conflictual than during non conflictual stimuli. The specific low‐frequency oscillatory pattern recorded in patients with Parkinsons disease who gamble could reflect a subthalamic dysfunction that makes their decisional threshold highly sensitive to risky options. When parkinsonian patients process stimuli related to an economics task, low‐frequency subthalamic activity increases. This task‐related change suggests that the cognitive‐affective system that drives economics decisional processes includes the subthalamic nucleus. The specific subthalamic neuronal activity during conflictual decisions in patients with pathological gambling supports the idea that the subthalamic nucleus is involved in behavioral strategies and in the pathophysiology of gambling.

The adaptive deep brain stimulation challenge.

Sub-optimal clinical outcomes of conventional deep brain stimulation (cDBS) in treating Parkinsons Disease (PD) have boosted the development of new solutions to improve DBS therapy. Adaptive DBS (aDBS), consisting of closed-loop, real-time changing of stimulation parameters according to the patients clinical state, promises to achieve this goal and is attracting increasing interest in overcoming all of the challenges posed by its development and adoption. In the design, implementation, and application of aDBS, the choice of the control variable and of the control algorithm represents the core challenge. The proposed approaches, in fact, differ in the choice of the control variable and control policy, in the system design and its technological limits, in the patients target symptom, and in the surgical procedure needed. Here, we review the current proposals for aDBS systems, focusing on the choice of the control variable and its advantages and drawbacks, thus providing a general overview of the possible pathways for the clinical translation of aDBS with its benefits, limitations and unsolved issues.

Increased short latency afferent inhibition after anodal transcranial direct current stimulation.

Transcranial direct current stimulation (tDCS), a technique for central neuromodulation, has been recently proposed as possible treatment in several neurological and psychiatric diseases. Although shifts on focal brain excitability have been proposed to explain the clinical effects of tDCS, how tDCS-induced functional changes influence cortical interneurones is still largely unknown. The assessment of short latency afferent inhibition (SLAI) of motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS), provides the opportunity to test non-invasively interneuronal cholinergic circuits in the human motor cortex. The aim of the present study was to assess whether anodal tDCS can modulate interneuronal circuits involved in SLAI. Resting motor threshold (RMT), amplitude of unconditioned MEPs and SLAI were assessed in the dominant hemisphere of 12 healthy subjects (aged 21-37) before and after anodal tDCS (primary motor cortex, 13min, 1mA). SLAI was assessed delivering electrical conditioning stimuli to the median nerve at the wrist prior to test TMS given at the interstimulus interval (ISI) of 2ms. Whereas RMT and the amplitude of unconditioned MEPs did not change after anodal tDCS, SLAI significantly increased. In conclusion, anodal tDCS-induced effects depend also on the modulation of cortical interneuronal circuits. The enhancement of cortical cholinergic activity assessed by SLAI could be an important mechanism explaining anodal tDCS action in several pathological conditions.