The Effect of Uni- and Bilateral Thalamic Deep Brain Stimulation on Speech in Patients With Essential Tremor: Acoustics and Intelligibility.

BACKGROUND: Deep brain stimulation (DBS) of the ventral intermediate nucleus (VIM) is performed to suppress medically-resistant essential tremor (ET). However, stimulation induced dysarthria (SID) is a common side effect, limiting the extent to which tremor can be suppressed. To date, the exact pathogenesis of SID in VIM-DBS treated ET patients is unknown. OBJECTIVE: We investigate the effect of inactivated, uni- and bilateral VIM-DBS on speech production in patients with ET. We employ acoustic measures, tempo, and intelligibility ratings and patient's self-estimated speech to quantify SID, with a focus on comparing bilateral to unilateral stimulation effects and the effect of electrode position on speech. METHODS: Sixteen German ET patients participated in this study. Each patient was acoustically recorded with DBS-off, unilateral-right-hemispheric-DBS-on, unilateral-left-hemispheric-DBS-on, and bilateral-DBS-on during an oral diadochokinesis task and a read German standard text. To capture the extent of speech impairment, we measured syllable duration and intensity ratio during the DDK task. Naïve listeners rated speech tempo and speech intelligibility of the read text on a 5-point-scale. Patients had to rate their "ability to speak". RESULTS: We found an effect of bilateral compared to unilateral and inactivated stimulation on syllable durations and intensity ratio, as well as on external intelligibility ratings and patients' VAS scores. Additionally, VAS scores are associated with more laterally located active contacts. For speech ratings, we found an effect of syllable duration such that tempo and intelligibility was rated worse for speakers exhibiting greater syllable durations. CONCLUSION: Our data confirms that SID is more pronounced under bilateral compared to unilateral stimulation. Laterally located electrodes are associated with more severe SID according to patient's self-ratings. We can confirm the relation between diadochokinetic rate and SID in that listener's tempo and intelligibility ratings can be predicted by measured syllable durations from DDK tasks.

Individualized current-shaping reduces DBS-induced dysarthria in patients with essential tremor.

OBJECTIVE: To investigate in patients with essential tremor (ET) treated with thalamic/subthalamic deep brain stimulation (DBS) whether stimulation-induced dysarthria (SID) can be diminished by individualized current-shaping with interleaving stimulation (cs-ILS) while maintaining tremor suppression (TS). METHODS: Of 26 patients screened, 10 reported SID and were invited for testing. TS was assessed by the Tremor Rating Scale and kinematic analysis of postural and action tremor. SID was assessed by phonetic and logopedic means. Additionally, patients rated their dysarthria on a visual analog scale. RESULTS: In 6 of the 10 patients with ET, DBS-ON (relative to DBS-OFF) led to SID while tremor was successfully reduced. When comparing individualized cs-ILS with a non-current-shaped interleaving stimulation (ILS) in these patients, there was no difference in TS while 4 of the 6 patients showed subjective improvement of speech during cs-ILS. Phonetic analysis (ILS vs cs-ILS) revealed that during cs-ILS there was a reduction of voicing during the production of voiceless stop consonants and also a trend toward an improvement in oral diadochokinetic rate, reflecting less dysarthria. Logopedic rating showed a trend toward deterioration in the diadochokinesis task when comparing ON with OFF but no difference between ILS and cs-ILS. CONCLUSION: This is a proof-of-principle evaluation of current-shaping in patients with ET treated with thalamic/subthalamic DBS and experiencing SID. Data suggest a benefit on SID from individual shaping of current spread while TS is preserved. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in patients with ET treated with DBS with SID, individualized cs-ILS reduces dysarthria while maintaining tremor control.

Agraphia caused by an infarction in Exner's area.

Sigmund Exner postulated in 1881 that lesions of the base of the medial frontal gyrus could specifically produce writing impairments and attributed the writing centre to this area. We report two patients who suffered from strokes in this area. These patients suffered from writing disturbances comprising both omitted words within a sentence or badly written words, as well as aphasia. These patients, in line with prior reports, illustrate the crucial role of the Exner area at the base of the medial frontal gyrus for the cerebral writing network; we suggest that this region plays an important role for phoneme-grapheme conversions.

Early semantic and phonological effects on temporal- and muscle-specific motor resonance.

Previous studies using functional magnetic resonance imaging and transcranial magnetic stimulation (TMS) explored the relationships between linguistic processing and motor resonance, i.e. the activation of the motor system while perceiving others performing an action. These studies have mainly investigated a specific linguistic domain, i.e. semantics, whereas phonology has been largely neglected. Here we used single-pulse TMS to compare the effects of semantic and phonological processing with motor resonance effects. We applied TMS to the primary motor hand area while subjects observed object-oriented actions and performed semantic and phonological tasks related to the observed action. Motor evoked potentials were recorded in two hand muscles, one of them more involved in the execution of the observed actions than the other one, at three different timepoints (0, 200 and 400 ms after stimulus onset). The results demonstrated increased corticospinal excitability that was muscle-specific (i.e. restricted to the hand muscle involved in the observed action), hemisphere-specific (left), and time-specific (400 ms after stimulus onset). The results suggest an additive effect of independent semantic and phonological processing on motor resonance. The novel phonological effect reported here expands the links between language and the motor system and is consistent with a theory of shared control for hand and mouth. Furthermore, the timing of the semantic effect suggests that motor activation during semantic processing is not an 'epiphenomenon' but rather is essential to the construction of meaning.

Isometric contraction interferes with transcranial direct current stimulation (tDCS) induced plasticity: evidence of state-dependent neuromodulation in human motor cortex.

BACKGROUND AND PURPOSE: Neuroplastic alterations of cortical excitability and activity represent the likely neurophysiological foundation of learning and memory formation. Beyond their induction, alterations of these processes by subsequent modification of cortical activity, termed metaplasticity, came into the focus of interest recently. Animal slice experiments demonstrated that neuroplastic excitability enhancements, or diminutions, can be abolished by consecutive subthreshold stimulation. These processes, termed de-potentiation, and de-depression, have so far not been explored in humans. METHODS: We combined neuroplasticity induction by transcranial direct current stimulation (tDCS) applied to the hand area of primary motor cortex (M1), which can be used to induce long-lasting excitability enhancements or reductions, dependent on the polarity of stimulation, with short-lasting voluntary muscle contraction (VMC), which itself does not induce plastic cortical excitability changes. Corticospinal and intra-cortical M1 excitability were monitored by different transcranial magnetic stimulation (TMS) protocols. RESULTS: VMC reduced or tended to reverse the anodal tDCS-driven motor cortical excitability enhancement and the cathodal tDCS-induced excitability diminution. Our findings thus demonstrate de-potentiation- and de-depression-like phenomena at the system level in the human motor cortex. CONCLUSION: This neurophysiological study may contribute to a better understanding of the balance between induction and reversal of plasticity associated with motor learning and rehabilitation processes.

Masked auditory feedback affects speech motor learning of a plosive duration contrast.

Adult speakers have developed precise forward models of articulation for their native language and seem to rely less on auditory sensory feedback. However, for learning of the production of new speech sounds, auditory perception provides a corrective signal for motor control. We assessed adult German speakers' speech motor learning capacity in the absence of auditory feedback but with clear somatosensory information. Learners were presented with a nonnative singleton-geminate duration contrast of voiceless, unaspirated bilabial plosives /p/ vs. /pp/ which is present in Italian. We found that the lack of auditory feedback had no immediate effect but that deviating productions emerged during the course of learning. By the end of training, speakers with masked feedback produced strong lengthening of segments and showed more variation on their production than speakers with normal auditory feedback. Our findings indicate that auditory feedback is necessary for the learning of precise coordination of articulation even if somatosensory feedback is salient.

Processing of auditory motion in inferior parietal lobule: evidence from transcranial magnetic stimulation.

The neural substrates of auditory motion processing are, at present, still a matter of debate. It has been hypothesized that motion information is, as in the visual system, processed separately from other aspects of auditory information, such as stationary location. Here we aimed to differentiate the location of auditory motion processing in human cortex using low-frequency repetitive transcranial magnetic stimulation (rTMS) in combination with a psychophysical task of motion discrimination. rTMS was applied offline to right posterior superior temporal gyrus, right inferior parietal lobule, right dorsal premotor cortex, or right primary somatosensory cortex (as reference site). A significant decrease in performance was obtained exclusively for sounds presented in left hemispace after rTMS over the right inferior parietal lobule (BA 40). This finding indicates that the inferior parietal lobule plays a crucial role in the analysis of moving sound, with an apparent contralaterality of cortical processing. Combined with previous studies which have demonstrated effects of rTMS on static sound localization for both inferior parietal and posterior temporal cortices, the results suggest a hierarchical processing of auditory spatial information, with higher-order functions of motion analysis, such as discrimination of motion direction, mainly taking place beyond the temporal lobe.

How the brain handles temporally uncoupled bimanual movements.

Whereas the cerebral representation of bimanual spatial coordination has been subject to prior research, the networks mediating bimanual temporal coordination are still unclear. The present study used functional imaging to investigate cerebral networks mediating temporally uncoupled bimanual finger movements. Three bimanual tasks were designed for the execution of movements with different timing and amplitude, with same timing but different amplitude, and with same timing and amplitude. Functional magnetic resonance imaging results showed an increase of activation within right premotor and dorsolateral prefrontal, bilateral inferior parietal, basal ganglia, and cerebellum areas related to temporally uncoupled bilateral finger movements. Further analyses showed a decrease of connectivity between homologous primary hand motor regions. In contrast, there was an increase of connectivity between motor regions and anterior cingulate, premotor and posterior parietal regions during bimanual movements that were spatially or both temporally and spatially uncoupled, compared with bimanual movements that were both spatially and temporally coupled. These results demonstrate that the extent of bihemispheric coupling of M1 areas is related to the degree of temporal synchronization of bimanual finger movements. Furthermore, inferior parietal and premotor regions play a key role for the implementation not only of spatial but also of temporal movement parameters in bimanual coordination.

The dorsal premotor cortex orchestrates concurrent speech and fingertapping movements.

Human speech and hand use both involve highly specialized complex movement patterns. Whereas previous studies in detail characterized the cortical motor systems mediating speech and finger movements, the network that provides coordination of concurrent speech and hand movements so far is unknown. Using functional magnetic resonance imaging (fMRI), the present study investigated differential cortical networks devoted to speech or fingertapping, and regions mediating integration of these complex movement patterns involving different effectors. The conjunction contrasts revealing regions activated both during sole fingertapping and sole repetitive articulation or reading aloud showed contralateral regions at the border of ventral and dorsal motor cortex. In contrast, the analyses revealing regions showing a higher level of fMRI activation for concurrent movements of both effectors compared with sole hand movements or repetitive articulation or reading aloud showed distinct premotor activations, which were situated dorsal and caudal to the areas activated across speech and fingertapping tasks. These results indicate that the premotor cortex (PMC) subserves coordination of concurrent speech with hand movements. This integrative motor region is not identical with the area that shows overlapping activations for speech and fingertapping. Thus, concurrent performance of these complex movement patterns involving different effectors requires, in addition to somatotopic motor cortex activation, orchestration subserved by a distinct PMC area.

The role of the anterior intraparietal sulcus in crossmodal processing of object features in humans: an rTMS study.

Investigations in macaques and humans have shown that the anterior intraparietal sulcus (IPS) has an important function in the integration of information from tactile and visual object manipulation. The goal of this study was to investigate the special functional role of the anterior IPS in visuo-tactile matching in humans. We used the "virtual-lesion" technique of repetitive transcranial magnetic stimulation (rTMS) to test the functional relevance of anterior IPS for visuo-tactile crossmodal matching. Two crossmodal (visual encoding and tactile recognition and vice versa) and two unimodal delayed matching-to-sample tests with geometrical patterns were performed by 12 healthy subjects. We determined error rates before and after focal low-frequency rTMS applied over the left anterior IPS, right anterior IPS and vertex. During the manipulation of objects with the right hand, rTMS over the left anterior IPS induced a significant deterioration for visual encoding and tactile recognition, but not for tactile encoding and visual recognition. For the visual and tactile unimodal conditions, no significant alterations in task performance were found. rTMS application over right IPS when manipulating objects with the left hand did not affect crossmodal task performance. In conclusion, we have demonstrated an essential functional role of the left anterior IPS for visuo-tactile matching when manipulating objects with the right hand. However, we found no clear evidence for left IPS involvement in tactile encoding and visual recognition. The differential effect of rTMS on tactile and visual encoding and recognition are not consistently explained by previous concepts of visuo-tactile integration.

Processing of sound location in human cortex.

This functional magnetic resonance imaging study was focused on the neural substrates underlying human auditory space perception. In order to present natural-like sound locations to the subjects, acoustic stimuli convolved with individual head-related transfer functions were used. Activation foci, as revealed by analyses of contrasts and interactions between sound locations, formed a complex network, including anterior and posterior regions of temporal lobe, posterior parietal cortex, dorsolateral prefrontal cortex and inferior frontal cortex. The distinct topography of this network was the result of different patterns of activation and deactivation, depending on sound location, in the respective voxels. These patterns suggested different levels of complexity in processing of auditory spatial information, starting with simple left/right discrimination in the regions surrounding the primary auditory cortex, while the integration of information on hemispace and eccentricity of sound may take place at later stages. Activations were identified as being located in regions assigned to both the dorsal and ventral auditory cortical streams, that are assumed to be preferably concerned with analysis of spatial and non-spatial sound features, respectively. The finding of activations also in the ventral stream could, on the one hand, reflect the well-known functional duality of auditory spectral analysis, that is, the concurrent extraction of information based on location (due to the spectrotemporal distortions caused by head and pinnae) and spectral characteristics of a sound source. On the other hand, this result may suggest the existence of shared neural networks, performing analyses of auditory 'higher-order' cues for both localization and identification of sound sources.

Transcranial magnetic stimulation and the challenge of coil placement: a comparison of conventional and stereotaxic neuronavigational strategies.

The combination of transcranial magnetic stimulation (TMS) with functional neuroimaging has expanded the potential of TMS for human brain mapping. The precise and reliable positioning of the TMS coil is not a simple task, however. Modern frameless stereotaxic systems allow investigators to base navigation either on the subject's structural magnetic resonance imaging (MRI), functional MRI data, or the use of functional neuroimaging data from the literature, so-called "probabilistic approach." The latter assumes consistency across individuals in the location of task-related "activations" in standardized stereotaxic space. Conventional nonstereotaxic localization of brain areas is also a common method for defining the coil position. Our aim was to evaluate the accuracy of five different localization strategies in one single study. The left primary motor cortex (left M1-Hand) was used as target region. Three approaches were based on real-time frameless stereotaxy using information based on either anatomical or functional MRI. The remaining two strategies relied either on standard cranial landmarks (i.e., the International 10-20 EEG system) or a standardized function-guided procedure (i.e., the spatial relationship between the left and right M1-Hand). The results were compared to a TMS-based mapping of the primary motor cortex; center of gravity of motor-evoked potentials (MEP-CoG) was calculated for each subject (n = 10). Our findings suggest that highest precision can be achieved with fMRI-guided stimulation, which was accurate within the range of millimeters. Very consistent results were also obtained with the "probabilistic" approach. In view of these findings, we discuss the methods and special characteristics of each localization strategy.

Enhancing language performance with non-invasive brain stimulation--a transcranial direct current stimulation study in healthy humans.

In humans, transcranial direct current stimulation (tDCS) can be used to induce, depending on polarity, increases or decreases of cortical excitability by polarization of the underlying brain tissue. Cognitive enhancement as a result of tDCS has been reported. The purpose of this study was to test whether weak tDCS (current density, 57 microA/cm(2)) can be used to modify language processing. Fifteen healthy subjects performed a visual picture naming task before, during and after tDCS applied over the posterior perisylvian region (PPR), i.e. an area which includes Wernicke's area [BA 22]. Four different sessions were carried out: (1) anodal and (2) cathodal stimulation of left PPR and, for control, (3) anodal stimulation of the homologous region of the right hemisphere and (4) sham stimulation. We found that subjects responded significantly faster following anodal tDCS to the left PPR (p<0.01). No decreases in performance were detected. Our finding of a transient improvement in a language task following the application of tDCS together with previous studies which investigated the modulation of picture naming latency by transcranial magnetic stimulation (TMS) and repetitive TMS (rTMS) suggest that tDCS applied to the left PPR (including Wernicke's area [BA 22]) can be used to enhance language processing in healthy subjects. Whether this safe, low cost, and easy to use brain stimulation technique can be used to ameliorate deficits of picture naming in aphasic patients needs further investigations.

No language-specific activation during linguistic processing of observed actions.

BACKGROUND: It has been suggested that cortical neural systems for language evolved from motor cortical systems, in particular from those fronto-parietal systems responding also to action observation. While previous studies have shown shared cortical systems for action--or action observation--and language, they did not address the question of whether linguistic processing of visual stimuli occurs only within a subset of fronto-parietal areas responding to action observation. If this is true, the hypothesis that language evolved from fronto-parietal systems matching action execution and action observation would be strongly reinforced. METHODOLOGY/ PRINCIPAL FINDINGS: We used functional magnetic resonance imaging (fMRI) while subjects watched video stimuli of hand-object-interactions and control photo stimuli of the objects and performed linguistic (conceptual and phonological), and perceptual tasks. Since stimuli were identical for linguistic and perceptual tasks, differential activations had to be related to task demands. The results revealed that the linguistic tasks activated left inferior frontal areas that were subsets of a large bilateral fronto-parietal network activated during action perception. Not a single cortical area demonstrated exclusive--or even simply higher--activation for the linguistic tasks compared to the action perception task. CONCLUSIONS: These results show that linguistic tasks do not only share common neural representations but essentially activate a subset of the action observation network if identical stimuli are used. Our findings strongly support the evolutionary hypothesis that fronto-parietal systems matching action execution and observation were co-opted for language, a process known as exaptation.

The essential role of premotor cortex in speech perception.

Besides the involvement of superior temporal regions in processing complex speech sounds, evidence suggests that the motor system might also play a role [1-4]. This suggests that the hearer might perceive speech by simulating the articulatory gestures of the speaker [5, 6]. It is still an open question whether this simulation process is necessary for speech perception. We applied repetitive transcranial magnetic stimulation to the premotor cortex to disrupt subjects' ability to perform a phonetic discrimination task. Subjects were impaired in discriminating stop consonants in noise but were unaffected in a control task that was matched in difficulty, task structure, and response characteristics. These results show that the disruption of human premotor cortex impairs speech perception, thus demonstrating an essential role of premotor cortices in perceptual processes.

A repetition suppression effect lasting several days within the semantic network.

Performance in a semantic task is speeded up for repeated stimuli compared to novel stimuli. This conceptual priming effect is related to a decrease in functional activation within the left inferior prefrontal cortex for repeated stimulus exposure (repetition suppression). However, in contrast to perceptual priming which is known to be very robust over long periods of time, previous studies on semantic priming focused on short-term effects. The present study combined a behavioral and functional imaging experiment to investigate long-term conceptual repetition priming (retention interval 3 days). We found a highly significant decrease of reaction time for word stimuli which were presented repeatedly after 3 days both compared to initial presentation and to a matched word list. The functional magnetic resonance imaging data showed a repetition suppression within the left inferior (BA45, BA47) and middle (BA9) frontal gyrus for the comparison of known with unknown words. These data demonstrate that even over a period as long as 3 days, a repetition suppression within the left frontal network involved in semantic decision can be found. Thus, priming-related mechanisms in the semantic network may be robust over several days.

Excitability of human motor and visual cortex before, during, and after hyperventilation.

In humans, hyperventilation (HV) has various effects on systemic physiology and, in particular, on neuronal excitability and synaptic transmission. However, it is far from clear how the effects of HV are mediated at the cortical level. In this study we investigated the effects of HV-induced hypocapnia on primary motor (M1) and visual cortex (V1) excitability. We used 1) motor threshold (MT) and phosphene threshold (PT) and 2) stimulus-response (S-R) curves (i.e., recruitment curves) as measures of excitability. In the motor cortex, we additionally investigated 3) the intrinsic inhibitory and facilitatory neuronal circuits using a short-interval paired-pulse paradigm. Measurements were performed before, during, and after 10 min of HV (resulting in a minimum end-tidal Pco(2) of 15 Torr). HV significantly increased motor-evoked potential (MEP) amplitudes, particularly at lower transcranial magnetic stimulation (TMS) intensities. Paired-pulse stimulation indicated that HV decreases intracortical inhibition (ICI) without changing intracortical facilitation. The results suggestthat low Pco(2) levels modulate, in particular, the intrinsic neuronal circuits of ICI, which are largely mediated by neurons containing gamma-aminobutyric acid. Modulation of MT probably resulted from alterations of Na(+) channel conductances. A significant decrease of PT, together with higher intensity of phosphenes at low stimulus intensities, furthermore suggested that HV acts on the excitability of M1 and V1 in a comparable fashion. This finding implies that HV also affects other brain structures besides the corticospinal motor system. The further exploration of these physiological mechanisms may contribute to the understanding of the various HV-related clinical phenomenona.