Salvatore Galati

Nitric oxide modulation of the basal ganglia circuitry: therapeutic implication for Parkinson's disease and other motor disorders.

Several recent studies have emphasized a crucial role for the interactions between serotonergic and dopaminergic systems in movement control and the pathophysiology of basal ganglia. These observations are supported by anatomical evidence demonstrating large serotonergic innervation of all the basal ganglia nuclei. In fact, serotonergic terminals have been reported to make synaptic contacts with both substantia nigra dopamine-containing neurons and their terminal areas such as the striatum, the globus pallidus and the subthalamus. These brain areas contain a high concentration of serotonin (5-HT), with the substantia nigra pars reticulata receiving the greatest input. In this chapter, the distribution of different 5-HT receptor subtypes in the basal ganglia nuclei will be described. Furthermore, evidence demonstrating the serotonergic control of basal ganglia activity will be reviewed and the contribution of the different 5-HT receptor subtypes examined. The new avenues that the increasing knowledge of 5-HT in motor control has opened for exploring the pathophysiology and pharmacology of Parkinsons disease and other movement disorders will be discussed. It is clear that these avenues will be fruitful, despite the disappointing results so far obtained by clinical studies with selective 5-HT ligands. Nevertheless, these studies have led to a great increase in the attention given to the neurotransmitters of the basal ganglia and their connections.

Subthalamic stimulation activates internal pallidus: Evidence from cGMP microdialysis in PD patients

Parkinsons disease patients benefit from deep brain stimulation (DBS) in subthalamic nucleus (STN), but the basis for this effect is still disputed. In this intraoperative microdialysis study, we found elevated cGMP extracellular concentrations in the internal segment of the globus pallidus, despite negligible changes in glutamate levels, during a clinically effective STN‐DBS. This supports the view that a clinically beneficial effect of STN‐DBS is paralleled by an augmentation (and not an inactivation) of the STN output onto the GPi. Ann Neurol 2005;57:448–452

Non-motor functions in parkinsonian patients implanted in the pedunculopontine nucleus: Focus on sleep and cognitive domains

Between 2005 and 2007, six patients affected by idiopathic Parkinsons disease (IPD) were submitted to the bilateral implantation (and subsequent deep brain stimulation - DBS) of the pedunculopontine nucleus (PPN) plus the subthalamic nucleus (STN). This review synthesizes the effects of PPN low-frequency stimulation on non-motor functions, focusing on patient sleep quality and cognitive performance. If not associated to STN-DBS, PPN-DBS promoted a modest amelioration of patient motor performance. However, during PPN-DBS, they experienced on the one hand a significant improvement in executive functions and working memory, on the other hand a beneficial change in sleep architecture. Overall, the limited sample hampers definite conclusions. Yet, although the PPN-DBS induced motor effects are quite disappointing (discouraging extended trials based upon the sole PPN implantation), the neuropsychological profile supports the contention by which in selected PD patients, with subtle cognitive deficits or vanished efficacy of previous implanted STN, PPN-DBS might still represent a reliable and compassionate option.

Multi-target strategy for Parkinsonian patients : The role of deep brain stimulation in the centromedian-parafascicularis complex

The intra-laminar (IL) thalamic complex, composed of centromedian (CM) and parafascicular (Pf) nucleus, is a strategic crossroad for the activity of the basal ganglia and is recently regaining its position has a putative neurosurgical target for Parkinsonian syndromes. The multi-target approach we have encouraged since the late nineties has allowed the combined implantation of a standard target (the subthalamic nucleus-STN or the internal pallidus-GPi) plus an innovative one (CM/Pf) in well-identified Parkinsons disease (PD) patients; hence, it is possible to study, in the same PD patients, the specific target-mediated effects on different clinical signs. Here, we focus on the potential usefulness of implanting the CM/Pf complex when required in the management of contra-lateral tremor (resistant to standard deep brain stimulation-DBS - in STN - , n=2) and disabling involuntary movements, partially responsive to GPi-DBS (n=6). When considering global UPDRS scores, CM/Pf-DBS ameliorate extra-pyramidal symptoms but not as strongly as STN (or GPi) does. Yet, CM/Pf acts very powerfully on tremor and contributes to the long-term management of l-Dopa-induced involuntary movements. The lack of cognitive deficits and psychic impairment associated with the improvement of their quality of life, in our small cohort of CM/Pf implanted patients, reinforces the notion of CM/Pf as a safe and attractive area for surgical treatment of advanced PD, possibly affecting not only motor but also associative functions.

High-frequency stimulation of the subthalamic nucleus modulates the activity of pedunculopontine neurons through direct activation of excitatory fibres as well as through indirect activation of inhibitory pallidal fibres in the rat

Recent data suggest a potential role of pedunculopontine nucleus (PPN) electrical stimulation in improving gait and posture in Parkinsons disease. Because the PPN receives fibres from the subthalamic nucleus (STN), we investigated the effects of STN‐high‐frequency stimulation (HFS) on PPN neuronal activity in intact rats and in rats bearing either an ibotenate lesion of the entopeduncular nucleus (EP) or a lesion of the substantia nigra (SN). The main response of PPN neurons to STN single‐shock stimulations in the three experimental groups was a short latency (4.5 ± 2.1 ms) and brief (15.3 ± 6.5 ms) excitation. This response was maintained during 1–5 s of STN‐HFS (130 Hz, 60 µs, 100–1000 µA). In EP‐lesioned rats the percentage (75.0%) of PPN neurons showing a modulation of activity following STN‐HFS was significantly higher compared with that observed in intact (39.7%) and in SN‐lesioned rats (35.4%). Furthermore, in EP‐lesioned rats the most frequent response of PPN neurons following STN‐HFS was a 5–20 s excitation, which was present in 76.6% of responsive neurons in comparison to 15.4% and 9.1% of neurons responsive in intact and in 6‐hydroxydopamine‐lesioned rats, respectively. Neurons responsive to STN‐HFS in the three experimental groups showed either a sharp positively skewed distribution of interspike intervals or multisecond oscillations in autocorrelograms. The results support that STN‐HFS modulates the PPN through a balance of excitatory and inhibitory influences, which may be independent from the dopaminergic nigral neurons. In the absence of inhibitory EP fibres, the direct excitatory influence exerted by the STN on the PPN appears to predominate.

Pedunculopontine nucleus stimulation influences REM sleep in Parkinson’s disease

OBJECTIVE: To investigate the sleep-wake cycle and the effects of cabergoline monotherapy in a homogenous group of de novo Parkinsons Disease (PD) patients without confounding comorbid factors. DESIGN AND PARTICIPANTS: Twelve de novo patients affected by idiopathic PD underwent two ambulatory polysomnographic (APSG)monitoring sessions. The first was performed at baseline, and the second recording one-month after stable treatment with cabergoline monotherapy. Subjective daytime sleepiness was evaluated by means of the Epworth Sleepiness Scale.Data obtained in PD patients at baseline were compared with those obtained in 12 age- and sex-matched healthy subjects. RESULTS: Diurnal sleep parameters did not show significant differences between controls and PD patients at baseline. In PD patients, no significant changes in diurnal sleep were observed between baseline and cabergoline treatment. Regarding nocturnal sleep, patients at baseline showed a significantly lower sleep efficiency and a significantly higher Wakefulness After Sleep Onset than controls. With respect to baseline, a significant increase in REM latency and a significant reduction in REM sleep were observed during cabergoline treatment. CONCLUSIONS: In the early stage of PD, the neurodegenerative process does not seem to be directly responsible for daytime somnolence, but it may be directly involved in the alteration of nocturnal sleep. Cabergoline monotherapy does not affect daytime sleep propensity and, despite clinical improvement, it may have negative effects on REM sleep.

Central acute D2 stimulation worsens bladder function in patients with mild Parkinson's disease.

PURPOSE The different roles of D1 and D2 dopamine receptors in LUT behavior have been demonstrated in animal studies. In particular D2 selective agonists and D1 selective antagonists seem to produce a reduction of the bladder capacity in conscious rats. This finding has never been confirmed in human studies. Thus, in this study we investigated the role of D1 and D2 agonists/antagonists on LUT behavior in patients with PD. MATERIALS AND METHODS A total of 87 patients with mild PD were evaluated. Patients were evaluated with urodynamic studies (cystometry followed by a pressure flow study with perineal floor electromyography) performed in off status and after oral administration of 250 mg of LD. In 70 patients a third urodynamic evaluation was conducted in one of the following conditions: after simultaneous administration of 250 mg oral LD and 60 or 120 mg oral domperidone (D2 peripheral antagonist); after simultaneous administration of 250 mg oral LD and 25, 50 or 150 mg intramuscular L-sulpiride (D2 central and peripheral antagonist). Several urodynamic parameters were evaluated and results obtained in different conditions compared. RESULTS LD alone worsened detrusor overactivity: in particular, a reduction of first urinary sensation, involuntary detrusor contraction threshold (reflex volume) and bladder capacity was observed. L-sulpiride (central and peripheral D2 antagonist) coadministration counteracted the worsening in a dose dependent manner. Domperidone (peripheral D2 antagonist) coadministration failed to determine the same counteraction. CONCLUSIONS According to our results, a central acute D2 stimulation seems to be responsible of a reduction of bladder capacity with worsening of detrusor overactivity in patients with mild PD.

Effect of Vigabatrin on motor responses to transcranial magnetic stimulation: An effective tool to investigate in vivo GABAergic cortical inhibition in humans

In this study, transcranial magnetic stimulation (TMS) of the hand primary motor area was used to test possible excitability changes induced by the administration of Vigabatrin (Gamma-Vinyl-gamma-aminobutryic acid;4-amino-hex-5-enoic acid; GVG), a selective GABAergic drug, on cortical inhibitory mechanisms in healthy subjects. In a group of 15 healthy volunteers, the level of motor cortical excitability was studied by means of paired-pulse TMS (p-TMS) protocols exploring the early (1-6 ms of interstimulus intervals, ISI) and the late cortical inhibition (20-250 ms ISI), and by evaluating the cortical silent period (CSP) duration obtained in response to single pulse stimulation of cortical motor area. In all participants TMS procedures were carried out before and after administering GVG for three consecutive days at a daily dosage of 50 mg/kg. Three months later, a third TMS recording session was repeated to investigate possible long-lasting GVG effects on cortical excitability. GVG induces relevant changes of cortical excitability consisting in an increase of late cortical inhibition in response to the long ISI p-TMS and in a prolonged duration of the CSP. No significant change in the early cortical inhibition was observed in response to the short ISI p-TMS. The analysis of peripheral motor excitability was also assessed, with no effects. The present electrophysiological data show that GVG is able to induce a significant increase of the late cortical inhibition, whereas it does not affect the early cortical inhibition. These data suggest that the great availability of synaptic GABA differently acts on the inhibitory circuitries controlled by different GABA-receptor subtypes.

Dynamic changes of anandamide in the cerebrospinal fluid of Parkinson's disease patients

A correct balance between endocannabinoid and dopamine‐dependent systems is believed to underlie physiological motor control. We measured the levels of the endocannabinoid anandamide in the cerebrospinal fluid of Parkinsons disease (PD) patients. Subjects were divided into three groups: newly diagnosed de novo patients, subjects undergoing drug withdrawal, and patients under pharmacological therapy. These groups were compared to age‐matched control subjects. Anandamide levels in untreated patients were more than doubled as compared to controls. However, chronic dopaminergic replacement restored control anandamide levels. Abnormal anandamide increase might reflect a compensatory mechanism occurring in course of PD, aimed at normalizing dopamine depletion.

Correlation between changes in CSF dopamine turnover and development of dyskinesia in Parkinson's disease

To assess possible differences in dopamine metabolism that could parallel disease progression in Parkinsons disease (PD), we measured dopamine (DA) and its metabolites in the cerebrospinal fluid (CSF) in PD patients at different stages of disease: de novo (DEN), advanced not showing dyskinesias (ADV), and advanced with dyskinesias (DYS). DA, homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) were significantly higher in DEN patients compared with other groups. A negative exponential correlation related DA level and disease duration. The HVA/DA ratio was significantly higher in the ADV and DYS group than that found in DEN group. Our data show that disease progression produces an early large decay of DA levels, followed by a stabilization. On the contrary, a late change in DA turnover (increased HVA/DA ratio) is documented in patients with longer disease duration. Our results suggest that the appearance of dyskinesia may not be related to a further loss of DA terminals but to a different, abnormal, DA turnover.