Revisiting Forel Field Surgery.

BACKGROUND: Lesioning the Forel field or the subthalamic region is considered a possible treatment for tremoric patients with Parkinson disease, essential tremor, and other diseases. This surgical treatment was performed in the 1960s to 1970s and was an alternative to thalamotomy. Recently, there has been increasing interest in the reappraisal of stimulating and/or lesioning these targets, partly as a result of innovations in imaging and noninvasive ablative technologies, such as magnetic resonance-guided focused ultrasonography. OBJECTIVE: We wanted to perform a thorough review of the subthalamic region, both from an anatomic and a surgical standpoint, to offer a comprehensive and updated analysis of the techniques and results reported for patients with tremor treated with different techniques. METHODS: We performed a systematic review of the literature, gathering articles that included patients who underwent ablative or stimulation surgical techniques, targeting the pallidothalamic pathways (pallidothalamic tractotomy), cerebellothalamic pathway (cerebellothalamic tractotomy), or subthalamic area. RESULTS: Pallidothalamic tractotomy consists of a reduced area that includes pallidofugal pathways. It may be considered an interesting target, given the benefit/risk ratio and the clinical effect, which, compared with pallidotomy, involves a lower risk of injury or involvement of vital structures such as the internal capsule or optic tract. Cerebellothalamic tractotomy and/or posterior subthalamic area are other alternative targets to thalamic stimulation or ablative surgery. CONCLUSIONS: Based on the significant breakthrough that magnetic resonance-guided focused ultrasonography has meant in the neurosurgical world, some classic targets such as the pallidothalamic tract, Forel field, and posterior subthalamic area may be reconsidered as surgical alternatives for patients with movement disorders.

Transient increased thalamic-sensory connectivity and decreased whole-brain dynamism in autism.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with social communication deficits and restricted/repetitive behaviors and is characterized by large-scale atypical subcortical-cortical connectivity, including impaired resting-state functional connectivity between thalamic and sensory regions. Previous studies have typically focused on the abnormal static connectivity in ASD and overlooked potential valuable dynamic patterns in brain connectivity. However, resting-state brain connectivity is indeed highly dynamic, and abnormalities in dynamic brain connectivity have been widely identified in psychiatric disorders. In this study, we investigated the dynamic functional network connectivity (dFNC) between 51 intrinsic connectivity networks in 170 individuals with ASD and 195 age-matched typically developing (TD) controls using independent component analysis and a sliding window approach. A hard clustering state analysis and a fuzzy meta-state analysis were conducted respectively, for the exploration of local and global aberrant dynamic connectivity patterns in ASD. We examined the group difference in dFNC between thalamic and sensory networks in each functional state and group differences in four high-dimensional dynamic measures. The results showed that compared with TD controls, individuals with ASD show an increase in transient connectivity between hypothalamus/subthalamus and some sensory networks (right postcentral gyrus, bi paracentral lobule, and lingual gyrus) in certain functional states, and diminished global meta-state dynamics of the whole-brain functional network. In addition, these atypical dynamic patterns are significantly associated with autistic symptoms indexed by the Autism Diagnostic Observation Schedule. These converging results support and extend previous observations regarding hyperconnectivity between thalamic and sensory regions and stable whole-brain functional configuration in ASD. Dynamic brain connectivity may serve as a potential biomarker of ASD and further investigation of these dynamic patterns might help to advance our understanding of behavioral differences in this complex neurodevelopmental disorder.

Modulation of the cerebello-thalamo-cortical network in thalamic deep brain stimulation for tremor: a diffusion tensor imaging study.

BACKGROUND: Deep brain stimulation alleviates tremor of various origins. Several regions like the ventralis intermediate nucleus of thalamus, the caudal zona incerta, and the posterior subthalamic region are generally targeted. Previous work with fiber tractography has shown the involvement of the cerebello-thalamo-cortical network in tremor control. OBJECTIVE: To report the results of a prospective trial in a group of patients with tremor who underwent post hoc tractographic analysis after treatment with traditional thalamic deep brain stimulation. METHODS: A total of 11 patients (aged 64 ± 17 years, 6 male) were enrolled (essential tremor [6], Parkinson tremor [3], and myoclonic tremor in myoclonus dystonia [2]). Patients received 1 (3 patients), 2 (7 patients), or 3 (1 patient) quadripolar electrodes. A 32-direction diffusion tensor magnetic resonance imaging sequence was acquired preoperatively. Tractography was processed postoperatively for evaluation and the dentato-rubro-thalamic tract (DRT) was individually tracked. Electrode positions were determined with helical computed tomography. Electric fields (EFs) were simulated according to individual stimulation parameters in a standardized atlas brain space (ICBM-MNI 152). RESULTS: Tremor was reduced in all patients (69.4% mean) on the global (bilateral) tremor score. Effective contacts were located inside or in proximity to the DRT. In moderate tremor reduction (2 patients), the EFs were centered on its anterior border. In good and excellent tremor reduction (9 patients), EFs focused on its center. CONCLUSION: Deep brain stimulation of the cerebello-thalamo-cortical network reduces tremor. The DRT connects 3 traditional target regions for deep brain stimulation in tremor disease. Tractography techniques can be used to directly visualize the DRT and, therefore, optimize target definition in individual patients.

Individualized current-shaping reduces DBS-induced dysarthria in patients with essential tremor.

OBJECTIVE: To investigate in patients with essential tremor (ET) treated with thalamic/subthalamic deep brain stimulation (DBS) whether stimulation-induced dysarthria (SID) can be diminished by individualized current-shaping with interleaving stimulation (cs-ILS) while maintaining tremor suppression (TS). METHODS: Of 26 patients screened, 10 reported SID and were invited for testing. TS was assessed by the Tremor Rating Scale and kinematic analysis of postural and action tremor. SID was assessed by phonetic and logopedic means. Additionally, patients rated their dysarthria on a visual analog scale. RESULTS: In 6 of the 10 patients with ET, DBS-ON (relative to DBS-OFF) led to SID while tremor was successfully reduced. When comparing individualized cs-ILS with a non-current-shaped interleaving stimulation (ILS) in these patients, there was no difference in TS while 4 of the 6 patients showed subjective improvement of speech during cs-ILS. Phonetic analysis (ILS vs cs-ILS) revealed that during cs-ILS there was a reduction of voicing during the production of voiceless stop consonants and also a trend toward an improvement in oral diadochokinetic rate, reflecting less dysarthria. Logopedic rating showed a trend toward deterioration in the diadochokinesis task when comparing ON with OFF but no difference between ILS and cs-ILS. CONCLUSION: This is a proof-of-principle evaluation of current-shaping in patients with ET treated with thalamic/subthalamic DBS and experiencing SID. Data suggest a benefit on SID from individual shaping of current spread while TS is preserved. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in patients with ET treated with DBS with SID, individualized cs-ILS reduces dysarthria while maintaining tremor control.

Expanded functional coupling of subcortical nuclei with the motor resting-state network in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) impairs signal transmission along cortico-cortical and cortico-subcortical connections, affecting functional integration within the motor network. Functional magnetic resonance imaging (fMRI) during motor tasks has revealed altered functional connectivity in MS, but it is unclear how much motor disability contributed to these abnormal functional interaction patterns. OBJECTIVE: To avoid any influence of impaired task performance, we examined disease-related changes in functional motor connectivity in MS at rest. METHODS: A total of 42 patients with MS and 30 matched controls underwent a 20-minute resting-state fMRI session at 3 Tesla. Independent component analysis was applied to the fMRI data to identify disease-related changes in motor resting-state connectivity. RESULTS: Patients with MS showed a spatial expansion of motor resting-state connectivity in deep subcortical nuclei but not at the cortical level. The anterior and middle parts of the putamen, adjacent globus pallidus, anterior and posterior thalamus and the subthalamic region showed stronger functional connectivity with the motor network in the MS group compared with controls. CONCLUSION: MS is characterised by more widespread motor connectivity in the basal ganglia while cortical motor resting-state connectivity is preserved. The expansion of subcortical motor resting-state connectivity in MS indicates less efficient funnelling of neural processing in the executive motor cortico-basal ganglia-thalamo-cortical loops.

Kinematic analysis of thalamic versus subthalamic neurostimulation in postural and intention tremor.

Deep brain stimulation of the thalamus (thalamic DBS) is an established therapy for medically intractable essential tremor and tremor caused by multiple sclerosis. In both disorders, motor disability results from complex interaction between kinetic tremor and accompanying ataxia with voluntary movements. In clinical studies, the efficacy of thalamic DBS has been thoroughly assessed. However, the optimal anatomical target structure for neurostimulation is still debated and has never been analysed in conjunction with objective measurements of the different aspects of motor impairment. In 10 essential tremor and 11 multiple sclerosis patients, we analysed the effect of thalamic DBS through each contact of the quadripolar electrode on the contralateral tremor rating scale, accelerometry and kinematic measures of reach-to-grasp-movements. These measures were correlated with the anatomical position of the stimulating electrode in stereotactic space and in relation to nuclear boundaries derived from intraoperative microrecording. We found a significant impact of the stereotactic z-coordinate of stimulation contacts on the TRS, accelerometry total power and spatial deviation in the deceleration and target period of reach-to-grasp-movements. Most effective contacts clustered within the subthalamic area (STA) covering the posterior Zona incerta and prelemniscal radiation. Stimulation within this region led to a mean reduction of the lateralized tremor rating scale by 15.8 points which was significantly superior to stimulation within the thalamus (P < 0.05, student's t-test). STA stimulation resulted in reduction of the accelerometry total power by 99%, whereas stimulation at the ventral thalamic border (68%) or within the thalamus proper (2.5%) was significantly less effective (P < 0.01). Concomitantly, STA stimulation led to a significantly higher increase of tremor frequency and decrease in EMG synchronization compared to stimulation within the thalamus proper (P < 0.001). In reach-to-grasp movements, STA stimulation reduced the spatial variability of the movement path in the deceleration period by 28.9% and in the target period by 58.4%, whereas stimulation within the thalamus was again significantly less effective (P < 0.05), with a reduction in the deceleration period between 6.5 and 21.8% and in the target period between 1.2 and 11.3%. An analysis of the nuclear boundaries from intraoperative microrecording confirmed the anatomical impression that most effective electrodes were located within the STA. Our data demonstrate a profound effect of deep brain stimulation of the thalamic region on tremor and ataxia in essential tremor and tremor caused by multiple sclerosis. The better efficacy of stimulation within the STA compared to thalamus proper favours the concept of a modulation of cerebello-thalamic projections underlying the improvement of these symptoms.

The time course of the return of upper limb bradykinesia after cessation of subthalamic stimulation in Parkinson's disease.

To investigate the time span within which bradykinesia re-occurs, we registered movement parameters immediately after the termination of deep brain stimulation of the subthalamic nucleus (STN) in nine Parkinson patients with chronically implanted bilateral STN electrodes. Two repetitive movements were investigated: finger-tapping and forearm pronation-supination. When stimulation was switched off, the amplitude and velocity of the investigated movements significantly declined, but the frequency did not. The time course of this decline was modeled by an exponential function that yielded time constants between 15 and 30s. The effect of stimulation had completely disappeared within 1 min. These results suggest that it is necessary to wait at least for 1 min after the end of stimulation before performing further assessments.

Neurological control of human sexual behaviour: insights from lesion studies.

We review the human literature examining the effects of neurological insult on human sexual behaviour. We provide a synthesis of the findings to date, and identify key brain regions associated with specific aspects of human sexual behaviour. These include subcortical and cortical regions, with the mesial temporal lobe and the amygdala in particular being a crucial structure in the mediation of human sexual drive.

Effects of stimulation of the subthalamic area on oscillatory pallidal activity in Parkinson's disease.

The pattern of neuronal discharge within the basal ganglia is disturbed in Parkinson's disease (PD). In particular, there is a tendency for neuronal elements to synchronise at around 20 Hz in the absence of dopaminergic treatment, whereas this activity can be replaced by spontaneous synchronisation at much higher frequencies (>70 Hz) following dopaminergic treatment [J. Neurosci. 21 (2001) 1033; Brain 126 (2003) 2153]. In two PD patients (3 sides), we show that stimulating the subthalamic area at around 20 Hz exacerbates synchronisation at similar frequencies in the globus pallidus interna, the major output structure of the human basal ganglia. In contrast, stimulating the subthalamic area at >70 Hz suppresses pallidal activity at about 20 Hz. Clinically, stimulation of the subthalamic area at similar high frequencies reverses parkinsonism and forms the basis of therapeutic deep brain stimulation in PD. The results point to a possible common mechanism by which both dopaminergic treatment associated synchronisation of subthalamic activity at very high frequency and synchronisation imposed by therapeutic stimulation of the subthalamic area inhibit an abnormal and potentially deleterious synchronisation of basal ganglia output at around 20 Hz. If this activity is unchecked by synchronisation at higher frequency, then pathological 20-Hz oscillations may cascade through the basal ganglia, increasing at subsequent levels of processing.

Autonomic and emotional responses to open and hidden stimulations of the human subthalamic region.

We performed a microstimulation study of the subthalamic region of Parkinsonian patients who underwent bilateral electrode implantation in the subthalamic nuclei and whose heart rate and heart rate variability were recorded. The stimulation of the dorsalmost region, which includes the zona incerta and the dorsal pole of the subthalamic nucleus, produced autonomic responses that were constant over time. In fact, hidden stimulations (the patient is not aware of being stimulated) and open stimulations (the patient is aware of being stimulated) always induced the same responses. By contrast, the stimulation of the ventralmost region, which includes the ventral pole of the subthalamic nucleus and the substantia nigra pars reticulata, produced autonomic and emotional responses that were inconstant over time and varied according to the condition. In fact, different responses were elicited with hidden and open stimulations. These data suggest that the dorsal subthalamic nucleus and/or the zona incerta are involved in autonomic control, whereas the ventral subthalamic nucleus and/or the substantia nigra reticulata are involved in associative/limbic-related autonomic activity. The difference between the open and hidden stimulations in the ventral subthalamic region can explain previous studies in which open and hidden stimulations produced different therapeutic outcomes.

Responses of diencephalic nociceptive neurones to orofacial stimuli and effects of internal capsule stimulation in the rat.

The effect of conditioning stimulation of the internal capsule on nociceptive neurones in the rat diencephalon was investigated. The animals were anaesthetised with N(2)O/O(2) (2:1) and 0.5% halothane, and immobilised with pancuronium bromide. Nociceptive neurones responding to noxious stimulation of the face and oral structures were recorded in the ventral posteromedial nucleus, posterior group and zona incerta. These neurones were classified into wide dynamic range and nociceptive-specific types. Functional segregation of these nociceptive neurones was not apparent within the nucleus or between nuclei. A test stimulus with a single rectangular pulse (5-70 V) was applied to the centre of the receptive field; the nociceptive neurones exhibited short- and/or long-latency responses. Both responses in about 45% of the nociceptive neurones were inhibited by conditioning stimuli to the contralateral internal capsule with trains of 33 pulses (300 microA) at 330 Hz. The percent inhibitory effects on the nociceptive neurones of each area were 68.0+/-14.8% (n = 6) in the ventral posteromedial nucleus, 72.8+/-12.4% (n = 4) in the posterior group and 61.5+/-7.5% (n = 4) in the zona incerta. Effective sites for conditioning stimulation were concentrated in the lateral side of the internal capsule, through which the corticofugal fibres from the somatosensory cortex pass. These findings suggest that the transmission of nociceptive information to the diencephalon is modulated by stimulation of the internal capsule at the level of the trigeminal sensory complex in the brainstem. They might provide a novel way to elucidate the neurophysiological basis for antinociception by stimulation of the internal capsule observed in clinical studies.

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.

Electrophysiological confirmation of the zona incerta as a target for surgical treatment of disabling involuntary arm movements in multiple sclerosis: use of local field potentials.

Lesioning or chronic deep brain stimulation (DBS) of the nucleus ventralis intermedius results in abolition of tremor in the contralateral limbs in Parkinson's disease (PD) and also in essential tremor. Recently, chronic DBS of the subthalamic nucleus has also proved to be very effective in reducing contralateral limb tremor in PD. These targets have been less effective in controlling the complex limb tremor often seen in multiple sclerosis (MS). Consequently, other targets have been sought in cases of MS with tremor. We describe a patient with MS with disabling proximal and distal involuntary arm movements in whom we were able to obtain sustained control of contralateral arm tremor and achieve functional improvement of the affected arm by chronic DBS of the region of the zona incerta. We also highlight the important role played by local field potentials recorded from the brain, with simultaneous recording of corresponding EMGs, in target localisation.

[Pallidal and subthalamic stimulation in Parkinson's disease: lessons from the unsatisfactory results]. / Estimulación palidal y subtalámica en la enfermedad de Parkinson: enseñanzas de los malos resultados.

BACKGROUND: Deep brain stimulation is being widely used in advanced Parkinson's disease (PD). Outcome determinants are not known. OBJECTIVE: Some relevant data about outcome may be obtained from the study of patients with unsatisfactory results. PATIENTS AND METHODS: We have retrospectively analyzed the number and causes of unsatisfactory results (insufficient improvement 6 months after the intervention) in 211 patients. RESULTS: Forty patients (18.9%) experienced an unsatisfactory result. Inadequate clinical selection by advanced age, abnormal MRI and levodopa unresponsive symptoms was the main cause in 28 cases. In 11 patients a misplacement of the electrode was reported. In 2 cases no cause was identified. Thirty-four out of the 40 patients corresponded to the early experience of the teams involved in the study. CONCLUSION: We conclude that the main factors responsible for a negative outcome are related to the inadequate clinical selection of the patients and the incorrect placement of the electrode. The experience of the team may also be a key factor.

Physiologic study of the subthalamic volume.

Deep brain stimulation (DBS) obtains good control of advanced PD symptoms. Chronic stimulation of Stn may alleviate rigidity, dyskinesia and tremor. Anatomical and functional intraoperative mapping are mandatory to obtain careful target localisation. Per-operative macrostimulation was carried out in 22 patients undergoing bilateral DBS in Stn; a volume 6 mm above to 4 mm below Stn was explored. Positive, collateral and adverse effects were recorded every 2 mm. Results obtained during acute stimulation were correlated to anatomical data from stereotactic atlases. Our findings suggest a volume, encompassing the zona incerta, Forel's fields and the lowermost part of anterior thalamus, functionally homogeneous to Stn. In fact, the stimulation of this volume obtains reduction of PD symptoms comparable to Stn.

Effect and time course of deep brain stimulation of the globus pallidus and subthalamus on motor features of Parkinson's disease.

We studied the effect and temporal profile of deep brain stimulation (DBS) of the globus pallidus and subthalamic nucleus on the motor signs of Parkinson's disease (PD). Four patients with bilateral deep brain stimulators of the globus pallidus and four patients with bilateral deep brain stimulators of the subthalamus were studied while taking no medication and at 15 and 30 minutes and 1, 2, 4, and 6 hours after turning stimulation on. An immediate (15 minutes) and sustained (6 hours) benefit was observed for all the motor manifestations of PD for both stimulation sites. Deep brain stimulation of the globus pallidus and subthalamus is highly effective in reducing all the cardinal motor features of PD.