Morphological basis for the spectrum of clinical deficits in spinocerebellar ataxia 17 (SCA17).

Spinocerebellar ataxia 17 (SCA17) is a rare genetic disorder characterized by cerebellar, extrapyramidal, pyramidal as well as psychiatric signs. The pathoanatomical basis of this disorder is still not well known. A total of 12 patients and 12 age- and sex-matched controls were examined by in vivo MRI voxel-based morphometry (VBM). Besides general patterns of disease-related brain atrophy, characteristic syndrome-related morphological changes in SCA17 patients were studied. In comparison with normal controls, SCA17 patients showed a pattern of degeneration of the grey matter centred around mesial cerebellar structures, occipito-parietal structures, the anterior putamen bilaterally, the thalamus and other parts of the motor network, reflecting the cerebellar, pyramidal and extrapyramidal signs. A correlation analysis revealed a clear association between the clinical cerebellar, extrapyramidal and psychiatric scores and degeneration in specific areas. Two degeneration patterns were found as follows: regarding motor dysfunction, atrophy of the grey matter involved mainly the cerebellum and other motor networks, in particular the basal ganglia. In contrast, correlations with psychiatric scores revealed grey matter degeneration patterns in the frontal and temporal lobe, the cuneus and cingulum. Most interestingly, there was a highly significant correlation between the clinical Mini-Mental State Examination scores and atrophy of the nucleus accumbens, probably accounting for the leading psychiatric signs.

Functional MRI reveals activation of a subcortical network in a 5-year-old girl with genetically confirmed myoclonus-dystonia.

We investigated a five-year-old girl suffering from genetically confirmed, action-induced myoclonus-dystonia (M-D) with functional magnetic resonance imaging (MRI). We compared the activation pattern by movements of her right hand as if drawing a picture, which elicited M-D, with simple snapping movements (without overt M-D). The drawing and snapping conditions resulted in activation of a motor network including the motor cortex, the putamen, and the cerebellar hemispheres. The direct comparison of the drawing condition with snapping as control revealed specific activations within the thalamus and the dentate nucleus. An age matched healthy control did not show significant activation within the thalamus or dentate nucleus.

The cerebellum in the cerebro-cerebellar network for the control of eye and hand movements--an fMRI study.

The coordination of optical information and manipulation of objects in space by eye and hand movements is controlled by a cerebro-cerebellar network. The differential influence of prefrontal, motor, or parietal areas in combination with cerebellar areas, especially within the posterior hemispheres, on the control of eye and hand movements is not very well defined. Using fMRI we investigated the functional representation of isolated or combined eye and hand movements within the cerebellum and the impact of differential cognitive preload on the activation patterns. Each task consisted of the performance of saccades or hand movements triggered by a cue presented on a screen in front of the scanner. Saccades were tested for visually guided saccades, triple step saccades, and for visuospatial memory. Sequential finger opposition movements were tested for predictive and nonpredictive movements. Combined and isolated eye-hand reaching movements were tested toward a target presented in 5 different horizontal positions. Visually guided saccades activated the cerebellar vermis lobuli VI-VII, triple step saccades, including visuospatial memorization, in addition the cerebellar hemispheres lobuli VII-VIII. Sequential finger movements and reaching movements activated a cerebellar network consisting of the lobuli IV-VI, the vermis, and the lobuli VII-VIII with broader areas and additional regions especially within the lobus VII for more complex movements. The combined in contrast to the isolated performance of eye and hand movements demonstrated specialized activation foci within the cerebellar vermis and posterior hemispheres. We could demonstrate a differential representation of eye and hand movements within the cerebellum. Additional "cognitive" preload within a given task leads to additional activation of the posterior cerebellar hemispheres, with a subspecialization corresponding to premotor and parietal area connections.

Differential cerebellar activation related to perceived pain intensity during noxious thermal stimulation in humans: a functional magnetic resonance imaging study.

Little is known about the cerebellar involvement in pain processing in spite of the fact that the cerebellum probably plays a crucial role in pain-related behavior. Using functional magnetic resonance imaging we examined the differential cerebellar activation in 18 healthy subjects in relation to their perceived pain-intensity of noxious and non-noxious thermal stimuli. In contrast to non-noxious (40 degrees C) stimuli, noxious (48.5 degrees C) stimuli revealed activation in the deep cerebellar nuclei, anterior vermis and bilaterally in the cerebellar hemispheric lobule VI. With the same noxious stimulus (48.5 degrees C) there was differential cerebellar activation depending on the perceived pain intensity: high pain intensity ratings were associated with activation in ipsilateral hemispheric lobule III-VI, deep cerebellar nuclei and in the anterior vermis (lobule III). This differential cerebellar activation pattern probably reflects not only somatosensory processing but also perceived pain intensity that may be important for cerebellar modulation of nociceptive circuits.

Voluntary palatal tremor is associated with hyperactivation of the inferior olive: a functional magnetic resonance imaging study.

Voluntary palatal tremor in a patient with essential palatal tremor induced activation predominantly within regions corresponding to the inferior olive, adjacent brainstem, and dentate nuclei. Finger movements elicited only ipsilateral lobular cerebellar activation, suggesting a dysfunctional nuclear activation by palatal tremor.

Activation of frontoparietal cortices during memorized triple-step sequences of saccadic eye movements: an fMRI study.

To determine the cortical areas controlling memory-guided sequences of saccadic eye movements, we performed functional magnetic resonance imaging (fMRI) in six healthy adults. Subjects had to perform a memorized sequence of three saccades in darkness, after a triple-step stimulus of successively flashed laser targets. To assess the differential contribution of saccadic subfunctions, we applied several control conditions, such as central fixation with or without triple-step visual stimulation, self-paced saccades in darkness, visually guided saccades and single memory-guided saccades. Triple-step saccades strongly activated the regions of the frontal eye fields, the adjacent ventral premotor cortex, the supplementary eye fields, the anterior cingulate cortex and several posterior parietal foci in the superior parietal lobule, the precuneus, and the middle and posterior portion of the intraparietal sulcus, the probable location of the human parietal eye field. Comparison with the control conditions showed that the right intraparietal sulcus and parts of the frontal and supplementary eye fields are more involved in the execution of triple-step saccades than in the other saccade tasks. In accordance with evidence from clinical lesion studies, we propose that the supplementary eye field essentially controls the triggering of memorized saccadic sequences, whereas activation near the middle portion of the right intraparietal sulcus appears to reflect the necessary spatial computations, including the use of extraretinal information (efference copy) about a saccadic eye displacement for updating the spatial representation of the second or third target of the triple-step sequence.

Activation of the cerebellum by sensory finger stimulation and by finger opposition movements. A functional magnetic resonance imaging study.

Activation of the ipsilateral anterior lobe of the cerebellum by means of hand movements by humans is a well-known phenomenon, but the cerebellar encoding of sensory information has not been well established. The authors delineated the representation of sensory stimulation of fingers in the anterior lobe of the cerebellum using functional magnetic resonance imaging sensitized to changes in blood oxygenation and compared these areas to the regions activated by means of finger opposition movements. Activation was determined by means of pixel-by-pixel correlation of the signal intensity time course with a reference waveform equivalent to the stimulus protocol. All subjects showed significant activation of the anterior lobe of the cerebellum, mainly located in the ipsilateral Larsell lobules IV-V and less consistent in the vermis in relation to sensory finger stimulation. Among some subjects the authors also found activation in the anterior lobe on the contralateral side. The finger movements activated regions that overlapped with the areas activated by sensory finger stimulation but showing a larger and more intense activation pattern.

Preoperative functional magnetic resonance imaging (fMRI) of the motor system in patients with tumours in the parietal lobe.

Intracranial lesions may compromise structures critical for motor performance, and mapping of the cortex, especially of the motor hand area, is important to reduce postoperative morbidity. We investigated nine patients with parietal lobe tumours and used functional MRI sensitized to changes in blood oxygenation to define the different motor areas, especially the primary sensorimotor cortex, in relation to the localization of the tumour. Activation was determined by pixel-by-pixel correlation of the signal intensity time course with a reference waveform equivalent to the stimulus protocol. All subjects showed significant activation of the primary sensorimotor cortex while performing a finger opposition task with the affected and unaffected side. In five patients the finger opposition task additionally activated the ipsilateral sensorimotor cortex and the supplementary motor area (SMA). Extension and flexion of the foot, additionally performed in two patients, also activated the sensorimotor cortex, in one case within the perifocal oedema of the tumour. Tumour localization near the central sulcus induced displacement of the sensorimotor cortex as compared to the unaffected side in all patients with a relevant mass effect. The results of our study demonstrate that functional MRI at 1.5 T with a clinically used tomograph can reproducibly localize critical brain regions in patients with intracranial lesions.

Double-blind crossover study with physostigmine in patients with degenerative cerebellar diseases.

OBJECTIVE: To determine whether treatment with physostigmine can improve the conditions of patients with ataxia. DESIGN: A double-blind crossover study with physostigmine was performed in 19 patients with degenerative cerebellar diseases. SETTING: Patients were selected from an ongoing prospective follow-up study at the university hospital in Lübeck, Germany. PATIENTS: Eleven patients with autosomal dominant cerebellar ataxia and 8 patients with idiopathic cerebellar ataxia. INTERVENTION: Physostigmine was administered by using a transdermal system (patch) containing 30 mg of physostigmine as a base, of which about 6 mg is released during 24 hours along a diffusion gradient. Each treatment phase with the physostigmine patch or the placebo lasted 4 weeks, after which the treatment of patients was crossed over to the other phase. MAIN OUTCOME MEASURES: Ataxia was documented and quantified by using a clinical score and posturographic measures. RESULTS: Physostigmine patches had no significant effect on cerebellar symptoms. CONCLUSION: Treatment with physostigmine does not improve the conditions of patients with ataxia.

Cerebellar somatotopic representation and cerebro-cerebellar interconnections in ataxic patients.

Different methods of functional neuroimaging were used for studying somatotopic encoding of function in the cerebellum and for investigating cerebro-cerebellar interconnections in patients with cerebellar degeneration. fMRI showed, that the center of activation for hand function was located in the intermediate hemispheric portion of Larsell lobules H IV-V. Foot movements activated areas medial and anterior to the corresponding hand areas within Larsell lobules II-III. Changed function in motor cortices could be demonstrated in patients with cerebellar degeneration as compared to normal controls by recording movement-related cortical potentials (BP). In patients the motor potential was almost lacking and transcranial magnetic stimulation demonstrated enhancement of inhibitory mechanisms (prolonged postexcitatory inhibition) in the motor cortex. PET-findings suggested, that both effects are correlated to increased activity of inhibitory interneurons. Cerebellar patients showed increased activation in relation to movements in the SMA and basal ganglia and reduced activation in the cerebellum and lateral premotor areas. It could be speculated, that compensatory mechanisms are the reason for a stronger activation of the medial premotor system, including SMA, in patients with cerebellar degeneration. On the basis of our results it appears, that the cerebellum facilitates the lateral premotor system areas much more than it does the medial areas.

Somatotopy in the human motor cortex hand area. A high-resolution functional MRI study.

Fine-scale somatotopic encoding in brain areas devoted to sensorimotor processing has recently been questioned by functional neuroimaging studies which suggested its absence within the hand area of the human primary motor cortex. We re-examined this issue by addressing somatotopy both in terms of functional segregation and of cortical response preference using oxygenation-sensitive magnetic resonance imaging at high spatial resolution. In a first step, spatial representations of self-paced isolated finger movements were mapped by using motor rest as a control state. A subsequent experimental design studied the predominance of individual finger movements by using contrasting finger movements as the control task. While the first approach confirmed previous reports of extensive overlap in spatial representations, the second approach revealed foci of differential activation which displayed an orderly mediolateral progression in accordance with the classical cortical motor homunculus. We conclude that somatotopy within the hand area of the primary motor cortex does not present as qualitative functional segregation but as quantitative predominance of certain movement or digit representation embedded in an overall joint hand area.

Enhancement of inhibitory mechanisms in the motor cortex of patients with cerebellar degeneration: a study with transcranial magnetic brain stimulation.

The excitatory state of the primary motor cortex can be studied by measuring either the postexcitatory inhibition after transcranial magnetic single stimulation (pI-S) or the refractory period with magnetic double stimulation (rP-D). The cerebellum may influence the excitability of the motor cortex by cerebellar inputs and outputs from side loops of transcortical projections. Therefore, we studied pI-S and rP-D in 24 patients with autosomal dominant cerebellar ataxia or idiopathic cerebellar ataxia, who were allocated to one group (Group A) with mild to moderate ataxia (n = 11) and to another group (Group B) with severe ataxia (n = 13). The results were compared with those obtained in 21 normal age-matched control subjects. The central motor conduction time (CMCT) was delayed in approximately half of the patients, demonstrating that the degenerative process, beyond the cerebellum, also affects the pyramidal tract. Mean CMCT was significantly delayed only in patients of Group B. pI-S was prolonged in 10 of our 24 patients; incidence of pathology in pI-S did not differ between the two patient groups. In 5 patients with normal CMCT, pathological pI-S results were found. Mean pI-S was prolonged in the whole patient group and in both subgroups as well. rP-D was prolonged in two patients of Group B only, but mean rP-D was significantly prolonged in the whole patient group. Prolonged postexcitatory inhibition and refractory period may be a consequence of a transient facilitation of cortical inhibitory interneurons, which results in a decreased excitability of primary motor cortex in patients with cerebellar degeneration.

Somatotopic motor representation in the human anterior cerebellum. A high-resolution functional MRI study.

Though somatotopic encoding of function is a prominent feature in brain structures involved in sensori-motor processing, it has not been well established for the human cerebellum. We delineated the representation of hand, foot and tongue movements in the anterior cerebellar lobe of eight healthy subjects using dynamic high-resolution MRI sensitized to changes in cerebral blood oxygenation (CBO). Activation was determined by pixel-by-pixel correlation of signal intensity time courses with the performance protocol. All subjects showed task-related signal increases in an ipsilateral region during distal limb movements. For the hand task, the centre of activation was located in the intermediate hemispheric portion of Larsell lobules H IV-V. Foot movements activated areas within the central lobule, Larsell lobules II-III, medial and anterior to the corresponding hand areas in all subjects. Responses for tongue movements were less consistent across subjects but found in areas posterior to the respective individual hand representation.