Jerome Coste

Brain mapping in stereotactic surgery: A brief overview from the probabilistic targeting to the patient-based anatomic mapping

In this article, we briefly review the concept of brain mapping in stereotactic surgery taking into account recent advances in stereotactic imaging. The gold standard continues to rely on probabilistic and indirect targeting, relative to a stereotactic reference, i.e., mostly the anterior (AC) and the posterior (PC) commissures. The theoretical position of a target defined on an atlas is transposed into the stereotactic space of a patients brain; final positioning depends on electrophysiological analysis. The method is also used to analyze final electrode or lesion position for a patient or group of patients, by projection on an atlas. Limitations are precision of definition of the AC-PC line, probabilistic location and reliability of the electrophysiological guidance. Advances in MR imaging, as from 1.5-T machines, make stereotactic references no longer mandatory and allow an anatomic mapping based on an individual patients brain. Direct targeting is enabled by high-quality images, an advanced anatomic knowledge and dedicated surgical software. Labeling associated with manual segmentation can help for the position analysis along non-conventional, interpolated planes. Analysis of final electrode or lesion position, for a patient or group of patients, could benefit from the concept of membership, the attribution of a weighted membership degree to a contact or a structure according to its level of involvement. In the future, more powerful MRI machines, diffusion tensor imaging, tractography and computational modeling will further the understanding of anatomy and deep brain stimulation effects.

Basal ganglia dysfunction in OCD: subthalamic neuronal activity correlates with symptoms severity and predicts high-frequency stimulation efficacy.

Functional and connectivity changes in corticostriatal systems have been reported in the brains of patients with obsessive–compulsive disorder (OCD); however, the relationship between basal ganglia activity and OCD severity has never been adequately established. We recently showed that deep brain stimulation of the subthalamic nucleus (STN), a central basal ganglia nucleus, improves OCD. Here, single-unit subthalamic neuronal activity was analysed in 12 OCD patients, in relation to the severity of obsessions and compulsions and response to STN stimulation, and compared with that obtained in 12 patients with Parkinsons disease (PD). STN neurons in OCD patients had lower discharge frequency than those in PD patients, with a similar proportion of burst-type activity (69 vs 67%). Oscillatory activity was present in 46 and 68% of neurons in OCD and PD patients, respectively, predominantly in the low-frequency band (1–8 Hz). In OCD patients, the bursty and oscillatory subthalamic neuronal activity was mainly located in the associative–limbic part. Both OCD severity and clinical improvement following STN stimulation were related to the STN neuronal activity. In patients with the most severe OCD, STN neurons exhibited bursts with shorter duration and interburst interval, but higher intraburst frequency, and more oscillations in the low-frequency bands. In patients with best clinical outcome with STN stimulation, STN neurons displayed higher mean discharge, burst and intraburst frequencies, and lower interburst interval. These findings are consistent with the hypothesis of a dysfunction in the associative–limbic subdivision of the basal ganglia circuitry in OCDs pathophysiology.

A role for wind-up in trigeminal sensory processing : intensity coding of nociceptive stimuli in the rat

Wind-up is a progressive, frequency-dependent increase in the excitability of trigeminal and spinal dorsal horn wide dynamic range (WDR) nociceptive neurons evoked by repetitive stimulation of primary afferent nociceptive C-fibres. The correlate of wind-up in humans is temporal summation, which is an increase in pain perception to repetitive constant nociceptive stimulation. Although wind-up is widely used as a tool for studying the processing of nociceptive information, including central sensitization, its actual role is still unknown. Here, we recorded from trigeminal WDR neurons using in vivo electrophysiological techniques in rats and assessed the wind-up phenomenon in response to stimuli of different intensities and frequencies. First, we found that the amplitude of C-evoked responses of WDR neurons to repetitive stimulation increased progressively to reach a peak, then consistently showed a stable or slightly decreasing plateau phase. Only the first phase of this time course fitted in with the wind-up description. Therefore, to assess wind-up, we measured a limited number of initial responses. Second, we showed that wind-up, i.e. the slope of the frequency-dependent increase in the response to C-fibre stimulation, was linearly correlated to the stimulus intensity. Intensities of brief C-fibre inputs were thus coded into frequencies of action potentials by second-order neurons through frequency-dependent potentiation of the evoked responses. Third, wind-up also occurred at stimulation intensities below the threshold for C-evoked responses in WDR neurons, suggesting that wind-up can amplify subthreshold C-fibre inputs to WDR neurons. This might account for the observation that sparse, subliminal, neuronal activity in nociceptors can become painful via central integration of neural responses. Altogether, the present results show that wind-up can provide trigeminal WDR neurons with the capability to encode the intensity of short-duration orofacial nociceptive stimuli and to detect subthreshold nociceptive input. Thus, not only may wind-up play a physiological role in trigeminal sensory processing, but its enhancement may also underlie the pathophysiology of chronic orofacial pain conditions.

Dorsal horn NK1-expressing neurons control windup of downstream trigeminal nociceptive neurons

&NA; Windup is a progressive, frequency‐dependent increase in the excitability of trigeminal and spinal dorsal horn wide dynamic range (WDR) nociceptive neurons to repetitive stimulation of primary afferent nociceptive C‐fibers. Superficial dorsal horn neurokinin 1 receptor (NK1R)‐expressing neurons were recently shown to regulate sensitization of WDR nociceptive neurons through activation of a defined spino‐bulbo‐spinal loop. However, the windup of WDR nociceptive neurons was not regulated through this loop. In the present study, we sought to identify the alternative circuit activated by dorsal horn NK1Rs that mediates WDR neuron windup. As a model we used the rat spinal trigeminal nucleus, in which the subnucleus oralis (Sp5O) contains a pool of WDR neurons that receive their nociceptive C‐input indirectly via interneurons located in the medullary dorsal horn (MDH). First, we found that intravenous injection of NK1R antagonists (SR140333 and RP67580) produced a reversible inhibition of Sp5O WDR neuron windup. Second, we anatomically identified in the MDH lamina III a subpopulation of NK1R‐expressing local interneurons that relay nociceptive information from the MDH to downstream Sp5O neurons. Third, using microinjections of NK1R antagonists during in vivo electrophysiological recordings from Sp5O WDR neurons, we showed that WDR neuron windup depends on activation of NK1Rs located in the MDH laminae I–III. We conclude that, in contrast to central sensitization that is controlled by a spino‐bulbo‐spinal loop, Sp5O WDR neuron windup is regulated through a local circuit activated by MDH lamina III NK1Rs.

Electrical modulation of neuronal networks in brain-injured patients with disorders of consciousness: A systematic review

Six clinical studies of chronic electrical modulation of deep brain circuits published between 1968 and 2010 have reported effects in 55 vegetative or minimally conscious patients. The rationale stimulation was to activate the cortex through the reticular-thalamic complex, comprising the tegmental ascending reticular activating system and its thalamic targets. The most frequent intended target was the central intralaminar zone and adjacent nuclei. Hassler et al. also proposed to modulate the pallidum as part of the arousal and wakefulness system. Stimulation frequency varied from 8Hz to 250Hz. Most patients improved, although in a limited way. Schiff et al. found correlations between central thalamus stimulation and arousal and conscious behaviours. Other treatments that have offered some clinical benefit include drugs, repetitive magnetic transcranial stimulation, median nerve stimulation, stimulation of dorsal column of the upper cervical spinal cord, and stimulation of the fronto-parietal cortex. No one treatment has emerged as a gold standard for practice, which is why clinical trials are still on-going. Further clinical studies are needed to decipher the altered dynamics of neuronal network circuits in patients suffering from severe disorders of consciousness as a step towards novel therapeutic strategies.

Subthalamic Nucleus Location: Relationships between Stereotactic AC-PC-Based Diagrams and MRI Anatomy-Based Contours

Subthalamic nucleus (STN) targeting is classically performed based on AC-PC probabilistic position. Nevertheless, MRI allows direct visualization and targeting. We aimed to compare the position localized on MR images with standard stereotactic diagrams. The STN was manually contoured on MR images (22 Parkinson’s disease patients); boundaries were simplified in a schematic polygonal form. Front and lateral stereotactic diagrams were constructed according to Talairach and Benabid. We compared x, y and z coordinates of the geometrical center of MRI-based polygons and stereotactic diagrams (Wilcoxon matched-pairs tests). There was significant discordance between MRI-based polygons and AC-PC-based images. MRI shows the STN as more posterior, medial and slightly inferior.

New electrophysiological mapping combined with MRI in parkinsonian's subthalamic region.

The subthalamic nucleus (STN) is the main target for deep brain stimulation in Parkinson’s disease. We analysed the relationships between magnetic resonance imaging (MRI) anatomy and spontaneous neuronal activity to confirm the potential of microelectrode recordings to assist in determining the optimal surgical target. Ten bilateral surgeries were performed after 1.5‐T (T2‐weighted) anatomical MRI identification of the STN, zona incerta (ZI), Forel’s field H2 (H2) and substantia nigra (SN). Spontaneous neuronal activity was recorded simultaneously along the distal 10 mm on a central track (optimally covering the STN) and a 2‐mm anterior track. We calculated off‐line mean firing rate and burst frequency on 248 neurons clustered according to anatomical structure. Subjective visual analysis of signal was also realized on‐line, during surgery, to classify patterns of activity. Mean firing rate and burst frequency increased from H2–ZI to SN. The mean firing rate was higher in SN only using paired comparison (SN vs. its neighbours). The burst frequency was lower in H2 than in SN; using comparison with neighbours, it was lower in H2 and ZI. An irregular high activity (type 2C) was more often detected in STN and SN than in H2 and ZI. Anatomical boundaries and unitary recordings appear to be linked, supporting the ability of MRI to provide a detailed anatomy. Electrophysiological mapping combined with MRI is a useful tool for precise targeting in the subthalamic region.

Stimulation sous-thalamique dans la maladie de Parkinson sévère: Étude de la localisation des contacts effectifs

The subthalamic nucleus (STN) is the main target of deep brain stimulation (DBS) treatment for severe idiopathic Parkinsons disease. But there is still no clear information on the location of the effective contacts (used during the chronic phase of stimulation). Our aim was to assess the anatomical structures of the subthalamic area (STA) involved during chronic DBS. Ten patients successfully treated were included. The surgical procedure was based on direct STN targeting (stereotactic MRI based) pondered by the acute effects of intraoperative stimulation. We used a formaldehyde-fixed human specimen to compare by matching MRI images obtained at 1.5 Tesla (performed in clinical stereotactic conditions) and at very high field at 4.7 Tesla. This allowed accurate analysis of the anatomy of the STA and retrospective precision of the location of the center of effective contacts which were located within the STN in 4 patients, at the interface between the STN and the ZI and/or FF in 13, at the interface between ZI and FF in 2 and between the STN and the substantia nigra in one. These results were consistent with the literature, revealing the implication of neighboring structures, especially the zona incerta and Forels Field, in the clinical benefit.Le noyau sous-thalamique (NST) s’est impose comme la cible de choix de la stimulation cerebrale profonde (SCP) dans la maladie de Parkinson idiopathique severe. Toutefois, la position des contacts utilises lors de la stimulation chronique (contacts effectifs) reste mal connue. Notre but etait de preciser, au sein de la region sous-thalamique (RST), la topographie des contacts effectifs. Pour cela, nous avons realise en prealable un travail sur specimen anatomique, par mise en correspondance d’images IRM a 1,5 Tesla (en conditions cliniques) et a tres haut champ a 4,7 Tesla, explorant la RST. Nous avons ensuite etudie une serie de 10 patients traites par DBS bilaterale avec un bon resultat clinique. L’implantation avait ete realisee en visee directe (reperage direct du STN sur IRM stereotaxique) ponderee en fonction des effets de la stimulation aigue per-operatoire. Nous avons revu a posteriori, en s’aidant de l’anatomie IRM tres haut champ, la position du centre des contacts effectifs. Si certains contacts etaient places a l’interieur du NST (4 fois), la plupart se trouvaient a l’interface de ce dernier et de la zona incerta et/ou des champs de Forel (13 fois), a l’interface zona incerta et champs de Forel (2 fois) et a l’interface NST substance noire (1 fois). Ces resultats sont en accord avec la litterature. L’implication des structures voisines du NST dans le benefice clinique, en particulier la zona incerta et le champ de Forel, semble donc probable.

Time-course of myelination and atrophy on cerebral imaging in 35 patients with PLP1-related disorders.

Brain magnetic resonance imaging (MRI) motor development score (MDS) correlations were used to analyze the natural time‐course of hypomyelinating PLP1‐related disorders (Pelizaeus‐Merzbacher disease [PMD] and spastic paraplegia type 2).

Bidirectional modulation of windup by NMDA receptors in the rat spinal trigeminal nucleus.

Activation of afferent nociceptive pathways is subject to activity‐dependent plasticity, which may manifest as windup, a progressive increase in the response of dorsal horn nociceptive neurons to repeated stimuli. At the cellular level, N‐methyl‐d‐aspartate (NMDA) receptor activation by glutamate released from nociceptive C‐afferent terminals is currently thought to generate windup. Most of the wide dynamic range nociceptive neurons that display windup, however, do not receive direct C‐fibre input. It is thus unknown where the NMDA mechanisms for windup operate. Here, using the Sprague–Dawley rat trigeminal system as a model, we anatomically identify a subpopulation of interneurons that relay nociceptive information from the superficial dorsal horn where C‐fibres terminate, to downstream wide dynamic range nociceptive neurons. Using in vivo electrophysiological recordings, we show that at the end of this pathway, windup was reduced (24 ± 6%, n = 7) by the NMDA receptor antagonist AP‐5 (2.0 fmol) and enhanced (62 ± 19%, n = 12) by NMDA (1 nmol). In contrast, microinjections of AP‐5 (1.0 fmol) within the superficial laminae increased windup (83 ± 44%, n = 9), whereas NMDA dose dependently decreased windup (n = 19).These results indicate that NMDA receptor function at the segmental level depends on their precise location in nociceptive neural networks. While some NMDA receptors actually amplify pain information, the new evidence for NMDA dependent inhibition of windup we show here indicates that, simultaneously, others act in the opposite direction. Working together, the two mechanisms may provide a fine tuning of gain in pain.