Enabling and promoting walking rehabilitation by paired associative stimulation after incomplete paraplegia: a case report.

INTRODUCTION: Paired associative stimulation (PAS) is a combination of transcranial magnetic stimulation (TMS) and peripheral nerve stimulation (PNS) and induces plastic changes in the human corticospinal tract. We have previously shown that PAS consisting of TMS pulses given at 100% of stimulator output and high-frequency PNS is beneficial for motor rehabilitation of patients with a chronic incomplete spinal cord injury (SCI). The therapeutic possibilities of this PAS variant for walking rehabilitation of paraplegic patients are unexplored. CASE PRESENTATION: A 47-year old man with traumatic incomplete paraplegia (AIS D, neurological level T7) received PAS to his left leg for 3 months at 12 months post injury (PAS1) and for an additional 3 months at 24 months post injury (PAS2). The right leg had normal AIS scores and was not stimulated. Before PAS, the patient was nonambulatory, could not stand without weight support, and was consequently not eligible for conventional walking rehabilitation. After PAS1, the patient could stand for 1.5 min and take 13 steps (24 steps in follow up) on parallel bars without weight support and was enrolled into conventional walking rehabilitation. He achieved independent walking ability with a rollator. During PAS2, walking distance increased 2.4 times faster than during the preceding year. The left leg AIS score and spinal cord independence measure mobility subscore increased. No adverse effects were detected. DISCUSSION: This is the first report of PAS with a high-frequency peripheral component that enabled and promoted walking rehabilitation. Together with previous reports on this technique, this result encourages further research into its therapeutic potential and mechanism.

Neuromagnetic speech discrimination responses are associated with reading-related skills in dyslexic and typical readers.

Poor neural speech discrimination has been connected to dyslexia, and may represent phonological processing deficits that are hypothesized to be the main cause for reading impairments. Thus far, neural speech discrimination impairments have rarely been investigated in adult dyslexics, and even less by examining sources of neuromagnetic responses. We compared neuromagnetic speech discrimination in dyslexic and typical readers with mismatch fields (MMF) and determined the associations between MMFs and reading-related skills. We expected weak and atypically lateralized MMFs in dyslexic readers, and positive associations between reading-related skills and MMF strength. MMFs were recorded to a repeating pseudoword /ta-ta/ with occasional changes in vowel identity, duration, or syllable frequency from 43 adults, 21 with confirmed dyslexia. Phonetic (vowel and duration) changes elicited left-lateralized MMFs in the auditory cortices. Contrary to our hypothesis, MMF source strengths or lateralization did not differ between groups. However, better verbal working memory was associated with stronger left-hemispheric MMFs to duration changes across groups, and better reading was associated with stronger right-hemispheric late MMFs across speech-sound changes in dyslexic readers. This suggests a link between neural speech processing and reading-related skills, in line with previous work. Furthermore, our findings suggest a right-hemispheric compensatory mechanism for language processing in dyslexia. The results obtained promote the use of MMFs in investigating reading-related brain processes.

Combined use of non-invasive techniques for improved functional localization for a selected group of epilepsy surgery candidates.

Invasive cortical mapping is conventionally required for preoperative identification of epileptogenic and eloquent cortical regions before epilepsy surgery. The decision on the extent and exact location of the resection is always demanding and multimodal approach is desired for added certainty. The present study describes two non-invasive preoperative protocols, used in addition to the normal preoperative work-up for localization of the epileptogenic and sensorimotor cortical regions, in two young patients with epilepsy. Magnetoencephalography (MEG) was used to determine the primary somatosensory cortex (S1) and the ictal onset zones. Navigated transcranial magnetic stimulation (nTMS) was used to determine the location and the extent of the primary motor representation areas. The localization results from these non-invasive methods were used for guiding the subdural grid deployment and later compared with the results from electrical cortical stimulation (ECS) via subdural grids, and validated by surgery outcome. The results from MEG and nTMS localizations were consistent with the ECS results and provided improved spatial precision. Consistent results of our study suggest that these non-invasive methods can be added to the standard preoperative work-up and may even hold a potential to replace the ECS in a subgroup of patients with epilepsy who have the suspected epileptogenic zone near the sensorimotor cortex and seizures frequent enough for ictal MEG.

Restoration of hand function with long-term paired associative stimulation after chronic incomplete tetraplegia: a case study.

Introduction: This case study explores the gains in hand function in an individual with a chronic spinal cord injury (SCI). The intervention was long-term paired associative simulation (PAS). We aimed to provide PAS until full recovery of hand muscle strength occurred, or until improvements ceased. Case presentation: A 46-year-old man with traumatic C7 AIS B tetraplegia was administered PAS three times per week. After 24 weeks, PAS was combined with concomitant motor training of the remaining weak hand muscles. Outcome measures included the manual muscle test (MMT), motor-evoked potentials (MEPs), F-responses, hand functional tests, and the spinal cord independence measure (SCIM). Discussion: After 47 weeks of PAS the subject had improved self-care and indoor mobility and was able to perform complex motor tasks (SCIM score improved from 40 to 56). His left hand regained maximum MMT score (total 75; increase of score from baseline condition 19); the effect remained stable in the 32-week follow up. In the right-hand muscles, MMT scores of 4-5 were observed in follow up (total 71; increase from baseline 48). Improved values were also observed in other outcomes. This is the first demonstration of long-term PAS restoring muscle strength corresponding to MMT scores of 4-5 in an individual with chronic SCI. The effect persisted for several months, indicating that PAS induces stable plastic changes in the corticospinal pathway.

Neuromagnetic cortical signals in a patient with hydrocephalus.

We studied a patient with a communicating hydrocephalus using a whole-head neuromagnetometer. Auditory evoked fields (AEFs) were elicited with 600 ms tones, 0.25, 0.5, 1, 2 and 4 kHz in frequency. The source locations were more superficial and posterior in the patient than in controls, but still agreed with activation of the supratemporal cortex. Tonotopic organization of the AEF sources was similar in the patient and healthy control subjects. The amplitude spectra, source strengths and sites, and reactivity of the patient's spontaneous activity were normal. Despite apparent decrease of white matter, the patient's thalamocortical connections thus seem to be able to maintain normal evoked and spontaneous cortical activity.

Neuromagnetic auditory evoked responses after a stroke in the right temporal lobe.

Auditory evoked magnetic fields were recorded with a 24-SQUID magnetometer on a patient with a vascular lesion in the right auditory cortex and its vicinity. The contralateral transient 100 ms response (N100m) was absent over the damaged side, with no recovery within 16 months. Responses were normal over the healthy side. The responses to a binaural click train where interaural delays caused the perception of a shifting sound source; responses were again normal over the left side. Ipsilateral tones elicited N100m over the normal hemisphere but with smaller amplitude and longer latency than in healthy subjects. We suggest that ipsilateral responses are triggered by ipsilateral afferents but are significantly modified by excitatory callosal connections which did not work in our patient.

Hemispheric differences in processing tone frequency and amplitude modulations.

Transient frequency and amplitude modulations (FMs, AMs) of sound are requisite to speech recognition. We recorded whole-head magnetoencephalographic signals from seven subjects to binaural 620 ms 667 Hz tones, with 3, 30, or 300 ms FMs or AMs in the beginning or middle of the tone. Responses were significantly larger and earlier for FMs than AMs, for rapid than slow modulations, and for modulations at the beginning (BEG) than in the middle (MID) of the sound. BEG 3 ms FMs elicited strongest signals in the left and MID 3 ms FMs in the right hemisphere. Fast MID modulations produced significantly stronger responses in the right than left hemisphere. These differences may reflect different functions of the left and right hemisphere in speech perception.

Abrupt unilateral deafness modifies function of human auditory pathways.

We studied nine patients with unilateral abrupt deafness caused by acoustic neuroma surgery. Cortical responses to tones delivered to the intact ear were recorded postoperatively with a 122-channel whole-scalp neuromagnetometer. In three patients, followed for 12 months with 2-4 measurements, evoked responses originating in the auditory cortices were weak and delayed one month after the operation in both hemispheres. During the follow-up, the amplitudes reached the control level. No response abnormalities were found in patients who were studied 1.5-4.5 years after the operation. Our findings suggest that abrupt unilateral deafness causes immediate changes in the function of auditory pathways of adult humans and that reorganization takes place within 1 year.

Trigeminally triggered epileptic hemifacial convulsions.

We present whole-head magnetoencephalographic recordings from a patient suffering from trigeminally triggered left-sided hemifacial convulsions. The patient was a candidate for surgical treatment, but regardless of extensive scalp EEG, videotelemetry and PET recordings, an epileptic focus could not be identified. Magnetic signal distribution during a seizure suggested focal epileptic activity in the face area of the right primary motor cortex. A secondary focus was activated 22 ms later in the left hemisphere. Discharges could be triggered by sensory stimulation of the left lower gum. The similarities of this seizure production mechanism to trigeminal neuralgia and kindling are discussed.

Parietal epileptic mirror focus detected with a whole-head neuromagnetometer.

Whole-head magnetoencephalographic recordings revealed two parietal epileptic foci in homotopic areas of the hemispheres. The discharges occurred 17-20 ms later on the left than on the right hemisphere, implying the existence of a left-sided mirror focus. The foci were about 1 cm posterior to the hand primary somatosensory area, identified by evoked response measurements, and thus suggested epileptic activity at the parietal association cortex, in agreement with the observed callosal conduction time.

Suppression of magnetic mu rhythm during parkinsonian tremor.

We recorded spontaneous magnetoencephalographic (MEG) activity and somatosensory-evoked fields (SEFs) with a 24-channel planar SQUIDgradiometer in five patients with hemiparkinsonism. The SEFs of the patients were within normal limits. During tremorless periods, the spontaneous activity over the somatomotor cortex had a frequency peak at approximately 10 Hz in all five patients and another at approximately 20 Hz in three. Tremor dampened the 10-Hz activity in all patients; in three the effect was bilateral. Tremor did not increase MEG activity at the tremor frequency. The suppression of the mu rhythm by the parkinsonian tremor resembled that occurring during voluntary movements in healthy subjects.

Human auditory cortex is activated by omissions of auditory stimuli.

Cortical signals associated with infrequent tone omissions were recorded from 9 healthy adults with a whole-head 122 channel neuromagnetometer. The stimulus sequence consisted of monaural (left or right) 50-ms 1-kHz tones repeated every 0.2 or 0.5 s, with 7% of the tones randomly omitted. Tones elicited typical responses in the supratemporal auditory cortices. Omissions evoked strong responses over temporal and frontal areas, independently of the side of stimulation, with peak amplitudes at 145-195 ms. Response amplitudes were 60% weaker when the subject was not attending to the stimuli. Omission responses originated in supratemporal auditory cortices bilaterally, indicating that auditory cortex plays an important role in the brain's modelling of temporal characteristics of the auditory environment. Additional activity was observed in the posterolateral frontal cortex and in the superior temporal sulcus, more often in the right than in the left hemisphere.

Cortical origin of middle-latency auditory evoked responses in man.

We have recorded middle-latency magnetic evoked responses to 50-ms noise bursts, presented once every 0.9 s, over the right hemisphere of healthy humans. The measurements were carried out with a sensitive 7-channel SQUID gradiometer with a passband of 0.5-2000 Hz. The response consisted of peaks at about 30, 50 and 65 ms. The location of the equivalent source of the 30-ms deflection agrees with activation of the supratemporal auditory cortex, slightly anterior to the source area of the well-known 100-ms deflection.

Auditory pathway plasticity in adult humans after unilateral idiopathic sudden sensorineural hearing loss.

We recorded auditory evoked magnetic fields from 8 patients with unilateral, idiopathic, sudden, sensorineural hearing loss and from 8 healthy controls, using a 122-channel whole-scalp neuromagnetometer. The stimuli were 50-ms l-kHz tone bursts, delivered to the healthy ear at interstimulus intervals (ISIs) of 1, 2, 4, 8, and 16 s. On average, as in normal-hearing controls, the dipole moments and the latencies of N100m, the 100-ms response, increased as a function of ISI over both hemispheres to left- and right-ear stimulation. Four patients had shorter response latencies and 4 had stronger dipole moments over the hemisphere ipsilateral to the stimulation. In 3 patients, one additional source was observed over the anterolateral right hemisphere and another near head midline. These findings suggest that unilateral sensorineural hearing loss may modify information processing in the central auditory pathways.

Auditory cortical responses in humans with profound unilateral sensorineural hearing loss from early childhood.

We recorded auditory evoked magnetic fields from five patients with profound unilateral sensorineural hearing loss from early childhood, using a 122-channel whole-scalp neuromagnetometer. The stimuli were 50-ms 1-kHz tone bursts delivered to the healthy ear at interstimulus intervals (ISI) of 1, 2, and 4 s. As the normal-hearing controls, four patients had shorter latencies of N100m, the 100-ms response, over the hemisphere contralateral to the stimulation than over the ipsilateral hemisphere. With 1-s ISI, three patients had, instead of N100m, a deflection of opposite polarity at about 100 ms (P100m) after the stimulus onset. A 10-year-old patient had a prominent P100m response, did not produce a clear N100m at any ISI, but had a clear N50m at the 4-s ISI. Four patients had bilateral N200m deflections peaking about 200 ms after the stimulus onset; the fifth patient showed N200m over the right hemisphere. N200m was also observed in the three youngest controls in both hemispheres. The ISI dependence of N100m amplitude and latency was similar in controls and patients. The amplitudes and latencies of N200m did not show any ISI dependence. In patients, the appearance of P100m-N200m deflections of auditory evoked fields, normally present in children, is more pronounced than in controls. The defect apparently delays the development of N100m, possibly by interfering with function of callosal connections.

Different analysis of frequency and amplitude modulations of a continuous tone in the human auditory cortex: a neuromagnetic study.

We have measured auditory evoked magnetic fields to intermittent frequency and amplitude modulations (FMs and AMs) of a continuous tone in 6 healthy humans. The stimuli were presented in pairs separated by 500 ms in four different combinations (FM-AM, FM-FM, AM-FM and AM-AM). Both modulations elicited neuromagnetic responses of similar waveforms: the largest deflection, N100m (magnetic counterpart of the electric N100), was preceded by a low amplitude P60m and followed by P200m. For stimuli of different types, the decrease of N100m from the first to the second response was less than expected from the recovery cycle of the responses, estimated from the pairs of similar stimuli. We interpret these results as evidence for different processing of amplitude and frequency modulations in the auditory pathways up to the level of supratemporal auditory cortex.

Effect of interaural time differences on middle-latency and late auditory evoked magnetic fields.

To determine if interaural time differences (ITDs) in binaural stimuli affect the middle-latency auditory evoked fields (AEFs) in the same manner as they affect the N100m deflection, neuromagnetic responses were recorded over the whole head using a 122-channel SQUID magnetometer. Binaural stimuli were lateralized to three positions, left, midline, and right, on the basis of ITDs. The N100m was significantly larger to stimuli with contralaterally-leading ITDs than to stimuli with no, or with ipsilaterally-leading ITDs. Neither the P30m nor the P50m deflections of the middle-latency response were significantly affected by ITD, although the P30m showed a tendency, similar to but smaller than that of N100m, to be larger to stimuli with contralaterally-leading ITDs. In some subjects, the source location of the P50m was anterior and inferior to the sources of the P30m and N100m, which are generated in the superior surface of the temporal lobe. Sound-related muscular artifacts were seen in the posterior recording channels of one subject, and the contribution of this activity to the signals over the temporal area was determined.

Temporal integration and oscillatory responses of the human auditory cortex revealed by evoked magnetic fields to click trains.

We recorded neuromagnetic evoked responses from the right auditory cortex of 7 healthy adults with a 24-channel planar SQUID gradiometer. The stimuli were 200-ms click trains presented at rates of 40, 80, 160 and 320 Hz, with interstimulus intervals (ISIs) of 1 and 4 s. The transient N100m response to the train onset depended on the click rate: the peak latency shortened to the same extent as the interval between successive clicks decreased in trains with rates from 40 Hz to 320 Hz. The N100m amplitude increased simultaneously, saturating at rates of 160-320 Hz. The mean N100m latency was slightly longer with the 1-s than with the 4-s ISI for all click rates. The systematic changes of the N100m amplitude and latency according to click rate demonstrate the importance of temporal integration for N100m generation, and imply an integration time of 20-25 ms. The 20- and 40-Hz click trains also elicited oscillatory 40-Hz responses 80-250 ms after the train onset. The 40-Hz responses were more resistant than N100m to changes of the ISI, and their sources slightly differed from those of N100m. These two responses evidently reflect different aspects of auditory processing.

Auditory cortical responses in humans with congenital unilateral conductive hearing loss.

We recorded auditory evoked magnetic fields from 6 patients with congenital unilateral conductive hearing disorder with a 122-channel whole-head neuromagnetometer. The stimuli were 50-ms 1-kHz tones delivered to the better ear at interstimulus intervals (ISIs) of 2 and 8 s at two different intensities (50 and 70 dB HL). As in normal-hearing subjects, the amplitudes of N100m, the 100-ms response, were larger in 5 patients and the latencies were shorter in 3 patients over the hemisphere contralateral to stimulation. However, in one patient N100m peaked already at 61 ms over the contralateral hemisphere and amplitudes were larger over the ipsilateral hemisphere, possibly reflecting reorganization of the auditory pathways. In 3 patients the latencies were shorter over the ipsilateral hemisphere. The effects of ISI and intensity were similar over both hemispheres and did not differ from those in controls. It seems that congenital unilateral conductive hearing loss does not necessarily lead to any gross disturbances in the human auditory cortex.

Steady-state responses from the cat auditory cortex.

Responses to 350 ms trains of clicks with 10-100 Hz repetition rate were recorded from the auditory cortices of six cats. Click trains of 30-50 and 90-100 Hz elicited a clear steady-state response (SSR) in awake state. SSRs were small or absent below 30 Hz and in 60-70 Hz stimulus range. In slow wave sleep the optimal rate to elicit SSR shifted towards lower frequencies. 90 Hz SSR was largest in paradoxical sleep. SSRs were strongly suppressed by barbiturate anesthesia. The amplitude of the SSR from the medial geniculate body (MGB) in two cats gradually decreased from 20 to 100 Hz and was more resilient to barbiturate anesthesia than the cortical SSRs. Only low amplitude or no SSRs could be recorded from vertex, visual and association cortices and from the hippocampus in control recordings. The results suggest different generation mechanisms for SSRs recorded from cat auditory cortex and MGB. Human auditory SSRs resemble cat auditory cortical SSRs more than those recorded from cat MGB. The results imply that auditory SSRs in humans are generated in the cortex.