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.

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.

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 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.

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.

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.

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.

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.

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.

The hyperdense posterior cerebral artery sign: a computed tomography marker of acute ischemia in the posterior cerebral artery territory.

BACKGROUND AND PURPOSE: In the anterior circulation, the hyperdense middle cerebral artery (MCA) sign is a well-established marker for early ischemia. Similarly, the hyperdense basilar artery sign or the MCA "dot" sign may be a diagnostic clue for basilar artery or distal MCA branch thrombosis. The purpose of this study was to define the hyperdense posterior cerebral artery (PCA) sign and determine its incidence, diagnostic value, and reliability as a marker for ischemia in the territory of the PCA. METHODS: Cranial computed tomographies (CCTs) of 48 patients with proven acute ischemia (<12 hours) in the PCA territory were compared by 3 independent and blinded readers to the CCTs of 86 age-matched patients without PCA infarction. Using follow-up imaging, the correlation of the hyperdense PCA (HPCA) with infarct size, thalamic infarction, and bleeding were investigated. RESULTS: An HPCA was found in 35.4% of all patients with PCA infarction, typically within the ambient cistern, with a specificity of 95.4%. The thalamus was affected significantly more often (P=0.009) and the size of the infarct was significantly more often large than medium (P=0.018) or small (P<0.001) when an HPCA was present. Hemorrhagic transformation tended to occur more often when the HPCA was present. CONCLUSIONS: An HPCA was detected in more than one third of all patients with PCA ischemia, suiting the incidence of the hyperdense MCA. Based on our results, this sign may not only be helpful in the early diagnosis of PCA infarction but might also act as a prognostic marker in acute PCA territory ischemic stroke.

Interhemispheric imbalance during visuospatial attention investigated by unilateral and bilateral TMS over human parietal cortices.

We used single-pulse transcranial magnetic stimulation (TMS) to study visuospatial attention. TMS was applied over one hemisphere, or simultaneously over both the right and left posterior parietal cortex (PPC), at two different interstimulus intervals (ISI) during a visual detection task. Unilateral TMS over the right and left PPC, respectively, impaired detection of contralateral presented visual stimuli at an ISI of 150 ms. By contrast, simultaneous biparietal TMS induced no significant changes in correct stimulus detection. TMS at an ISI of 250 ms evoked no changes for magnetic stimulation over either the right or the left parietal cortex. These results suggest that both PPC play a crucial role at a relatively early stage in the widely distributed brain network of visuospatial attention. The abolition of behavioral deficits during simultaneous biparietal TMS underlines the common hypothesis that an interhemispheric imbalance might underlie the disorders of neglect and extinction seen following unilateral brain damage.

Investigation of the primary visual cortex using short-interval paired-pulse transcranial magnetic stimulation (TMS).

Previous studies using short-interval paired-pulse TMS have provided valuable insights into physiology of human motor cortex. Depending on the interstimulus interval (ISI) between the two pulses intra-cortical facilitation (ICF) or intra-cortical inhibition (ICI) can be observed. Similar patterns of inhibition and facilitation have also been demonstrated in prefrontal and parietal cortices. In order to prove whether principles that govern cortical excitability in the motor system also extend to the visual system and to further characterize possible neural correlates of phosphene generation, we applied short-interval paired-pulse TMS to the occipital cortex. In addition, we examined the effect of different coil orientations on perception of phosphenes induced by paired-pulse TMS. In all of 10 healthy subjects, a general facilitation of phosphene perception could be observed for interstimulus intervals of 2-12 ms (conditioning stimulus (CS) 90% and test stimulus (TS) 100% of subject's phosphene threshold) compared to TS alone. With CS intensity decreasing to 80% or less, the effect diminished. No significant changes occurred when TS intensity was increased to 110%. Phosphene perception was enhanced with an induced current direction from lateral to medial at an ISI of 12 ms. Inhibition was not observed in any condition. Our results indicate that the mechanisms underlying phosphene induction in the visual cortex are different from those underlying intracortical inhibition and facilitation in the motor cortex.

Impact of aphasia on consciousness assessment: a cross-sectional study.

BACKGROUND: Previous findings suggest that language disorders may occur in severely brain-injured patients and could interfere with behavioral assessments of consciousness. However, no study investigated to what extent language impairment could affect patients' behavioral responses. Objective. To estimate the impact of receptive and/or productive language impairments on consciousness assessment. METHODS: Twenty-four acute and subacute stroke patients with different types of aphasia (global, n = 11; Broca, n = 4; Wernicke, n = 3; anomic, n = 4; mixed, n = 2) were recruited in neurology and neurosurgery units as well as in rehabilitation centers. The Coma Recovery Scale-Revised (CRS-R) was administered. RESULTS: We observed that 25% (6 out of 24) of stroke patients with a diagnosis of aphasia and 54% (6 out of 11) of patients with a diagnosis of global aphasia did not reach the maximal CRS-R total score of 23. An underestimation of the consciousness level was observed in 3 patients with global aphasia who could have been misdiagnosed as being in a minimally conscious state, even in the absence of any documented period of coma. More precisely, lower subscores were observed on the communication, motor, oromotor, and arousal subscales. CONCLUSION: Consciousness assessment may be complicated by the co-occurrence of severe language deficits. This stresses the importance of developing new tools or identifying items in existing scales, which may allow the detection of language impairment in severely brain-injured patients.

Motor cortex hand area and speech: implications for the development of language.

Recently a growing body of evidence has suggested that a functional link exists between the hand motor area of the language dominant hemisphere and the regions subserving language processing. We examined the excitability of the hand motor area and the leg motor area during reading aloud and during non-verbal oral movements using transcranial magnetic stimulation (TMS). During reading aloud, but not before or afterwards, excitability was increased in the hand motor area of the dominant hemisphere. This reading effect was found to be independent of the duration of speech. No such effect could be found in the contralateral hemisphere. The excitability of the leg area of the motor cortex remained unchanged during reading aloud. The excitability during non-verbal oral movements was slightly increased in both hemispheres. Our results are consistent with previous findings and may indicate a specific functional connection between the hand motor area and the cortical language network.

Repetitive transcranial magnetic stimulation of the parietal cortex transiently ameliorates phantom limb pain-like syndrome.

OBJECTIVE: Phantom pain is linked to a reorganization of the partially deafferented sensory cortex. In this study we have investigated whether the pain syndrome can be influenced by repetitive transcranial magnetic stimulation (rTMS). METHODS: Two patients with a longstanding unilateral avulsion of the lower cervical roots and chronic pain in the arm were studied. As a control the acute effects of rTMS (15 Hz, 2 s duration) on pain were studied in 4 healthy subjects. Pain intensity was assessed with the Visual Analogue Scale. RESULTS: Stimulation of the contralateral parietal cortex led to a reproducible reduction in pain intensity lasting up to 10 min. Stimulation of other cortical areas produced only minor alterations in the severity of the pain. Both 1 and 10 Hz rTMS trains applied to the contralateral parietal cortex on weekdays for 3 consecutive weeks did, however, not lead to permanent changes in the pain intensity. Experimentally induced pain (cold water immersion of the right hand) in normal subjects was not influenced by rTMS. CONCLUSIONS: These results do not favor the use of rTMS in the treatment of phantom limb pain. The results, however, support the concept that phantom pain is due to a dysfunctional activity in the parietal cortex. The transient rTMS-induced analgesic effect may be due to a temporary interference with the cerebral representation of the deafferented limb.

Visual and motor cortex excitability: a transcranial magnetic stimulation study.

OBJECTIVES: Phosphene thresholds (PTs) to transcranial magnetic stimulation over the occipital cortex and motor thresholds (MTs) have been used increasingly as measures of the excitability of the visual and motor cortex. MT has been utilized as a guide to the excitability of other, non-motor cortical areas such as dorsolateral prefrontal cortex. The aims of this study were to compare the PTs to MTs; to assess their stability across sessions; and to investigate their relation to MTs. METHODS: PTs and MTs were determined using focal transcranial magnetic stimulation over the visual and motor cortex. RESULTS: PTs were shown to be significantly higher than MTs. Both PTs and MTs were stable across sessions. No correlation between PTs and MTs could be established. CONCLUSIONS: Phosphene threshold is a stable parameter of the visual cortex excitability. MTs were not related to the excitability of non-motor cortical areas.

Motor representation in patients rapidly recovering after stroke: a functional magnetic resonance imaging and transcranial magnetic stimulation study.

OBJECTIVE: Neuroimaging studies have suggested an evolution of the brain activation pattern in the course of motor recovery after stroke. Initially poor motor performance is correlated with an recruitment of the uninjured hemisphere that continuously vanished until a nearly normal (contralateral) activation pattern is achieved and motor performance is good. Here we were interested in the early brain activation pattern in patients who showed a good and rapid recovery after stroke. METHODS: Ten patients with first-ever ischemic stroke affecting motor areas had to perform self-paced simple or more complex movements with the affected or the unaffected hand during functional magnetic resonance imaging (fMRI). The location and number of activated voxels above threshold were determined. To study possible changes in the cortical motor output map the amplitude of the motor evoked potentials (MEP) and the extent of the excitable area were determined using transcranial magnetic stimulation (TMS). RESULTS: The pattern of activation observed with movements of the affected and the unaffected hand was similar. In the simple motor task significant (P<0.05) increases were found in the primary motor cortex ipsilateral to the movement, the supplementary motor area and the cerebellar hemisphere contralateral to the movement during performance with the affected hand compared to movements with the unaffected hand. When comparing simple with more complex movements performed with either the affected or the unaffected hand, a further tendency to increased activation in motor areas was observed. The amplitude of MEPs obtained from the affected hemisphere was smaller and the extent of cortical output maps was decreased compared to the unaffected hemisphere; but none of the patients showed MEPs at the affected hand when the ipsilateral unaffected motor cortex was stimulated. CONCLUSIONS: Despite a rapid and nearly complete motor recovery the brain activation pattern was associated with increased activity in (bilateral) motor areas as revealed with fMRI. TMS revealed impaired motor output properties, but failed to demonstrate ipsilateral motor pathways. Successful recovery in our patients may therefore rely on the increased bilateral activation of existing motor networks spared by the injury.

Clinical hypnosis modulates functional magnetic resonance imaging signal intensities and pain perception in a thermal stimulation paradigm.

OBJECTIVE: This study was designed to describe regional changes in blood oxygenation level dependent signals in functional magnetic resonance images (fMRI) elicited by thermal pain in hypnotized subjects. These signals approximately identify the neural correlates of the applied stimulation to identify neuroanatomic structures involved in the putative effects of clinical hypnosis on pain perception. METHODS: After determination of the heat pain threshold of 12 healthy volunteers, fMRI scans were performed at 1.5 Tesla by using echoplanar imaging technique during repeated painful heat stimuli. Activation of brain regions in response to thermal pain during hypnosis (using a fixation and command technique of hypnosis) was compared with responses without hypnosis. RESULTS: With hypnosis, less activation in the primary sensory cortex, the middle cingulate gyrus, precuneus, and the visual cortex was found. An increased activation was seen in the anterior basal ganglia and the left anterior cingulate cortex. There was no difference in activation within the right anterior cingulate gyrus in our fMRI studies. No activation was seen within the brainstem and thalamus under either condition. CONCLUSION: Our observations indicate that clinical hypnosis may prevent nociceptive inputs from reaching the higher cortical structures responsible for pain perception. Whether the effects of hypnosis can be explained by increased activation of the left anterior cingulate cortex and the basal ganglia as part of a possible inhibitory pathway on pain perception remains speculative given the limitations of our study design.

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.

The effect of deep brain stimulation on the speech motor system.

PURPOSE: Chronic deep brain stimulation of the nucleus ventralis intermedius is an effective treatment for individuals with medication-resistant essential tremor. However, these individuals report that stimulation has a deleterious effect on their speech. The present study investigates one important factor leading to these effects: the coordination of oral and glottal articulation. METHOD: Sixteen native-speaking German adults with essential tremor, between 26 and 86 years old, with and without chronic deep brain stimulation of the nucleus ventralis intermedius and 12 healthy, age-matched subjects were recorded performing a fast syllable repetition task (/papapa/, /tatata/, /kakaka/). Syllable duration and voicing-to-syllable ratio as well as parameters related directly to consonant production, voicing during constriction, and frication during constriction were measured. RESULTS: Voicing during constriction was greater in subjects with essential tremor than in controls, indicating a perseveration of voicing into the voiceless consonant. Stimulation led to fewer voiceless intervals (voicing-to-syllable ratio), indicating a reduced degree of glottal abduction during the entire syllable cycle. Stimulation also induced incomplete oral closures (frication during constriction), indicating imprecise oral articulation. CONCLUSION: The detrimental effect of stimulation on the speech motor system can be quantified using acoustic measures at the subsyllabic level.