Mapping Subcortico-Cortical Coupling-A Comparison of Thalamic and Subthalamic Oscillations.

BACKGROUND: The ventral intermediate nucleus of the thalamus (VIM) is an effective target for deep brain stimulation in tremor patients. Despite its therapeutic importance, its oscillatory coupling to cortical areas has rarely been investigated in humans. OBJECTIVES: The objective of this study was to identify the cortical areas coupled to the VIM in patients with essential tremor. METHODS: We combined resting-state magnetoencephalography with local field potential recordings from the VIM of 19 essential tremor patients. Whole-brain maps of VIM-cortex coherence in several frequency bands were constructed using beamforming and compared with corresponding maps of subthalamic nucleus (STN) coherence based on data from 19 patients with Parkinson's disease. In addition, we computed spectral Granger causality. RESULTS: The topographies of VIM-cortex and STN-cortex coherence were very similar overall but differed quantitatively. Both nuclei were coupled to the ipsilateral sensorimotor cortex in the high-beta band; to the sensorimotor cortex, brainstem, and cerebellum in the low-beta band; and to the temporal cortex, brainstem, and cerebellum in the alpha band. High-beta coherence to sensorimotor cortex was stronger for the STN (P = 0.014), whereas low-beta coherence to the brainstem was stronger for the VIM (P = 0.017). Although the STN was driven by cortical activity in the high-beta band, the VIM led the sensorimotor cortex in the alpha band. CONCLUSIONS: Thalamo-cortical coupling is spatially and spectrally organized. The overall similar topographies of VIM-cortex and STN-cortex coherence suggest that functional connections are not necessarily unique to one subcortical structure but might reflect larger frequency-specific networks involving VIM and STN to a different degree. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Directional Deep Brain Stimulation of the Thalamic Ventral Intermediate Area for Essential Tremor Increases Therapeutic Window.

OBJECTIVES: Deep brain stimulation (DBS) of the posterior subthalamic area (PSA) and the ventral intermediate thalamic nucleus (VIM) is a well-established therapy for essential tremor (ET), but it is frequently associated with side effects like dysarthria or gait ataxia. Directional DBS (dDBS) may be a way to activate fiber tracts more selectively. Is dDBS for ET superior to omnidirectional DBS (oDBS) regarding therapeutic window and clinically as effective as oDBS? MATERIALS AND METHODS: Ten patients with ET treated with PSA/VIM-DBS were recruited. Therapeutic window served as primary outcome parameter; clinical efficacy, volume of neuronal activation, and total electrical energy delivered (TEED) served as secondary outcome parameters. Therapeutic window was calculated for all three dDBS directions and for oDBS by determining therapeutic thresholds and side effect thresholds. Clinical efficacy was assessed by comparing the effect of best dDBS and oDBS on tremor and ataxia rating scales, and accelerometry. Volume of neural activation and TEED were also calculated for both paradigms. RESULTS: For best dDBS, therapeutic window was wider and therapeutic threshold was lower compared to oDBS. While side effect threshold did not differ, volume of neural activation was larger for dDBS. In terms of clinical efficacy, dDBS was as effective as oDBS. CONCLUSIONS: dDBS for ET widens therapeutic window due to reduction of therapeutic threshold. Larger volume of neural activation for dDBS at side effect threshold supports the notion of persistent directionality even at higher intensities. dDBS may compensate for slightly misplaced leads and should be considered first line for PSA/VIM-DBS.

Auditory cortex sensitivity to the loudness attribute of verbs.

The auditory cortex was shown to be activated during the processing of words describing actions with acoustic features. The present study further examines whether processing visually presented action words characterized by different levels of loudness, i.e. "loud" (to shout) and "quiet" actions (to whisper), differentially engage the auditory cortex. Twenty healthy participants were measured with magnetoencephalography (MEG) while reading inflected verbs followed by a short tone and semantic tasks. Based on the results of a localizer task, loudness sensitive temporal Brodmann areas A22, A41/42, and pSTS were inspected in the word paradigm. "Loud" actions induced significantly stronger beta power suppression compared to "quiet" actions in the left hemisphere. Smaller N100m amplitude related to tones following "loud" compared to "quiet" actions confirmed that auditory cortex sensitivity was modulated by action words. Results point to possible selective auditory simulation mechanisms involved in verb processing and support embodiment theories.

Occurrence of thalamic high frequency oscillations in patients with different tremor syndromes.

OBJECTIVE: To assess whether high frequency oscillations (HFOs, >150 Hz), known to occur in basal ganglia nuclei, can be observed in the thalamus. METHODS: We recorded intraoperative local field potentials from the ventral intermediate nucleus (VIM) of the thalamus in patients with Essential Tremor (N = 16), Parkinsonian Tremor (3), Holmes Tremor (2) and Dystonic Tremor (1) during implantation of electrodes for deep brain stimulation. Recordings were performed with up to five micro/macro-electrodes that were simultaneously advanced to the stereotactic target. RESULTS: Thalamic HFOs occurred in all investigated tremor syndromes. A detailed analysis of the Essential Tremor subgroup revealed that medial channels recorded HFOs more frequently than other channels. The highest peaks were observed 4 mm above target. Macro- but not microelectrode recordings were dominated by peaks in the slow HFO band (150-300 Hz), which were stable across several depths and channels. CONCLUSION: HFOs occur in the thalamus and are not specific to any of the tremors investigated. Their spatial distribution is not homogeneous, and their appearance depends on the type of electrode used for recording. SIGNIFICANCE: The occurrence of HFOs in the thalamus of tremor patients indicates that HFOs are not part of basal ganglia pathophysiology.

Alteration of cortical excitability and its modulation by Miglustat in Niemann-Pick disease type C.

Niemann-Pick type C (NP-C) is a rare, neurodegenerative, lysosomal storage disease. Cortical excitability using different transcranial magnetic stimulation (TMS) protocols together with clinical and neuropsychological testing was longitudinally assessed in a patient with NP-C. Cerebellar inhibition, a measure for the integrity of the cerebello-thalamo-cortical network, was impaired. Short-latency afferent inhibition, a measure for cholinergic transmission, and cognitive functions were also impaired and improved under Miglustat treatment. Short interval intracortical facilitation, a marker for glutamatergic neurotransmission, was absent initially but increased after treatment with Miglustat. Our results provide new insights into pathophysiological mechanisms of NP-C and the response to Miglustat treatment.

Bicycling suppresses abnormal beta synchrony in the Parkinsonian basal ganglia.

OBJECTIVE: Freezing of gait is a poorly understood symptom of Parkinson disease, and can severely disrupt the locomotion of affected patients. However, bicycling ability remains surprisingly unaffected in most patients suffering from freezing, suggesting functional differences in the motor network. The purpose of this study was to characterize and contrast the oscillatory dynamics underlying bicycling and walking in the basal ganglia. METHODS: We present the first local field potential recordings directly comparing bicycling and walking in Parkinson disease patients with electrodes implanted in the subthalamic nuclei for deep brain stimulation. Low (13-22Hz) and high (23-35Hz) beta power changes were analyzed in 22 subthalamic nuclei from 13 Parkinson disease patients (57.5 ± 5.9 years old, 4 female). The study group consisted of 5 patients with and 8 patients without freezing of gait. RESULTS: In patients without freezing of gait, both bicycling and walking led to a suppression of subthalamic beta power (13-35Hz), and this suppression was stronger for bicycling. Freezers showed a similar pattern in general. Superimposed on this pattern, however, we observed a movement-induced, narrowband power increase around 18Hz, which was evident even in the absence of freezing. INTERPRETATION: These results indicate that bicycling facilitates overall suppression of beta power. Furthermore, movement leads to exaggerated synchronization in the low beta band specifically within the basal ganglia of patients susceptible to freezing. Abnormal ∼18Hz oscillations are implicated in the pathophysiology of freezing of gait, and suppressing them may form a key strategy in developing potential therapies. Ann Neurol 2017;82:592-601.

Cost-effectiveness of neurostimulation in Parkinson's disease with early motor complications.

BACKGROUND: Recent research efforts have focused on the effects of deep brain stimulation of the subthalamic nucleus (STN DBS) for selected patients with mild-to-moderate PD experiencing motor complications. OBJECTIVES: We assessed the cost utility of subthalamic DBS compared with the best medical treatment for German patients below the age of 61 with early motor complications of PD. METHODS: We applied a previously published Markov model that integrated health utilities based on EuroQoL and direct costs over patients' lifetime adjusted to the German health care payer perspective (year of costing: 2013). Effectiveness was evaluated using the Parkinson's Disease Questionnaire 39 summary index. We performed sensitivity analyses to assess uncertainty. RESULTS: In the base-case analysis, the incremental cost-utility ratio for STN DBS compared to best medical treatment was 22,700 Euros per quality-adjusted life year gained. The time to, and costs for, battery exchange had a major effect on the incremental cost-utility ratios, but never exceeded a threshold of 50,000 Euros per quality-adjusted life year. CONCLUSIONS: Our decision analysis supports the fact that STN DBS at earlier stages of the disease is cost-effective in patients below the age of 61 when compared with the best medical treatment in the German health care system. This finding was supported by detailed sensitivity analyses reporting robust results. Whereas the EARLYSTIM study has shown STN DBS to be superior to medical therapy with respect to quality of life for patients with early motor complications, this further analysis has shown its cost-effectiveness. © 2016 International Parkinson and Movement Disorder Society.

Combined Invasive Subcortical and Non-invasive Surface Neurophysiological Recordings for the Assessment of Cognitive and Emotional Functions in Humans.

In spite of the success in applying non-invasive electroencephalography (EEG), magneto-encephalography (MEG) and functional magnetic resonance imaging (fMRI) for extracting crucial information about the mechanism of the human brain, such methods remain insufficient to provide information about physiological processes reflecting cognitive and emotional functions at the subcortical level. In this respect, modern invasive clinical approaches in humans, such as deep brain stimulation (DBS), offer a tremendous possibility to record subcortical brain activity, namely local field potentials (LFPs) representing coherent activity of neural assemblies from localized basal ganglia or thalamic regions. Notwithstanding the fact that invasive approaches in humans are applied only after medical indication and thus recorded data correspond to altered brain circuits, valuable insight can be gained regarding the presence of intact brain functions in relation to brain oscillatory activity and the pathophysiology of disorders in response to experimental cognitive paradigms. In this direction, a growing number of DBS studies in patients with Parkinson's disease (PD) target not only motor functions but also higher level processes such as emotions, decision-making, attention, memory and sensory perception. Recent clinical trials also emphasize the role of DBS as an alternative treatment in neuropsychiatric disorders ranging from obsessive compulsive disorder (OCD) to chronic disorders of consciousness (DOC). Consequently, we focus on the use of combined invasive (LFP) and non-invasive (EEG) human brain recordings in assessing the role of cortical-subcortical structures in cognitive and emotional processing trough experimental paradigms (e.g. speech stimuli with emotional connotation or paradigms of cognitive control such as the Flanker task), for patients undergoing DBS treatment.

Modulation of central thalamic oscillations during emotional-cognitive processing in chronic disorder of consciousness.

We report on thalamic recordings in a patient with chronic disorder of consciousness (DOC). Implantation of central thalamic deep brain stimulation (CT-DBS) electrodes was chosen, as this treatment has been reported to display beneficial effects with respect to behavioural responsiveness in DOC. Local field potential (LFP) oscillations were recorded from central thalamic electrodes and their changes elicited by speech stimuli consisting either of familiar voices addressing the patient or unfamiliar non-addressing phrases were studied. In response to familiar-addressing speech we observed modulation of oscillatory activity in the beta and theta band within the central thalamus accompanied by an increase in thalamocortical coherence in the theta band. Furthermore, the theta phase was coupled to the amplitude of gamma locally in the thalamus. These findings indicate a local and long-range cross-frequency response which is not only indicative of the principle involvement of the central thalamus in processing emotional and cognitive information, but also point towards intact physiological functions that may serve as a marker in diagnosing DOC patients and determining novel targets and parameters concerning therapeutic efforts.

1 Hz rTMS of the left posterior parietal cortex (PPC) modifies sensorimotor timing.

In order to investigate the relevance of the left posterior parietal cortex (PPC) for precise sensorimotor timing we applied 1 Hz repetitive transcranial magnetic stimulation (rTMS) over left PPC, right PPC and visual cortex of healthy participants for 10 min, respectively. The impact on sensorimotor timing of the right hand was assessed using a synchronization task that required subjects to synchronize their right index finger taps with respect to constant auditory, visual or auditory-visual pacing. Our results reveal reduced negative tap-to-pacer asynchronies following rTMS of the left PPC in all pacing conditions. This effect lasted for about 5 min after cessation of rTMS. Right PPC and visual cortex stimulation did not yield any significant behavioural effects. Since suppression of left PPC modified right-hand synchronization accuracy independent of the pacing signal's modality, the present data support the significance of left PPC for anticipatory motor control over a primary role in multisensory integration. The present data suggest that 1 Hz rTMS might interrupt a matching process of anticipated and real sensorimotor feedback within PPC. Alternatively, downregulation of left PPC activity may affect M1 excitability via functional connections leading to a delay in motor output and, thus, smaller tap-to-pacer asynchronies.

Essential tremor and tremor in Parkinson's disease are associated with distinct 'tremor clusters' in the ventral thalamus.

Different tremor entities such as Essential Tremor (ET) or tremor in Parkinson's disease (PD) can be ameliorated by the implantation of electrodes in the ventral thalamus for Deep Brain Stimulation (DBS). The exact neural mechanisms underlying this treatment, as well as the specific pathophysiology of the tremor in both diseases to date remain elusive. Since tremor-related local field potentials (LFP) have been shown to cluster with a somatotopic representation in the subthalamic nucleus, we here investigated the neurophysiological correlates of tremor in the ventral thalamus in ET and PD using power and coherence analysis. Local field potentials (LFPs) at different recording depths and surface electromyographic signals (EMGs) from the extensor and flexor muscles of the contralateral forearm were recorded simultaneously in twelve ET and five PD patients. Data analysis revealed individual electrophysiological patterns of LFP-EMG coherence at single and double tremor frequency for each patient. Patterns observed varied in their spatial distribution within the Ventral lateral posterior nucleus of the thalamus (VLp), revealing a specific topography of 'tremor clusters' for PD and ET. The data strongly suggest that within VLp individual tremor-related electrophysiological signatures exist in ET and PD tremor.

Somatomotor mu rhythm amplitude correlates with rigidity during deep brain stimulation in Parkinsonian patients.

OBJECTIVE: Parkinsonian patients have abnormal oscillatory activity within the basal ganglia-thalamocortical circuitry. Particularly, excessive beta band oscillations are thought to be associated with akinesia. We studied whether cortical spontaneous activity is modified by deep brain stimulation (DBS) in advanced Parkinson's disease and if the modifications are related to the clinical symptoms. METHODS: We studied the effects of bilateral electrical stimulation of subthalamic nucleus (STN) on cortical spontaneous activity by magnetoencephalography (MEG) in 11 Parkinsonian patients. The artifacts produced by DBS were suppressed by tSSS algorithm. RESULTS: During DBS, UPDRS (Unified Parkinson's Disease Rating Scale) rigidity scores correlated with 6-10 Hz and 12-20 Hz somatomotor source strengths when eyes were open. When DBS was off UPDRS action tremor scores correlated with pericentral 6-10 Hz and 21-30 Hz and occipital alpha source strengths when eyes open. Occipital alpha strength decreased during DBS when eyes closed. The peak frequency of occipital alpha rhythm correlated negatively with total UPDRS motor scores and with rigidity subscores, when eyes closed. CONCLUSION: STN DBS modulates brain oscillations both in alpha and beta bands and these oscillations reflect the clinical condition during DBS. SIGNIFICANCE: MEG combined with an appropriate artifact rejection method enables studies of DBS effects in Parkinson's disease and presumably also in the other emerging DBS indications.

Lowered frequency and impaired modulation of gamma band oscillations in a bimodal attention task are associated with reduced critical flicker frequency.

Visual attention is associated with occipital gamma band activity. While gamma band power can be modulated by attention, the frequency of gamma band activity is known to decrease with age. The present study tested the hypothesis that reduced visual attention is associated with a change in induced gamma band activity. To this end, 26 patients with liver cirrhosis and 8 healthy controls were tested. A subset of patients showed symptoms of hepatic encephalopathy (HE), a frequent neuropsychiatric complication in liver disease, which comprises a gradual increase of cognitive dysfunction including attention deficits. All participants completed a behavioral task requiring shifts of attention between simultaneously presented visual and auditory stimuli. Brain activity was recorded using magnetoencephalography (MEG). The individual critical flicker frequency (CFF) was assessed as it is known to reliably reflect the severity of HE. Results showed correlations of behavioral data and HE severity, as indexed by CFF. Individual visual gamma band peak frequencies correlated positively with the CFF (r=0.41). Only participants with normal, but not with pathological CFF values showed a modulation of gamma band power with attention. The present results suggest that CFF and attentional performance are related. Moreover, a tight relation between the CFF and occipital gamma band activity both in frequency and power is shown. Thus, the present study provides evidence that a reduced CFF in HE, a disease associated with attention deficits, is closely linked to a slowing of gamma band activity and impaired modulation of gamma band power in a bimodal attention task.

Long-term time course of affective lability after subthalamic deep brain stimulation electrode implantation.

The mechanism and time course of emotional side effects of subthalamic deep brain stimulation in Parkinson's disease are a matter for discussion. We report a 53-month follow-up of a patient with affective lability. Postoperative lesion plus bilateral stimulation strongly influenced mood in the first week in terms of laughing behavior, while voltage changes had only minor long-term impact up to 37 months on negative emotion, possibly caused by the right electrode stimulating the subthalamic nucleus and adjacent fiber tracts involving the internal capsule. Thus we conclude that affective lability can occur with different temporal dynamics of microlesion, and early and chronic stimulation.

Effects of DBS on auditory and somatosensory processing in Parkinson's disease.

Motor symptoms of Parkinson's disease (PD) can be relieved by deep brain stimulation (DBS). The mechanism of action of DBS is largely unclear. Magnetoencephalography (MEG) studies on DBS patients have been unfeasible because of strong magnetic artifacts. An artifact suppression method known as spatiotemporal signal space separation (tSSS) has mainly overcome these difficulties. We wanted to clarify whether tSSS enables noninvasive measurement of the modulation of cortical activity caused by DBS. We have studied auditory and somatosensory-evoked fields (AEFs and SEFs) of advanced PD patients with bilateral subthalamic nucleus (STN) DBS using MEG. AEFs were elicited by 1-kHz tones and SEFs by electrical pulses to the median nerve with DBS on and off. Data could be successfully acquired and analyzed from 12 out of 16 measured patients. The motor symptoms were significantly relieved by DBS, which clearly enhanced the ipsilateral auditory N100m responses in the right hemisphere. Contralateral N100m responses and somatosensory P60m responses also had a tendency to increase when bilateral DBS was on. MEG with tSSS offers a novel and powerful tool to investigate DBS modulation of the evoked cortical activity in PD with high temporal and spatial resolution. The results suggest that STN-DBS modulates auditory processing in advanced PD. Hum Brain Mapp, 2011. © 2010 Wiley-Liss, Inc.

Functional network interactions during sensorimotor synchronization in musicians and non-musicians.

Precise timing as determined by sensorimotor synchronization is crucial for a wide variety of activities. Although it is well-established that musicians show superior timing as compared to non-musicians, the neurophysiological foundations - in particular the underlying functional brain network - remain to be characterized. To this end, drummers, professional pianists and non-musicians performed an auditory synchronization task while neuromagnetic activity was measured using a 122-channel whole-head magnetoencephalography (MEG) system. The underlying functional brain network was determined using the beamformer approach Dynamic Imaging of Coherent Sources (DICS). Behaviorally, drummers performed less variably than non-musicians. Neuromagnetic analysis revealed a cerebello-thalamo-cortical network in all subjects comprising bilateral primary sensorimotor cortices (S1/M1), contralateral supplementary motor and premotor regions (SMA and PMC), thalamus, posterior parietal cortex (PPC), ipsilateral cerebellum and bilateral auditory cortices. Stronger PMC-thalamus and PPC-thalamus interactions at alpha and beta frequencies were evident in drummers as compared to non-musicians. In professional pianists stronger PMC-thalamus interaction as compared to non-musicians at beta frequency occurred. The present data suggest that precise timing is associated with increased functional interaction within a PMC-thalamus-PPC network. The PMC-thalamus connectivity at beta frequency might be related to musical expertise, whereas the PPC-thalamus interaction might have specific relevance for precise timing.

Perception in action: the impact of sensory information on sensorimotor synchronization in musicians and non-musicians.

The present study aimed at investigating to what extent sensorimotor synchronization is related to (i) musical specialization, (ii) perceptual discrimination, and (iii) the movement's trajectory. To this end, musicians with different musical expertise (drummers, professional pianists, amateur pianists, singers, and non-musicians) performed an auditory and visual synchronization and a cross-modal temporal discrimination task. During auditory synchronization drummers performed less variably than amateur pianists, singers and non-musicians. In the cross-modal discrimination task drummers showed superior discrimination abilities which were correlated with synchronization variability as well as with the trajectory. These data suggest that (i) the type of specialized musical instrument affects synchronization abilities and (ii) synchronization accuracy is related to perceptual discrimination abilities as well as to (iii) the movement's trajectory. Since particularly synchronization variability was affected by musical expertise, the present data imply that the type of instrument improves accuracy of timekeeping mechanisms.

Synchronized brain network associated with essential tremor as revealed by magnetoencephalography.

Despite the fact that essential tremor (ET) is the most prevalent movement disorder, the underlying pathological mechanisms are not fully understood. There is accumulating evidence that this specific type of tremor is mainly of central origin, in particular involving inferior olive, cerebellum, thalamus, and primary motor cortex. We studied 8 patients with ET recording simultaneously neural activity with a whole-scalp neuromagnetometer and tremor activity with surface electromyography (EMG). Subjects performed an isometric contraction of the left forearm. Tremor frequency of 5 to 7 Hz and its first harmonic were clearly evident in power spectra of EMG recordings. We used the localization technique dynamic imaging of coherent sources (DICS) to identify cerebral areas coherent to the EMG signal at tremor frequency and its first harmonic. All subjects showed coherence to the contralateral primary motor cortex. In a further step, DICS was used to identify areas of significant cerebro-cerebral coherence. The analysis revealed a network of areas consisting of contralateral primary motor cortex, premotor cortex, thalamus, brainstem, and ipsilateral cerebellum. These results are consistent with the view that in ET, a network of cerebral areas including brainstem shows oscillatory interactions, which lead to a rhythmic modulation of muscle activity becoming apparent as tremor.

Levodopa affects functional brain networks in Parkinsonian resting tremor.

Resting tremor in idiopathic Parkinson's disease (PD) is associated with an oscillatory network comprising cortical as well as subcortical brain areas. To shed light on the effect of levodopa on these network interactions, we investigated 10 patients with tremor-dominant PD and reanalyzed data in 11 healthy volunteers mimicking PD resting tremor. To this end, we recorded surface electromyograms of forearm muscles and neuromagnetic activity using a 122-channel whole-head magnetometer (MEG). Measurements were performed after overnight withdrawal of levodopa (OFF) and 30 min after oral application of fast-acting levodopa (ON). During OFF, patients showed the typical antagonistic resting tremor. Using the analysis tool Dynamic Imaging of Coherent Sources, we identified the oscillatory network associated with tremor comprising contralateral primary sensorimotor cortex (S1/M1), supplementary motor area (SMA), contralateral premotor cortex (PMC), thalamus, secondary somatosensory cortex (S2), posterior parietal cortex (PPC), and ipsilateral cerebellum oscillating at 8 to 10 Hz. After intake of levodopa, we found a significant decrease of cerebro-cerebral coupling between thalamus and motor cortical areas. Similarly, in healthy controls mimicking resting tremor, we found a significant decrease of functional interaction within a thalamus-premotor-motor network during rest. However, in patients with PD, decrease of functional interaction between thalamus and PMC was significantly stronger when compared with healthy controls. These data support the hypothesis that (1) in patients with PD the basal ganglia and motor cortical structures become more closely entrained and (2) levodopa is associated with normalization of the functional interaction between thalamus and motor cortical areas.

Word deafness as a cortical auditory processing deficit: a case report with MEG.

Pure word deafness is a rare disorder dramatically impairing comprehension of spoken language, while auditory functions remain relatively intact. We present a 71-year-old woman with a slowly progressive disturbance of speech perception due to pure word deafness. MRI revealed degeneration of the temporal lobes. A magnetoencephalographic investigation using alternating single tone stimulation showed that N100 was followed by a second transient response and was abnormally prolonged up to 600-700 ms. We conclude that auditory processing is disturbed at long latency ranges following the N100, which may result in the clinical presentation of pure word deafness.