Network Effects of Brain Lesions Causing Central Poststroke Pain.

OBJECTIVE: This study was undertaken to test whether lesions causing central poststroke pain (CPSP) are associated with a specific connectivity profile, whether these connections are associated with metabolic changes, and whether this network aligns with neuromodulation targets for pain. METHODS: Two independent lesion datasets were utilized: (1) subcortical lesions from published case reports and (2) thalamic lesions with metabolic imaging using 18F- fluorodeoxyglucose positron emission tomography-computed tomography. Functional connectivity between each lesion location and the rest of the brain was assessed using a normative connectome (n = 1,000), and connections specific to CPSP were identified. Metabolic changes specific to CPSP were also identified and related to differences in lesion connectivity. Therapeutic relevance of the network was explored by testing for alignment with existing brain stimulation data and by prospectively targeting the network with repetitive transcranial magnetic stimulation (rTMS) in 7 patients with CPSP. RESULTS: Lesion locations causing CPSP showed a specific pattern of brain connectivity that was consistent across two independent lesion datasets (spatial r = 0.82, p < 0.0001). Connectivity differences were correlated with postlesion metabolism (r = -0.48, p < 0.001). The topography of this lesion-based pain network aligned with variability in pain improvement across 12 prior neuromodulation targets and across 32 patients who received rTMS to primary motor cortex (p < 0.05). Prospectively targeting this network with rTMS improved CPSP in 6 of 7 patients. INTERPRETATION: Lesions causing pain are connected to a specific brain network that shows metabolic abnormalities and promise as a neuromodulation target. ANN NEUROL 2022;92:834-845.

Repetitive transcranial magnetic stimulation for neuropathic pain: a randomized multicentre sham-controlled trial.

Repetitive transcranial magnetic stimulation (rTMS) has been proposed to treat neuropathic pain but the quality of evidence remains low. We aimed to assess the efficacy and safety of neuronavigated rTMS to the primary motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC) in neuropathic pain over 25 weeks. We carried out a randomized double-blind, placebo-controlled trial at four outpatient clinics in France. Patients aged 18-75 years with peripheral neuropathic pain were randomly assigned at a 1:1 ratio to M1 or DLPFC-rTMS and rerandomized at a 2:1 ratio to active or sham-rTMS (10 Hz, 3000 pulses/session, 15 sessions over 22 weeks). Patients and investigators were blind to treatment allocation. The primary end point was the comparison between active M1-rTMS, active DLPCF-rTMS and sham-rTMS for the change over the course of 25 weeks (Group × Time interaction) in average pain intensity (from 0 no pain to 10 maximal pain) on the Brief Pain Inventory, using a mixed model repeated measures analysis in patients who received at least one rTMS session (modified intention-to-treat population). Secondary outcomes included other measures of pain intensity and relief, sensory and affective dimensions of pain, quality of pain, self-reported pain intensity and fatigue (patients diary), Patient and Clinician Global Impression of Change (PGIC, CGIC), quality of life, sleep, mood and catastrophizing. This study is registered with ClinicalTrials.gov NCT02010281. A total of 152 patients were randomized and 149 received treatment (49 for M1; 52 for DLPFC; 48 for sham). M1-rTMS reduced pain intensity versus sham-rTMS (estimate for Group × Session interaction: -0.048 ± 0.02; 95% CI: -0.09 to -0.01; P = 0.01). DLPFC-rTMS was not better than sham (estimate: -0.003 ± 0.01; 95% CI: -0.04 to 0.03, P = 0.9). M1-rRMS, but not DLPFC-rTMS, was also superior to sham-rTMS on pain relief, sensory dimension of pain, self-reported pain intensity and fatigue, PGIC and CGIC. There were no effects on quality of pain, mood, sleep and quality of life as all groups improved similarly over time. Headache was the most common side effect and occurred in 17 (34.7%), 23 (44.2%) and 13 (27.1%) patients from M1, DLPFC and sham groups, respectively (P = 0.2). Our results support the clinical relevance of M1-rTMS, but not of DLPFC-rTMS, for peripheral neuropathic pain with an excellent safety profile.

Retrieving autobiographical experience of painful events in a phantom limb: brain concomitants in a case report.

We report the case of a patient who had an important experience with painful events, allowing the investigation of brain concomitants to painful (P) memories in fMRI. The patient had to recall P events that were contrasted with non-painful (NP) memories. Painful memories of the right lower limb activated the left paracentral lobule,fronto-insular operculum and superior parietal cortex. Additionally, whilst the recall of non-painful events activated the hippocampus, the recall of painful events did not enhance the hippocampal signal to significant levels. These suggest that brain activations differ for the autobiographical recall of painful and non-painful memories.

Robot-Guided Neuronavigated Repetitive Transcranial Magnetic Stimulation (rTMS) in Central Neuropathic Pain.

OBJECTIVES: To confirm and extend previous results involving repetitive transcranial magnetic stimulation (rTMS) aimed at alleviating refractory central neuropathic pain (CNP). To evaluate pain relief in detail and to assess ongoing benefits after one year of treatment. DESIGN: Prospective observational study. SETTING: University hospital. Outpatient settings. PARTICIPANTS: Patients (N=80) with chronic central pain after brain or spinal cord injuries. INTERVENTIONS: High-frequency (20Hz) neuronavigated-rTMS sessions were applied on the primary motor cortex using a figure-of-eight coil positioned by a robotized arm. Patients received a minimum of 4 consecutive sessions, each separated by 3-4 weeks. MAIN OUTCOME MEASURES: Percentage of pain relief (%R), duration of pain relief (DPR), numeric rating scale (NRS), neuropathic pain symptom inventory (NPSI), and pain relief score (PRS). RESULTS: Seventy-one patients completed the study. On average, after the first 4 sessions, %R was 28% and DPR was 11 days. Fifty-four patients (76%) were responders with a permissive threshold of ≥10%R and 61% (43 patients) with a stringent threshold ≥30%R. After 12 months of treatment (15 sessions) we observed a cumulative effect on %R (48%), DPR (20d), and on the prevailing NPSI sub-score (-28%). This effect reached significance after 4 sessions and was further maintained over 12 months. Across participants, more than 1000 rTMS sessions were delivered over 6 years without any adverse effect. CONCLUSION: These results confirm that multiple rTMS sessions are both safe and have potential as a treatment for CNP. An ongoing randomized controlled trial will allow teasing out of this effect from placebo analgesia.

Hearing eyeball and/or eyelid movements on the side of a unilateral superior semicircular canal dehiscence.

Hearing of eyeball movements has been reported in superior semicircular canal dehiscence (SSCD), but not hearing of eyelid movements. Our main objective was to report the hearing of eyeball and/or eyelid movements in unilateral SSCD. Our secondary objective was to access its specificity to SSCD and discuss the underlying mechanism. Six patients with SSCD who could hear their eyeball and/or eyelid movements were retrospectively reviewed. With the aim of comparisons, eight patients with an enlarged vestibular aqueduct (EVA), who share the same mechanism of an abnormal third window, were questioned on their ability to hear their eyeball and/or eyelid movements. Three patients with SSCD could hear both their eyeball and eyelid movements as a soft low-pitch friction sound. Two patients with SSCD could hear only their eyelid movements, one of whom after the surgery of a traumatic chronic subdural hematoma. The latter remarked that every gently tapping on the skin covering the burr-hole was heard in his dehiscent ear as the sound produced when banging on a drum, in keeping with a direct transmission of the sound to the inner ear via the cerebrospinal fluid. One patient with SSCD, who could hear only his eyeball movements, had other disabling symptoms deserving operation through a middle fossa approach with an immediate relief of his symptoms. None of the eight patients with EVA could hear his/her eyeball or eyelid movements. Hearing of eyeball and/or eyelid movements is highly suggestive of a SSCD and do not seem to occur in EVA. In case of radiological SSCD, clinicians should search for hearing of eyeball and/or eyelid movements providing arguments for a symptomatic dehiscence. The underlying mechanism is discussed particularly the role of a cerebrospinal fluid transmission.

Thalamic pain: anatomical and physiological indices of prediction.

Thalamic pain is a severe and treatment-resistant type of central pain that may develop after thalamic stroke. Lesions within the ventrocaudal regions of the thalamus carry the highest risk to develop pain, but its emergence in individual patients remains impossible to predict. Because damage to the spino-thalamo-cortical system is a crucial factor in the development of central pain, in this study we combined detailed anatomical atlas-based mapping of thalamic lesions and assessment of spinothalamic integrity using quantitative sensory analysis and laser-evoked potentials in 42 thalamic stroke patients, of whom 31 had developed thalamic pain. More than 97% of lesions involved an area between 2 and 7 mm above the anterior-posterior commissural plane. Although most thalamic lesions affected several nuclei, patients with central pain showed maximal lesion convergence on the anterior pulvinar nucleus (a major spinothalamic target) while the convergence area lay within the ventral posterior lateral nucleus in pain-free patients. Both involvement of the anterior pulvinar nucleus and spinothalamic dysfunction (nociceptive thresholds, laser-evoked potentials) were significantly associated with the development of thalamic pain, whereas involvement of ventral posterior lateral nucleus and lemniscal dysfunction (position sense, graphaesthesia, pallaesthesia, stereognosis, standard somatosensory potentials) were similarly distributed in patients with or without pain. A logistic regression model combining spinothalamic dysfunction and anterior pulvinar nucleus involvement as regressors had 93% sensitivity and 87% positive predictive value for thalamic pain. Lesion of spinothalamic afferents to the posterior thalamus appears therefore determinant to the development of central pain after thalamic stroke. Sorting out of patients at different risks of developing thalamic pain may be achievable at the individual level by combining lesion localization and functional investigation of the spinothalamic system. As the methods proposed here do not need complex manipulations, they can be added to routine patients' work up, and the results replicated by other investigators in the field.

Effects of aging on laser evoked potentials.

INTRODUCTION: Aging has been reported to reduce the amplitude of laser evoked potentials. However, it is unknown whether this effect depends on the length of the sensory fibers. This is an important issue, because most painful neuropathies are length-dependent. METHODS: We conducted a study of 40 healthy subjects, half of whom were older than age 50 years. Nociceptive stimuli were delivered to the feet and thighs using a CO2 laser stimulator. RESULTS: Detection and pain perception thresholds did not correlate with age. Latencies of N1, N2, and P2 correlated positively with age on the feet but not on the thighs, whereas the amplitude of N2-P2 decreased with age for both areas. CONCLUSIONS: The effects of aging on latencies may reflect a distal loss of peripheral inputs and a length-dependent de-synchronization of the ascending nociceptive volley. Additional changes in peripheral and central processes may explain the diffuse decrease of N2-P2 amplitudes observed with aging.

[Drug Shortage May Have Serious Outcome: the French Exemple of Phenytoine]. / Des ruptures de stock aux conséquences parfois graves : l'exemple de la phénytoïne, à propos de 7 cas.

In 2012, in France, phenytoin sodium was used as a substitute for phenytoin base during a shortage at the dose of 100 mg for 100 mg, according to the French Health Agency recommendations. However, this substitution was problematic because the two specialties were not bioequivalent. We report here the case of a 29-year old woman who presented with severe epilepsy. The substitution of phenytoin base by phenytoin sodium induced an increase of seizure frequency leading to several hospitalizations and sick leave. Phenytoin base was finally available again in 2013 which allowed a reduction of seizure frequency. Six similar cases, including one death, were reported to the French pharmacovigilance system. Drug shortages are increasingly common and can have serious consequences. Reporting the difficulties that drug shortage causes to health authorities is important in order to improve their management and to better support patients.

Fractal Similarity of Pain Brain Networks.

The conscious perception of pain is the result of dynamic interactions of neural activities from local brain regions to distributed brain networks. Mapping out the networks of functional connections between brain regions that form and disperse when an experimental participant received nociceptive stimulations allow to characterize the pattern of network connections related to the pain experience.Although the pattern of intra- and inter-areal connections across the brain are incredibly complex, they appear also largely scale free, with "fractal" connectivity properties reproducing at short and long-time scales. Our results combining intracranial recordings and functional imaging in humans during pain indicate striking similarities in the activity and topological representation of networks at different orders of temporality, with reproduction of patterns of activation from the millisecond to the multisecond range. The connectivity analyzed using graph theory on fMRI data was organized in four sets of brain regions matching those identified through iEEG (i.e., sensorimotor, default mode, central executive, and amygdalo-hippocampal).Here, we discuss similarities in brain network organization at different scales or "orders," in participants as they feel pain. Description of this fractal-like organization may provide clues about how our brain regions work together to create the perception of pain and how pain becomes chronic when its organization is altered.

Pain cues override identity cues in baby cries.

Baby cries can convey both static information related to individual identity and dynamic information related to the baby's emotional and physiological state. How do these dimensions interact? Are they transmitted independently, or do they compete against one another? Here we show that the universal acoustic expression of pain in distress cries overrides individual differences at the expense of identity signaling. Our acoustic analysis show that pain cries, compared with discomfort cries, are characterized by a more unstable source, thus interfering with the production of identity cues. Machine learning analyses and psychoacoustic experiments reveal that while the baby's identity remains encoded in pain cries, it is considerably weaker than in discomfort cries. Our results are consistent with the prediction that the costs of failing to signal distress outweigh the cost of weakening cues to identity.

Field recordings of transcranial magnetic stimulation in human brain postmortem models.

Introduction: The ability of repetitive transcranial magnetic stimulation (rTMS) to deliver a magnetic field (MF) in deep brain targets is debated and poorly documented. Objective: To quantify the decay of MF in the human brain. Methods: Magnetic field was generated by single pulses of TMS delivered at maximum intensity using a flat or angulated coil. Magnetic field was recorded by a 3D-magnetic probe. Decay was measured in the air using both coils and in the head of 10 postmortem human heads with the flat coil being positioned tangential to the scalp. Magnetic field decay was interpreted as a function of distance to the coil for 6 potential brain targets of noninvasive brain stimulation: the primary motor cortex (M1, mean depth: 28.5 mm), dorsolateral prefrontal cortex (DLPFC: 28 mm), secondary somatosensory cortex (S2: 35.5 mm), posterior and anterior insulae (PI: 38.5 mm; AI: 43.5 mm), and midcingulate cortex (MCC: 57.5 mm). Results: In air, the maximal MF intensities at coil center were 0.88 and 0.77 T for the flat and angulated coils, respectively. The maximal intracranial MF intensity in the cadaver model was 0.34 T, with a ∼50% decay at 15 mm and a ∼75% MF decay at 30 mm. The decay of the MF in air was similar for the flat coil and significantly less attenuated with the angulated coil (a ∼50% decay at 20 mm and a ∼75% MF decay at 45 mm). Conclusions: Transcranial magnetic stimulation coil MFs decay in brain structures similarly as in air, attenuation with distance being significantly lower with angulated coils. Reaching brain targets deeper than 20 mm such as the insula or Antérior Cingulate Cortex seems feasible only when using angulated coils. The abacus of MF attenuation provided here can be used to adjust modalities of deep brain stimulation with rTMS in future research protocols.

The 'where' and the 'when' of the BOLD response to pain in the insular cortex. Discussion on amplitudes and latencies.

The operculo-insular cortex has been recently pointed out to be the main area of the pain matrix to be involved in the integration of pain intensity. This fMRI study specified the pattern of response to laser stimuli by focusing on this cortical area, by optimizing the temporal sampling and by investigating pain-related differences in the amplitudes and latencies of the BOLD responses. Canonical and temporal derivative hemodynamic response function (HRF) and finite impulse response (FIR) modeling provided consistent results. Amplitude of BOLD response discriminated painful from non-painful conditions in posterior and mid-insular cortices, bilaterally. Pain conditions were characterized by a shortened latency (as compared to non-painful conditions) in the anterior insula. In the functional organization of the insula, these results suggest a double dissociation that can be summarized as the 'where' and the 'when' of the BOLD response to pain. These results suggest that differences in the amplitude of the BOLD activity in the posterior and in the mid-insular cortices as well as shortened latency of the response in the anterior insula deal with discriminative processes related to painful conditions.

Stimulation of the human cortex and the experience of pain: Wilder Penfield's observations revisited.

Thanks to the seminal work of Wilder Graves Penfield (1891-1976) at the Montreal Neurological Institute, electrical stimulation is used worldwide to localize the epileptogenic cortex and to map the functionally eloquent areas in the context of epilepsy surgery or lesion resections. In the functional map of elementary and experiential responses he described through >20 years of careful exploration of the human cortex via stimulation of the cortical surface, Penfield did not identify any 'pain cortical area'. We reinvestigated this issue by analysing subjective and videotaped behavioural responses to 4160 cortical stimulations using intracerebral electrodes implanted in all cortical lobes that were carried out over 12 years during the presurgical evaluation of epilepsy in 164 consecutive patients. Pain responses were scarce (1.4%) and concentrated in the medial part of the parietal operculum and neighbouring posterior insula where pain thresholds showed a rostrocaudal decrement. This deep cortical region remained largely inaccessible to the intraoperative stimulation of the cortical surface carried out by Penfield after resection of the parietal operculum. It differs also from primary sensory areas described by Penfield et al. in the sense that, with our stimulation paradigm, pain represented only 10% of responses. Like Penfield et al., we obtained no pain response anywhere else in the cortex, including in regions consistently activated by pain in most functional imaging studies, i.e. the first somatosensory area, the lateral part of the secondary somatosensory area, anterior and mid-cingulate gyri (mid-cingulate cortex), anterior frontal, posterior parietal and supplementary motor areas. The medial parietal operculum and posterior insula are thus the only areas where electrical stimulation is able to trigger activation of the pain cortical network and thus the experience of somatic pain.

Impaired emotional processing in a patient with a left posterior insula-SII lesion.

The present case-report investigated the influence of a lesion in the left posterior insula-SII cortices on the processing of emotions. MB and 16 normal controls explicitly rated the valence and the intensity of both facial expressions and emotional words. In addition, they had to perform a number comparison task and a lexical decision task without focusing their attention on emotional components of stimuli. MB identified the valence of emotional words as well as the control group. Nevertheless, she provided higher intensity scores for disgusted words and her responses in the lexical decision task were significantly delayed for these stimuli. In addition, MB's response times were not differently influenced by the presence of irrelevant emotional faces. However, she explicitly identified fewer facial expressions of disgust and she assessed them as significantly less intense. This pattern of results contributes to highlight the psychological and behavioral disorders observed after a left posterior insular stroke.

[Pathophysiology of chronic pain. Classification of three subtypes of pain]. / Physiopathologie de la douleur chronique et ses trois grands types.

Pain is a physiological sensation which aim is to alert for an upcoming danger that may threaten the individual. This system includes peripheral nociceptors that initiate the nociceptive message. Then, the information is conveyed to the brain through the spinothalamic tract that projects to the thalamus, insula, SII and other areas. In clinical situations, a dysfunction of this nociceptive system explains chronic pain that can be simply classified into 3 subtypes according to pathophysiological mechanisms. Case 1: the nociceptive system is functioning normally, and provides (appropriately) a pain message that informs the brain of a local inflammation, or cancer, or infection... This is the situation of chronic pain because of an excess of nociception. Case 2: there is a (past or present) lesion of the nervous system that induces a dysfunction in the pain system. This is the neuropathic pain. Case 3: between the two former cases, there is no evidence for a lesion in the nociceptive system, and there are no evidences for lesion at the peripheral level, but there are evidences of dysregulation(s). These are the cases of dysfunctional pain.

Spatial segregation of somato-sensory and pain activations in the human operculo-insular cortex.

The role of operculo-insular region in the processing of somato-sensory inputs, painful or not, is now well established. However, available maps from previous literature show a substantial overlap of cortical areas activated by these stimuli, and the region referred to as the "secondary somatosensory area (SII)" is widely distributed in the parietal operculum. Differentiating SII from posterior insula cortex, which is anatomically contiguous, is not easy, explaining why the "operculo-insular" label has been introduced to describe activations by somatosensory stimuli in this cortical region. Based on the recent cyto-architectural parcellation of the human insular/SII cortices (Eickhoff et al., 2006, Kurth et al., 2010), the present study investigates with functional MRI (fMRI), whether these structural subdivisions could subserve distinct aspects of discriminative somato-sensory functions, including pain. Responses to five types of stimuli applied on the left hand of 25 healthy volunteers were considered: i) tactile stimuli; ii) passive movements; iii) innocuous cold stimuli; iv) non-noxious warm and v) heat pain. Our results show different patterns of activation depending on the type of somato-sensory stimulation. The posterior part of SII (OP1 area), contralateral to stimuli, was the only sub-region activated by all type of stimuli and might therefore be considered as a common cortical target for different types of somato-sensory inputs. Proprioceptive stimulation by passive finger movements activated the posterior part of SII (OP1 sub-region) bilaterally and the contralateral median part of insula (PreCG and MSG). Innocuous cooling activated the contralateral posterior part of SII (OP1) and the dorsal posterior and median part of insula (OP2, PostCG). Pain stimuli induced the most widespread and intense activation that was bilateral in SII (OP1, OP4) and distributed to all sub-regions of contralateral insula (except OP2) and to the anterior part of the ipsilateral insula (PreCG, MSG, ASG). However, the posterior granular part of insula contralateral to stimulus (Ig area) and the anterior part of SII bilaterally (OP4) were specifically activated during pain stimulation. This raises the question whether these latter areas could be the anatomical substrate of the sensory-discriminative processing of thermal pain.

Improved dexterity after chronic electrical stimulation of the motor cortex for central pain: a special relevance for thalamic syndrome.

OBJECTIVES: To demonstrate that motor cortex stimulation (MCS) could improve motor function in patients with neuropathic pain. METHODS: In this prospective clinical study of 38 patients referred for MCS as treatment for their neuropathic pain, we collected any declaration of improvement in motor performance that could be attributed to MCS. RESULTS: Ten patients (26%) declared a benefit in their motor function. Eight presented objective evidence of recovered dexterity for rapid alternating movements. A minor proportion had improvement in dystonic posture (n = 2), but none had detectable increased motor strength or tonus changes. Overall, 73% of the patients with limb ataxia declared a benefit after MCS. In 6 out of 10 patients (60%), the anatomic lesion responsible for pain was restricted to the lateral aspect of the thalamus. All of them had either clinical or electrophysiological evidence of lemniscal dysfunction (proprioceptive ataxia). No correlation was found between the scores of pain relief and the modification of motor status. The correlation between thalamic lesions and benefits in motor performance was significant (Fisher's exact test, two-tailed, p = 0.0017). CONCLUSIONS: Up to 26% of patients estimated that MCS improved their motor outcome through recovered dexterity and in cases of lateral thalamic lesions.

Adults learn to identify pain in babies' cries.

Because the expression of pain in babies' cries is based on universal acoustic features, it is assumed that adult listeners should be able to detect when a crying baby is experiencing pain1-3. We report that detecting that a baby's cry expresses pain actually requires learning through experience. Our psychoacoustic experiments reveal that adults with no experience of caring for babies are unable to identify whether a baby's cry is a pain cry induced by vaccination or a mild discomfort cry recorded during a bath, even when they are familiar with the discomfort cries from this particular baby. In contrast, people with prior experience of babies - parents or professional caregivers - identify a familiar baby's pain cries without having heard these cries before. Parents of very young children are even able to identify the pain cries of a baby who is completely unfamiliar to them. Exposure through caregiving and/or parenting thus shapes the auditory and cognitive abilities involved in decoding the information conveyed by the baby's communication signals.

Benign Paroxysmal Vertigo of Childhood. Video Recordings of Episodes.

OBJECTIVES: The main objective was to describe the nystagmus observed during benign paroxysmal vertigo (BPV) of childhood, which is one of the criteria included in the three versions of the International Classification of Headache Disorders that has never been specified. The secondary objectives were to emphasize the usefulness of a mobile phone to record nystagmus and discuss the physiopathology of this nystagmus. PATIENT: A 6-year-old boy complained of approximately 30 to 50 vertigo attacks, most of them lasting around 1 minute, during a 6-month period. INTERVENTION: Otoneurologic history and examination, audiovestibular exploration, and brain imaging were performed between the attacks. Video recording by the parents' mobile phone and video electroencephalography recording during a 1-day hospitalization were performed during the episodes. MAIN OUTCOME MEASURE: Analysis of seven video recordings performed by the parents and four during a 1-day hospitalization, as well as follow-up. RESULTS: The assessment between the attacks confirmed the diagnosis of BPV according to International Classification of Headache Disorders criteria. Video recordings constantly demonstrated a strong left horizontal nystagmus present at fixation in all direction of gaze, enhanced in left gaze. This nystagmus was associated with a rightward body deviation. CONCLUSION: The clinical presentation was more consistent with a peripheral vestibular deficit than with a central disorder. We encourage video recording of their child by the parents because it will help both to define the ictal nystagmus and to understand the underlying pathophysiology. The latter is discussed and is probably more complex than initially thought in BPV.

Dissecting neuropathic from poststroke pain: the white matter within.

ABSTRACT: Poststroke pain (PSP) is a heterogeneous term encompassing both central neuropathic (ie, central poststroke pain [CPSP]) and nonneuropathic poststroke pain (CNNP) syndromes. Central poststroke pain is classically related to damage in the lateral brainstem, posterior thalamus, and parietoinsular areas, whereas the role of white matter connecting these structures is frequently ignored. In addition, the relationship between stroke topography and CNNP is not completely understood. In this study, we address these issues comparing stroke location in a CPSP group of 35 patients with 2 control groups: 27 patients with CNNP and 27 patients with stroke without pain. Brain MRI images were analyzed by 2 complementary approaches: an exploratory analysis using voxel-wise lesion symptom mapping, to detect significant voxels damaged in CPSP across the whole brain, and a hypothesis-driven, region of interest-based analysis, to replicate previously reported sites involved in CPSP. Odds ratio maps were also calculated to demonstrate the risk for CPSP in each damaged voxel. Our exploratory analysis showed that, besides known thalamic and parietoinsular areas, significant voxels carrying a high risk for CPSP were located in the white matter encompassing thalamoinsular connections (one-tailed threshold Z > 3.96, corrected P value <0.05, odds ratio = 39.7). These results show that the interruption of thalamocortical white matter connections is an important component of CPSP, which is in contrast with findings from nonneuropathic PSP and from strokes without pain. These data can aid in the selection of patients at risk to develop CPSP who could be candidates to pre-emptive or therapeutic interventions.