Deep brain stimulation in Parkinson's disease patients: biochemical evidence.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's disease (PD) patients augments STN-driven excitation of the internal globus pallidus (GPi). However, other DBS-induced changes are largely unknown. Here we report the biochemical effects of STN-DBS in two basal ganglia stations (putamen--PUT--and GPi) and in a thalamic relay nucleus, the anteroventral thalamus (VA). In six advanced PD patients undergoing surgery, microdialysis samples were collected from GPi, PUT and VA before, during and after one hour of STN-DBS. cGMP was measured in the GPi and PUT as an index of glutamatergic transmission, whereas GABA was measured in the VA. During clinically effective STN-DBS, we found a significant decrease in GABA extracellular concentrations in the VA (-25%). Simultaneously, cGMP extracellular concentrations were enhanced in the PUT (+200%) and GPi (+481%). DBS differentially affects fibers crossing the STN area: it activates the STN-GPi pathway while inhibiting the GPi-VA one. These findings support a thalamic dis-inhibition, as the main responsible for the clinical effect of STN-DBS. This, in turn, re-establishes a more physiological level of PUT activity.

Deep brain stimulation in Parkinson's disease: bilateral implantation of globus pallidus and subthalamic nucleus.

AIM: Deep brain stimulation (DBS) of subthalamic nucleus (STN) and of the pars interna of globus pallidus (GPi) is used to improve Parkinsonian symptoms and attenuate levodopa-induced motor complications in Parkinson's disease (PD). What are the physiological effect of DBS and the best anatomical structure to stimulate are still not completely clear. In this way we could evaluate the clinical effects of simultaneous stimulation of STN and GPi as well as the isolated stimulation of each target. METHODS: The stereotactic methods used to localise STN and GPi were based on non-telemetric ventriculography, with 3P Maranello or Leksell Stereotactic System. The effects of DBS have been assessed in 13 cases of PD, immediately after (30 minutes) the stimulation has turned on and during chronic stimulation (weeks or months). RESULTS: Most of the studies have been conducted on patients with STN implantation, and these studies reported relevant improvement in motor function and relatively low rate of complication. CONCLUSION: The large experience of ablative surgery associate with the DBS experience of some group worldwide indicate that GPi is a possible and very promising target for the management of Parkinsonian symptoms. Our patients demonstrate in acute and chronic evaluation, the best clinical results with contemporary activation of DBS in both targets.

Direct demonstration of reduction of the output of the human motor cortex induced by a fatiguing muscle contraction.

A brief period of strong muscle contraction suppresses the amplitude of EMG responses evoked in relaxed muscle by transcranial magnetic stimulation (TMS) of the contralateral motor cortex. Here we investigate this phenomenon in more detail by recording the descending motor volleys evoked by TMS from electrodes in the cervical epidural space of three conscious patients implanted with chronic electrical stimulators for control of pain. We confirm that fatigue suppresses I waves evoked by TMS. In addition, D waves were suppressed in two of the patients, suggesting that axonal excitability might also be compromised by a period of intense muscle contraction.

Direct demonstration of long latency cortico-cortical inhibition in normal subjects and in a patient with vascular parkinsonism.

OBJECTIVE: The motor evoked potential to a single suprathreshold transcranial magnetic stimulus (TMS) is suppressed by a preceding stimulus given 100-200 ms before (long latency intracortical inhibition, LICI). The effect is enhanced in patients with Parkinson's disease. Although previous studies have agreed that the effect is cortical, there is disagreement over exactly which cortical mechanisms are involved. The aim of this study was to provide further evidence for cortical involvement in LICI. METHODS: Recordings of corticospinal volleys evoked by the TMS stimulation were made from electrodes inserted into the cervical epidural space of 4 conscious subjects. Three of the patients had received the electrodes for treatment of lumbo-sacral pain; the other patient had vascular parkinsonism, and had the electrode implanted to evaluate its effect on cerebral blood flow. The number and amplitude of the volleys were compared with and without a conditioning stimulus. RESULTS: In 3 pain patients, a conditioning stimulus suppressed the later components of the corticospinal volley (I2 and later waves) when the interval between stimuli was 100-150 ms; at 50 ms the responses were enhanced. Early components of the volley were not affected. Inhibition was much more pronounced and involved all descending volleys except the D wave in the patient with vascular parkinsonism. CONCLUSIONS: LICI, which is conventionally described in EMG recordings, is also evident in recordings of descending corticospinal volleys and appears enhanced in a patient with vascular parkinsonism.

Deep brain stimulation of both subthalamic nucleus and internal globus pallidus restores intracortical inhibition in Parkinson's disease paralleling apomorphine effects: a paired magnetic stimulation study.

OBJECTIVE: We investigated the effect of bilateral subthalamic nucleus (STN) and internal globus pallidus (GPi) deep brain stimulation (DBS) on intracortical inhibition (ICI) in patients with advanced Parkinson's disease (PD). METHODS: The activity of intracortical inhibitory circuits was studied in 4 PD patients implanted with stimulating electrodes both in STN and GPi by means of paired-pulse transcranial magnetic stimulation, delivered in a conditioning-test design at short (1-6 ms) interstimulus intervals (ISI). The effect of apomorphine on the same PD patients was also investigated. RESULTS: We observed that implanted PD patients showed a significant increase in ICI during either bilateral STN or GPi DBS at 3 ms ISI, and during bilateral STN DBS at 2 ms ISI in comparison to their off DBS condition. The same statistical improvement was observed during apomorphine infusion at 3 and 2 ms ISI. In each condition, the electrophysiological changes were associated with a significant clinical improvement as measured by the Unified Parkinson's Disease Rating Scale motor examination. CONCLUSIONS: These results are consistent with the hypothesis that basal ganglia DBS can mimic the effects of pharmacological dopaminergic therapy on PD patients cortical activity. We propose that in PD patients, the basal ganglia DBS-induced improvement of ICI may be related to a recovery in modulation of thalamo-cortical motor pathway.

Deep brain stimulation (DBS) attentional effects parallel those of l-dopa treatment.

Aim of our study was to investigate the different effects on attentional capacity of deep brain stimulation DBS (STN or GPi) and of l-dopa in PD patients. Patients were evaluated on-DBS/off-l-dopa, on-l-dopa/off-DBS, on-l-dopa/on-DBS and off-l-dopa/off-DBS. Our results indicate that DBS effects on attentional functions parallel those of l-dopa. A site independent (both STN and GPi) worsening of verbal fluency was observed, possibly connected to the stimulus effect on the cortico-subcortical-cortical loop.

Atrial electroanatomic remodeling after circumferential radiofrequency pulmonary vein ablation: efficacy of an anatomic approach in a large cohort of patients with atrial fibrillation.

BACKGROUND: Circumferential radiofrequency ablation around pulmonary vein (PV) ostia has recently been described as a new anatomic approach for atrial fibrillation (AF). METHODS AND RESULTS: We treated 251 consecutive patients with paroxysmal (n=179) or permanent (n=72) AF. Circular PV lesions were deployed transseptally during sinus rhythm (n=124) or AF (n=127) using 3D electroanatomic guidance. Procedures lasted 148+/-26 minutes. Among 980 lesions surrounding individual PVs (n=956) or 2 ipsilateral veins with close openings or common ostium (n=24), 75% were defined as complete by a bipolar electrogram amplitude <0.1 mV inside the lesion and a delay >30 ms across the line. The amount of low-voltage encircled area was 3594+/-449 mm(2), which accounted for 23+/-9% of the total left atrial (LA) map surface. Major complications (cardiac tamponade) occurred in 2 patients (0.8%). No PV stenoses were detected by transesophageal echocardiography. After 10.4+/-4.5 months, 152 patients with paroxysmal AF (85%) and 49 with permanent AF (68%) were AF-free. Patients with and without AF recurrence did not differ in age, AF duration, prevalence of heart disease, or ejection fraction, but the LA diameter was significantly higher (P<0.001) in permanent AF patients with recurrence. The proportion of PVs with complete lesions was similar between patients with and without recurrence, but the latter had larger low-voltage encircled areas after radiofrequency (expressed as percent of LA surface area; P<0.001). CONCLUSIONS: Circumferential PV ablation is a safe and effective treatment for AF. Its success is likely due to both PV trigger isolation and electroanatomic remodeling of the area encompassing the PV ostia.

Intermuscular coherence in Parkinson's disease: relationship to bradykinesia.

We hypothesised that bradykinesia may be partly due to the failure of the corticomuscular system to engage in high frequency oscillatory activity in Parkinson's disease (PD). In healthy subjects such oscillations are evident in coherence between active muscles at 15--30 Hz. We therefore investigated the effects of therapeutic stimulation of the basal ganglia on this coherence and related it to changes in bradykinesia in the contralateral arm. Increases in coherence at 15--30 Hz and improvements in bradykinesia upon stimulation were correlated (r = 0.564, p < 0.001). This suggests that the basal ganglia modulate oscillatory activity in the corticomuscular system and that impairment of the motor system's ability to engage in synchronised oscillations at high frequency may contribute to bradykinesia in PD.

Microdialysis in Parkinsonian patient basal ganglia: acute apomorphine-induced clinical and electrophysiological effects not paralleled by changes in the release of neuroactive amino acids.

During stereotaxic neurosurgery for deep brain stimulation in Parkinson's disease (PD), we performed a microdialysis study of the extracellular amino acid (aspartate, glutamate, glycine, and GABA) concentrations. Their levels were measured in the GPe/GPi of five and in the STN of four different PD patients, after prolonged therapy washout. The results show stable values of basal release of the examined amino acids within 1 h. The basal levels of GABA in "OFF" state were significantly higher in the GPi than in the GPe. Acute apomorphine administration, while inducing clinical amelioration and electrophysiological changes in the examined nuclei, did not change amino acid concentrations. This result could be related to a limited microdialysis ability to detect subtle changes in amino acid spontaneous release. Alternatively, it could suggest that dopaminergic receptors located in the output nuclei, possibly present also in humans, might mediate the acute apomorphine clinical effects, not involving amino acid changes along the direct and/or indirect pathway.

Bilateral GPi DBS is useful to reduce abnormal involuntary movements in advanced Parkinson's disease patients, but its action is related to modality and site of stimulation.

In Parkinson's disease (PD) patients, internal globus pallidus (GPi) stimulation has been reported to produce good effects on abnormal involuntary movements (AIM); less improvement has been observed in extrapyramidal symptoms. We assessed the effect of monopolar dorsal (uppermost), ventral (lowest) and bipolar (uppermost vs. lowest) bilateral globus pallidus stimulation by quadripolar electrode on extrapyramidal symptoms and AIM induced by a dose of apomorphine. Six PD patients were studied in OFF therapy condition after surgery without stimulation (STIM OFF) and during stimulation (STIM ON) with the three different modalities. All patients were evaluated by the unified Parkinson's disease rating scale, section III (UPDRS) and by the AIM. Our results show that all three bilateral GPi stimulation modalities reduce the UPDRS score (between 49.7 and 31.5%), although the bipolar and lowest stimulation are the most effective. Similarly, bipolar and lowest stimulation were also the most effective in reducing the occurrence and intensity of the apomorphine-induced AIM. On the contrary, uppermost stimulation (UP ON) produced an AIM occurrence similar to that observed in the OFF stimulus condition. We suggest that bilateral GPi stimulation is an useful procedure to ameliorate extrapyramidal signs of advanced PD patients; however, it produces an antidyskinetic effect only if the ventral or the entire GPi is stimulated. On the contrary, the UP ON, most probably located in the external globus pallidus (GPe), does not modify the AIM occurrence.

Parallel processing of sensory inputs: an evoked potentials study in Parkinsonian patients implanted with thalamic stimulators.

In two drug-resistant Parkinsonian subjects, who underwent thalamic chronic stimulation for extrapyramidal symptoms relief, median nerve somatosensory evoked potentials (SEPs) were recorded before and at different times following the thalamic lead implant. In both subjects, a transient obliteration of post-rolandic SEPs components was detected; pre-rolandic waves' amplitude was preserved or showed a tendency to increase after the beginning of chronic stimulation. Parietal waves' amplitude totally recovered pre-surgical values after 1 month. Latency of both pre- and post-central components remained stable. The 'dissociate behaviour' of the examined waves following the thalamic implant reinforces the hypothesis that short-latency sensory inputs are processed by separate and independent routes which are functionally segregated at subcortical level.

Intracortical origin of the short latency facilitation produced by pairs of threshold magnetic stimuli applied to human motor cortex.

Under certain conditions, EMG responses evoked by pairs of transcranial magnetic stimuli over the motor cortex are larger than the sum of the responses to each stimulus given alone. This occurs with interstimulus intervals of around 1.3, 2.5 and 4.3 ms and could be due to interaction between the responses to each stimulus at either the cortex or spinal cord. We recorded the descending volleys set up by such pairs of stimuli from the cervical epidural space of five patients implanted with chronic stimulators for pain control. Interstimulus intervals of 1, 1.2, 1.4 and 2 ms were used to investigate the first peak of facilitation. Enhanced EMG responses occurred after pairs of stimuli at 1, 1.2 and 1.4 ms, and these were accompanied by larger and more numerous descending volleys than expected from the sum of each stimulus alone. We conclude that facilitatory interaction between the stimuli can occur within the cerebral cortex. This may involve elements that produce repetitive I-wave activity in response to a single stimulus.

Assessment of regional cerebral blood flow during spinal cord stimulation in humans.

Increased cerebral perfusion has been reported in both animal models and humans undergoing spinal cord stimulation (SCS). However, this was an inconsistent finding and variables able to influence regional cerebral blood flow (rCBF) following SCS are poorly investigated. We report our experience on rCBF measurements by the xenon-133 inhalation technique in 20 patients receiving acute and chronic SCS for different pathologies in basal conditions. Neither acute nor chronic SCS induced significant rCBF changes in the group of patients as a whole. However females, non-atherosclerotic patients and patients with a cervical SCS lead, showed a trend (borderline statistical significance) toward a redistribution of rCBF with increased values in frontoprerolandic and decreased values in postrolandic regions. Although SCS appears to influence intracerebral distribution more than absolute changes in blood flow, the mechanisms underlying such a phenomenon remain unknown. Functional activation of frontal lobes by the ascending reticular pathways through the thalamofrontal projections could be one possible hypothesis which has to be confirmed by further studies.

Cerebral blood flow and somatosensory evoked response changes induced by spinal cord stimulation: preliminary follow-up observations.

A group of 6 patients undergoing cervical spinal cord stimulation (SCS) because of different pathologies was studied. Multipolar leads (QUAD-Medtronic) were inserted percutaneously; following an SCS test period, leads were connected to a multiprogrammable, fully implantable generator (ITREL II). Neither surgical nor other side effects were found. Regional cerebral blood flow (rCBF) (xenon-133 inhalation) was determined in the basal condition and after 30 min of SCS. Somatosensory-evoked potential (SSERs) from the legs were recorded in basal conditions and after 45 min of SCS. In 2 patients SSERs could not be evaluated due to electrical noise from SCS. CBF increased mainly in anterior regions in 4/6 patients (P300 improved in 1 of them and in another case), and was unchanged in 2 patients. rCBF was retested after a mean of 9.5 months of continuous SCS with the same parameters. rCBF returned to basal values in the 4 patients showing an early flow increase; in contrast, rCBF increased in the other 2 cases without early flow changes. These preliminary data seem to support the view of an acute effect of SCS on rCBF as well as on SSER, at least in some patients. Differences in long-term rCBF modifications might depend on either the underlying pathology or on the different neuronal system involved by SCS.