Somatosensory-evoked magnetic fields following stimulation of the tongue in humans.

OBJECTIVE: To clarify the characteristics relating to the temporal dynamics of the tongue primary somatosensory cortex (SI). METHODS: We fabricated individual intraoral devices and recorded somatosensory-evoked magnetic fields (SEFs) from 10 normal subjects. The tongue was stimulated with a concentrated bipolar electrode in four areas: the right and left antero-lateral margins, and the right and left postero-lateral margins. RESULTS: The primary component was recorded about 19 ms post-stimulation. Six components, termed 1M, 2M, 3M, 4M, 5M, and 6M, respectively, were found within 130 ms of the stimulation. These activities were detected in hemispheres both contralateral and ipsilateral to the stimulation, and were estimated to be located around the tongue SI. In addition, the latency of the contralateral hemisphere was significantly shorter than that of the ipsilateral hemisphere for all components, independent of the area stimulated. CONCLUSIONS: Tactile stimulation of the tongue-elicited activity in the tongue SI in both hemispheres. SIGNIFICANCE: This is the first study to investigate the brain responses evoked by stimulating different areas of the tongue, using magnetoencephalography.     

Face representation in the human secondary somatosensory cortex.

OBJECTIVE: To investigate the somatotopic organization of the facial skin area in the secondary somatosensory cortex (SII) in humans. METHODS: Somatosensory evoked magnetic fields following air-puff stimulation of 5 body sites, the foot, the lip and 3 points of the facial skin (forehead, cheek and mandibular angle point), were recorded. We focused on activities in SII following stimulation of these 5 sites and compared dipole locations among them. RESULTS: There was a clear somatotopic organization in SII with lip in the most lateral area, foot in the most medial area and face in an intermediate area close to the lip area. However, there was no significant difference of dipole localization in SII among the 3 areas of facial skin, similar to the overlapped somatotopic organization of facial skin areas in the primary somatosensory cortex in our previous study. CONCLUSIONS: The facial skin areas are considered to occupy a small area in SII with insufficient spatial separation to differentiate each area of facial skin even using magnetoencephalography which has a high spatial resolution. SIGNIFICANCE: This is the first systematic study of the activated regions in SII following stimulation of the facial skin.     

Early secondary somatosensory area (SII) SEPs. Data from intracerebral recordings in humans.

OBJECTIVE: To record somatosensory evoked potentials (SEPs) to median nerve stimulation by chronically implanted electrodes in the parieto-rolandic opercular area of 9 epileptic patients, in order to evaluate whether somatosensory evoked responses could be generated in the second somatosensory area (SII) earlier than 40 ms after stimulus. METHODS: Nine patients (4 males, 5 females) with drug-resistant partial epileptic seizures were investigated using stereotactically implanted electrodes in the parietal cortex, posterior to vertical anterior commissure plane and in the frontal opercular region rostral to vertical anterior commissure (VAC). RESULTS: The main finding of this study is the recording of an early somatosensory evoked potential, (N30op), by chronically implanted electrodes in the SII area of 8 epileptic patients. In 3 patients where SEPs were performed after ipsilateral median nerve (MN) stimulation, a N30op was recorded 5.8+/-2 ms later than contralateral one. CONCLUSIONS: This is the first report of early SEPs recorded by electrodes implanted in SII area. The N30op potential, even if less consistent than later potentials, confirmed the important role of the SII area in the early processing of somatosensory inputs.     

Characteristics of the human contra- versus ipsilateral SII cortex.

OBJECTIVES: In order to study the interaction between left- and right-sided stimuli on the activation of cortical somatosensory areas, we recorded somatosensory evoked magnetic fields (SEFs) from 8 healthy subjects with a 122 channel whole-scalp SQUID gradiometer. METHODS: Right and left median nerves were stimulated either alternately within the same run, with interstimulus intervals (ISIs) of 1.5 and 3 s, or separately in different runs with a 3 s ISI. In all conditions 4 cortical source areas were activated: the contralateral primary somatosensory cortex (SI), the contra- and ipsilateral secondary somatosensory cortices (SII) and the contralateral posterior parietal cortex (PPC). RESULTS: The earliest activity starting at 20 ms was generated solely in the SI cortex, whereas longer-latency activity was detected from all 4 source areas. The mean peak latencies for SII responses were 86-96 ms for contralateral and 94-97 ms for ipsilateral stimuli. However, the activation of right and left SII areas started at 61+/-3 and 62+/-3 ms to contralateral stimuli and at 66+/-2 and 63+/-2 ms to ipsilateral stimuli, suggesting a simultaneous commencing of activation of the SII areas. PPC sources were activated between 70 and 110 ms in different subjects. The 1.5 s ISI alternating stimuli elicited smaller SII responses than the 3 s ISI non-alternating stimuli, suggesting that a considerable part of the neural population in SII responds both to contra- and ipsilateral stimuli. The earliest SI responses did not differ between the two conditions. There were no significant differences in source locations of SII responses to ipsi- and contralateral stimuli in either hemisphere. Subaverages of the responses in sets of 30 responses revealed that amplitudes of the SII responses gradually attenuated during repetitive stimulation, whereas the amplitudes of the SI responses were not changed. CONCLUSIONS: The present results implicate that ipsi- and contralateral SII receive simultaneous input, and that a large part of SII neurons responds both to contra- and ipsilateral stimulation. The present data also highlight the different behavior of SI and SII cortices to repetitive stimuli.     

Functional characterization of human second somatosensory cortex by magnetoencephalography

Magnetoencephalographic (MEG) recordings allow noninvasive monitoring of simultaneously active brain areas with reasonable spatial and excellent temporal resolution. Whole-scalp neuromagnetic recordings show activation of contralateral primary (SI) and bilateral second (SII) somatosensory cortices to unilateral median nerve stimulation. Recent MEG studies on healthy and diseased human subjects have shown some functional characteristics of SII cortex. Besides tactile input, the SII cortex also responds to nociceptive afferents. The SII activation is differentially modulated by isometric muscle contraction of various body parts. Lesions in the SII cortex may disturb the self-perception of body scheme. Moreover, the SI and SII cortices may be sequentially activated within one hemisphere, but the SII cortex may also receive direct peripheral input on the ipsilateral side.     

Dorsal penile nerve stimulation elicits left-hemisphere dominant activation in the second somatosensory cortex

Activation of peripheral mixed and cutaneous nerves activates a distributed cortical network including the second somatosensory cortex (SII) in the parietal operculum. SII activation has not been previously reported in the stimulation of the dorsal penile nerve (DPN). We recorded somatosensory evoked fields (SEFs) to DPN stimulation from 7 healthy adults with a 122-channel whole-scalp neuromagnetometer. Electrical pulses were applied once every 0.5 or 1.5 sec to the left and right DPN. For comparison, left and right median and tibial nerves were stimulated alternatingly at 1.5-sec intervals. DPN stimuli elicited weak, early responses in the vicinity of responses to tibial nerve stimulation in the primary somatosensory cortex. Strong later responses, peaking at 107-126 msec were evoked in the SII cortices of both hemispheres, with left-hemisphere dominance. In addition to tactile processing, SII could also contribute to mediating emotional effects of DPN stimuli.     

Primary somatosensory cortex is actively involved in pain processing in human

We recorded somatosensory evoked magnetic fields (SEFs) by a whole head magnetometer to elucidate cortical receptive areas involved in pain processing, focusing on the primary somatosensory cortex (SI), following painful CO(2) laser stimulation of the dorsum of the left hand in 12 healthy human subjects. In seven subjects, three spatially segregated cortical areas (contralateral SI and bilateral second (SII) somatosensory cortices) were simultaneously activated at around 210 ms after the stimulus, suggesting parallel processing of pain information in SI and SII. Equivalent current dipole (ECD) in SI pointed anteriorly in three subjects whereas posteriorly in the remaining four. We also recorded SEFs following electric stimulation of the left median nerve at wrist in three subjects. ECD of CO(2) laser stimulation was located medial-superior to that of electric stimulation in all three subjects. In addition, by direct recording of somatosensory evoked potentials (SEPs) from peri-Rolandic cortex by subdural electrodes in an epilepsy patient, we identified a response to the laser stimulation over the contralateral SI with the peak latency of 220 ms. Its distribution was similar to, but slightly wider than, that of P25 of electric SEPs. Taken together, it is postulated that the pain impulse is received in the crown of the postcentral gyrus in human.     

Sensorimotor organization in patients who have undergone hemispherectomy: a study with (15)O-water PET and somatosensory evoked potentials

To identify cortical structures that subserve residual motor and sensory function in patients with congenital hemiparesis due to a porencephalic cyst, we examined, using [(15)O]H2O, PET and somatosensory evoked potentials (SEPs) in three patients with left-sided hemiparesis who had undergone hemispherectomy. Motor stimulation of the affected hand produced ipsilateral activation in the premotor area in all patients, the SMA in two patients, and SII in two patients. Vibrotactile stimulation resulted in activation of the ipsilateral SII in all subjects. Median nerve stimulation of the affected hand produced ipsilateral long-latency SEPs in fronto-centro-parietal areas, whereas stimulation of the non-affected hand produced normal early cortical potentials in the contralateral hemisphere. Our results suggest that residual function in the paretic hand is warranted through non-primary motor and sensory areas, and higher order associative areas in the intact hemisphere.     

A magnetoencephalography study of cortical plasticity

Abstract

An 18-year-old left-handed female with a large left hemisphere arteriovenous malformation in the frontoparietal region underwent brain mapping of the somatosensory cortex using a whole-head neuromagnetometer. Results indicated the presence of two complete somatosensory maps in the unaffected, right hemisphere. A map of contralateral body surface areas was found in the expected location in the anterior parietal lobe. A second map of ipsilateral body surface areas was found inferior to the first, extending from the inferior parietal lobe into peri-insular cortex, including SII. A less topographically organized map of the right side of the body was also found in the left hemisphere. Evoked magnetic flux components associated with right-sided stimulation occurred earlier, were more numerous, and were stronger in the ipsilateral as compared to the contralateral hemisphere, suggesting that the ipsilateral map is functional. These findings are discussed in relationship to other functional imaging studies of reorganization of the functional cortex in response to early trauma or congenital anomaly.     

Somatosensory cortex responses to median nerve stimulation: fMRI effects of current amplitude and selective attention.

OBJECTIVES: The aim of this study was to localize and to investigate response properties of the primary (SI) and the secondary (SII) somatosensory cortex upon median nerve electrical stimulation. METHODS: Functional magnetic resonance imaging (fMRI) was used to quantify brain activation under different paradigms using electrical median nerve stimulation in healthy right-handed volunteers. In total 11 subjects were studied using two different stimulus current values in the right hand: at motor threshold (I(max)) and at I(min) (1/2 I(max)). In 7 of these 11 subjects a parametric study was then conducted using 4 stimulus intensities (6/6, 5/6, 4/6 and 3/6 I(max)). Finally, in 10 subjects an attention paradigm in which they had to perform a counting task during stimulation with I(min) was done. RESULTS: SI activation increased with current amplitude. SI did not show significant activation during stimulation at I(min). SII activation did not depend on current amplitude. Also the posterior parietal cortex appeared to be activated at I(min). The I(min) response in SII significantly increased by selective attention compared to I(min) without attention. At I(max) significant SI activity was observed only in the contralateral hemisphere, the ipsilateral cerebellum, while other areas possibly showed bilateral activation. CONCLUSIONS: Distributed activation in the human somatosensory cortical system due to median nerve stimulation was observed using fMRI. SI, in contrast to SII, appears to be exclusively activated on the contralateral side of the stimulated hand at I(max), in agreement with the concept of SI's important role in processing of proprioceptive input. Only SII remains significantly activated in case of lower current values, which are likely to exclusively stimulate the sensible fibres mediating cutaneous receptor input. Selective attention only enhances SII activity, indicating a higher-order role for SII in the processing of somatosensory input.     

Local gustatory functions associated with segmental organization of the anterior portion of cat's tongue

Neural basis for local taste specificity within the anterior two-thirds of the mammalian tongue remains obscure. The present electrophysiological study aimed to clarify the topographical organization of tongue receptive areas in the cat and monkey and, also, to evaluate taste responsiveness of different tongue regions within the field of the cat's lingual nerve. The anterior portion of the cat's tongue was found to consist of three receptive areas, each receiving somatic as well as gustatory fibers from one of three lingual nerve ramifications, namely the anterior, medial, and posterior branches. The organization of tongue receptive areas in the monkey was found to be similar to that in the cat except that the anterior portion of the tongue comprised at least five receptive zones which overlapped more extensively than in the cat. Summed responses of the chorda tympani nerve component of the three lingual nerve branches to gustatory and thermal stimulations of the cat's tongue were expressed relative to the whole chorda tympani response to 1 m NaCl, whereas the response of the trigeminal nerve component to cooling was expressed relative to the whole trigeminal nerve response to a standard temperature. It was found that the anterior branch field responded poorly to all taste qualities but strongly to cooling of the tongue. The medial branch field was highly responsive to NaCl, water and warmed saline, whereas the responsiveness of the posterior branch field to HC1 was stronger than other areas. The findings show localization of specific sensory properties over different tongue regions.     

Intracortical recordings of early pain-related CO2-laser evoked potentials in the human second somatosensory (SII) area.

We studied responses of the parieto-frontal opercular cortex to CO2-laser stimulation of A delta fiber endings, as recorded by intra-cortical electrodes during stereotactic-EEG (SEEG) presurgical assessment of patients with drug-resistant temporal lobe epilepsy. After CO2-laser stimulation of the skin at the dorsum of the hand, we consistently recorded in the upper bank of the sylvian fissure contralateral to stimulation, a negative response at a latency of 135 +/- 18 ms (N140), followed by a positivity peaking around 171 +/- 22 ms (P170). The stereotactic coordinates in the Talairach's atlas of the electrode contacts recording these early responses covered the pre- and post-rolandic part of the upper bank of the sylvian fissure (-27 < y < +12 mm; 31 < x < 57 mm; 4 < z < 23 mm), corresponding to the accepted localization of the SII area in man, possibly including the upper part of the insular cortex. The spatial distribution of these early contralateral responses in the SII-insular cortex fits wit that of the modeled sources of scalp CO2-laser evoked potentials (LEPs) and with PET data from pain activation studies. Moreover, this study showed the likely existence of dipolar sources radial to the scalp surface in SII, which are overlooked in magnetic recordings. Early responses also occurred in the SII area ipsilateral to stimulation peaking 15 ms later than in contralateral SII, suggesting a callosal transmission of nociceptive inputs between the two SII areas. Other pain responsive areas such as the anterior cingulate gyrus, the amygdala and the orbitofrontal cortex did not show early LEPs in the 200 ms post-stimulus. These findings suggest that activation of SII area contralateral to stimulation, possibly through direct thalamocortical projections, represents the first step in the cortical processing of peripheral A delta fiber pain inputs.     

Cortical nociceptive responses and behavioral correlates in the monkey

Experiments were performed to characterize cerebral cortical activity and pain behavior elicited by electrical stimulation of the tooth pulp in unanesthetized monkeys. Four monkeys were trained on two different operant paradigms: two on a simple escape task and two on an appetitive tolerance-escape task. All monkeys were implanted with bipolar stimulating electrodes in the right maxillary canine tooth and subdural recording electrodes over the left primary (SI) and/or secondary (SII) somatosensory cortices. Subdural tooth pulp-evoked potentials (TPEPs) recorded over the SII consisted of components P1 (27.5 ms), N1 (40.3 ms), P2 (84.0 ms), N2 (163.5 ms), P3 (295.3 ms), and N3 (468.0 ms). The long latency component (P3-N3) was found exclusively over the SII and was elicited by high intensity stimulation. The appearance of component P3-N3 required the recruitment of A delta nerve fibers into the maxillary nerve compound action potential and was correlated with high frequencies of escape. Administration of morphine sulfate (4 mg/kg, i.m.) caused a contemporaneous reduction in escape frequency and in the amplitude of P3-N3 recorded over the SII. The relationships between TPEP amplitude, escape behavior and A delta nerve fiber activity strongly suggest that the SII is involved with nociception and pain behavior.     

Dipolar source modeling of somatosensory evoked potentials to painful and nonpainful median nerve stimulation

Dipolar source modeling might help in clarifying whether somatosensory evoked potentials (SEPs) after electrical stimulation at painful intensity contain any information related to the nociceptive processing. SEPs were recorded after left median nerve stimulation at three different intensities: intense but nonpainful (intensity 2); slightly painful (pain threshold; intensity 4); and moderately painful (intensity 6). Scalp SEPs at intensities 2, 4, and 6 were fitted by a five-dipole model. When the strength modifications of the source activities up to 40 ms were examined across the different stimulus intensities, no significant difference was found. In the later epoch (40-200 ms), a posterior parietal dipole and two bilateral sources probably located in the second somatosensory (SII) areas increased significantly their dipole moments when the stimulus was increased from 2 to 4 and became painful. Since no difference was found when the stimulus intensity was increased from 4 to 6, the observed increase of the dipolar strengths is probably related to a variation of the stimulus quality (nonpainful vs. painful), rather than of the stimulus intensity per se. Our findings lead us to conclude that a large convergence of nociceptive and non-nociceptive afferents probably occurs bilaterally in the SII areas.     

脑白质疏松症的磁共振扩散张量成像研究及其与急性腔隙性脑梗死的鉴别

目的 研究脑白质疏松症(LA)和急性腔隙性脑梗死(LD在磁共振扩散张量(DTI)影像学上的特点,探讨DTI对LA诊断及其与LI鉴别诊断的价值.方法 对28例LA患者、11例LI患者和20名正常老年人行DTI扫描,测量LA病灶区、形似正常(NAWM)区、LI梗死中心、健侧对应部位和对照组正常白质区的平均扩散系数(MD)、部分各项异性(FA)值.结果 LA患者病灶分别较NAWM、对照组以及LA NAWM区较对照组,MD值升高,FA值降低.各组大脑半球左右侧(除LA NAWM区侧脑室前端和后端周围MD值外)MD和FA值无显著性差异;随LA严重程度增加,MD值升高,而FA值降低;LI梗死中心较健侧对应部位和对照组MD值、FA值均较对照组降低.结论 DTI在监测脑白质病变上远比常规MRI灵敏度高,可发现早期的LA病变.LA的DTI参数变化反映了脑白质微结构改变.LA和急性LI在DTI的表现有特征性差异,显示出DTI在LA诊断及其与LI鉴别诊断的价值.     

Barbiturate spindle activity in the thalamic lateral ventro-posterior nucleus and the second somato-sensory area of the cortex.

(1) Barbiturate spindles recorded from the second somato-sensory cortical area (SII) were similar to spindles in the primary somato-sensory area (SI) both with respect to incidence, duration of each spindle and per cent spindle time. The spindle wave amplitude was smaller in SII. The highest spindle wave amplitude was observed in the anterior part of SII which receives input from nucleus ventralis postero-lateralis (VPL). No spindle activity was observed in the posterior part of SII which receives input from the posterior nuclear group (PO) of the thalamus. (2) Barbiturate spindles recorded from a locus in VPL and its projection area in SII were cross-correlated. The analysis resulted in high cross-correlation factors, indicating that a considerable degree of spindle wave synchrony existed between the spindles. This wave synchrony was reduced by moving the cortical electrode a short distance. (3) Cortical spindles recorded from corresponding sites in SI and SII were cross-correlated, and gave a high cross-correlation coefficient. This synchrony was markedly reduced if one of the electrodes was moved a few millimetres away from the optimal point. (4) Spindles started simultaneously in corresponding sites of SI and SII. A high degree of coincidence was found also between spindles in a VPL locus and the corresponding projection site in SII. Local anaesthesia applied to or total removal of SI failed to influence the spindle activity in SII and vice versa. Similarly, the SI-SII synchrony survived a deep incision cutting all connections between the two areas. (6) It is suggested that spindles in corresponding sites of SII and SI have a common thalamic pacemaker which probably projects to both areas by axonal branching.     

Relation of cortical language distribution and cognitive function in surgical epilepsy patients

PURPOSE: To investigate the relation between the number and spatial distribution of language sites and specific patient-and epilepsy-related variables. METHODS: Patients with stimulation-induced reading or naming errors from anterior or inferior temporal cortex (i.e., atypical temporal language sites) were compared with those with language sites confined to Wernicke's area (WA) in the posterosuperior temporal and inferior parietal perisylvian area. In a consecutive series of 44 left hemisphere language dominant patients with complex partial seizures before left temporal lobectomy, correlations were compared between cortical language distribution and measures of cognitive function. RESULTS: Patients with atypical temporal language sites (group 1) had significantly fewer years of education that did patients with language sites in WA (group 2). Patients in group 1 had poorer verbal learning and fluency than did patients in group 2. Patients with IQ <80 were significantly more likely to have multiple sites where stimulation disrupted language than did patients with normal IQ. Number of language sites had significant negative correlations with full-scale IQ, and measures of confrontation naming, verbal fluency, and immediate verbal memory. CONCLUSIONS: Language cortex has a wider spatial distribution in epilepsy surgery patients with lower intelligence, poorer education, and worse verbal and memory skills.     

Right hemispheric dominance of visual phenomena evoked by intracerebral stimulation of the human visual cortex

Electrical brain stimulation can provide important information about the functional organization of the human visual cortex. Here, we report the visual phenomena evoked by a large number (562) of intracerebral electrical stimulations performed at low‐intensity with depth electrodes implanted in the occipito‐parieto‐temporal cortex of 22 epileptic patients. Focal electrical stimulation evoked primarily visual hallucinations with various complexities: simple (spot or blob), intermediary (geometric forms), or complex meaningful shapes (faces); visual illusions and impairments of visual recognition were more rarely observed. With the exception of the most posterior cortical sites, the probability of evoking a visual phenomenon was significantly higher in the right than the left hemisphere. Intermediary and complex hallucinations, illusions, and visual recognition impairments were almost exclusively evoked by stimulation in the right hemisphere. The probability of evoking a visual phenomenon decreased substantially from the occipital pole to the most anterior sites of the temporal lobe, and this decrease was more pronounced in the left hemisphere. The greater sensitivity of the right occipito‐parieto‐temporal regions to intracerebral electrical stimulation to evoke visual phenomena supports a predominant role of right hemispheric visual areas from perception to recognition of visual forms, regardless of visuospatial and attentional factors. Hum Brain Mapp 35:3360–3371, 2014. © 2013 Wiley Periodicals, Inc .     

Side of the stimulated ear influences the hemispheric balance in coding tonal stimuli

OBJECTIVE: To evaluate whether the side of stimulated ear affects the hemispheric asymmetry of auditory evoked cortical activations. METHODS: Using a whole-head neuromagnetometer, we recorded neuromagnetic approximately 100 ms responses (N100m) in 21 healthy right-handers to 100 ms 1 kHz tones delivered alternatively to left and right ear. RESULTS: Although the peak latencies of N100m were shorter in contralateral than in ipsilateral hemisphere, the difference was significant only for the left ear stimulation. Based on the relative N100m amplitudes across hemispheres, the laterality evaluation showed a rightward predominance of N100m activation to tone stimuli, but the lateralization toward the right hemisphere was more apparent by the left than by the right ear stimulation (laterality index: -0.27 versus -0.10, p=0.008). Within the right hemisphere, the N100m was 2-4 mm more posterior for left ear than for right ear stimulation. CONCLUSIONS: The hemispheric asymmetry in auditory processing depends on the side of the stimulated ear. The more anterior localization of right N100m responses to ipsilateral than to contralateral ear stimulation suggests that there might be differential neuronal populations in the right hemisphere for processing spatially different auditory inputs.     

Transcranial magnetic stimulation to the parietal lobes reduces detection of contralateral somatosensory stimuli

OBJECTIVES: Neglect has been described in patients with lesions of the parietal cortex and has been interpreted as a disorder of the allocation of spatial attention. The persistence of neglect has been linked to poor rehabilitation outcome in patients suffering from acute stroke. Transcranial magnetic stimulation (TMS) applied to the parietal cortex has been shown to induce changes in the perception of stimuli including tactile stimulation of the fingers contra- and ipsilateral to the stimulated hemisphere. MATERIAL AND METHODS: In the current study, eleven normal young subjects performed a detection task for cutaneous electrical stimuli to the left or right forearm that had been precued by a preceding visual warning stimulus. To investigate the role of the parietal cortical areas for attentional processes TMS was applied to frontal and parietal scalp sites of each hemisphere in the cue-target interval before the somatosensory stimulus. RESULTS: Right and left parietal stimulation led to reduced detection sensitivity for near threshold stimuli to the forearm contralateral to the stimulated hemisphere without hemispheric differences. Ipsilateral tactile perception was not influenced by parietal TMS and there was no change in perception after frontal stimulation to left or right scalp sites. CONCLUSION: This pattern of results is consistent with a role of the right and left parietal lobe in the distribution of spatial attention and provides an experimental basis for possible therapeutical application of TMS to improve attentional deficits in stroke patients.