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Ferdinand Binkofski

Publications and source records attributed to Ferdinand Binkofski.

At least 19 recordsLinked to original sources
PubMed2007

Biological effects of the PINK1 c.1366C>T mutation: implications in Parkinson disease pathogenesis.

PINK1 gene mutations are a cause of recessively inherited, early-onset Parkinson's disease. In some patients, a single heterozygous mutation has been identified, including the recurrent c.1366C>T transition. The interpretation of this finding remains controversial. Furthermore, the c.1366C>T mutation is associated with lower levels of PINK1 transcript, raising the question of whether mRNA levels correlate with the clinical status. We sequenced genomic DNA and copy DNA (cDNA) from 20 subjects carrying the c.1366C>T mutation in the homozygous (n = 5) or heterozygous (n = 15) state. In 17 mutation carriers, messenger RNA (mRNA) was quantified by real-time PCR using four different assays (PINK1 exon 5-6 or exon 7-8 relative to control genes SDHA or YWHAZ). Genomic sequencing confirmed the presence and zygosity of PINK1 mutations. cDNA sequencing in heterozygous mutation carriers revealed a strong wild-type and a much weaker or almost absent mutant signal, whereas in the homozygous patients, only the mutant signal was detected. Homozygous and heterozygous carriers showed PINK1 mRNA levels relative to a reference gene in the range of 0.1-0.2 and 0.5-0.6, respectively, compared with values of 0.9-1.0 in mutation-negative individuals. Treatment of lymphoblasts from a heterozygous mutation carrier with cycloheximide markedly increased the mutant transcript signal. We conclude that the recurrent PINK1 c.1366C>T mutation exerts a major effect at the mRNA level (80-90% reduction), most likely via nonsense-mediated mRNA decay. The absence of correlation between PINK1 mRNA levels and clinical status in heterozygous mutation carriers suggests that other genetic or environmental factors play a role in determining the phenotypic variability associated with the c.1366C>T mutation.

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PubMed2006

Different extraretinal neuronal mechanisms of smooth pursuit eye movements in schizophrenia: An fMRI study.

Smooth pursuit eye movements (SPEM) are necessary to follow slowly moving targets while maintaining foveal fixation. In about 50% of schizophrenic patients SPEM velocity is reduced. In this study we were interested in identifying the cortical mechanisms associated with extraretinal processing of SPEM in schizophrenic patients. During condition A, patients and healthy subjects had to pursue a constantly visible target (10 degrees /s). During condition B the target was blanked out for 1000 ms while subjects were instructed to continue SPEM. Eye movement data were assessed during scanning sessions by a limbus tracker. During condition A, reduced SPEM velocity in patients was associated with reduced activation of the right ventral premotor cortex and increased activation of the left dorsolateral prefrontal cortex, the right thalamus and the Crus II of the left cerebellar hemisphere. During condition B, SPEM velocity was reduced to a similar extent in both groups. While in patients a decrease in activation was observed in the right cerebellar area VIIIA, the activation of the right anterior cingulate, the right superior temporal cortex, and the bilateral frontal eye fields was increased. The results implicate that schizophrenic patients employ different strategies during SPEM both with and without target blanking than healthy subjects. These strategies predominantly involve extraretinal mechanisms.

Adult↗
PubMed2006

The role of ventral premotor cortex in action execution and action understanding.

The human ventral premotor cortex overlaps, at least in part, with Broca's region in the dominant cerebral hemisphere, that is known to mediate the production of language and contributes to language comprehension. This region is constituted of Brodmann's areas 44 and 45 in the inferior frontal gyrus. We summarize the evidence that the motor related part of Broca's region is localized in the opercular portion of the inferior frontal cortex, mainly in area 44 of Brodmann. According to our own data, there seems to be a homology between Brodmann area 44 in humans and the monkey area F5. The non-language related motor functions of Broca's region comprise complex hand movements, associative sensorimotor learning and sensorimotor integration. Brodmann's area 44 is also a part of a specialized parieto-premotor network and interacts significantly with the neighbouring premotor areas. In the ventral premotor area F5 of monkeys, the so called mirror neurons have been found which discharge both when the animal performs a goal-directed hand action and when it observes another individual performing the same or a similar action. More recently, in the same area mirror neurons responding not only to the observation of mouth actions, but also to sounds characteristic to actions have been found. In humans, through an fMRI study, it has been shown that the observation of actions performed with the hand, the mouth and the foot leads to the activation of different sectors of Broca's area and premotor cortex, according to the effector involved in the observed action, following a somatotopic pattern which resembles the classical motor cortex homunculus. On the other hand the evidence is growing that human ventral premotor cortex, especially Brodmann's area 44, is involved in polymodal action processing. These results strongly support the existence of an execution-observation matching system (mirror neuron system). It has been proposed that this system is involved in polymodal action recognition and might represent a precursor of language processing. Experimental evidence in favour of this hypothesis both in the monkey and humans is shortly reviewed.

Animals↗
PubMed2006

Clinical spectrum of homozygous and heterozygous PINK1 mutations in a large German family with Parkinson disease: role of a single hit?

BACKGROUND: Although homozygous mutations in the PTEN-induced putative kinase 1 (PINK1) gene have been unequivocally associated with early-onset Parkinson disease (PD), the role of single heterozygous PINK1 mutations is less clear. OBJECTIVE: To investigate the role of homozygous and heterozygous PINK1 mutations in a large German pedigree (family W). DESIGN: Mutation analysis of PINK1 and results of standardized neurological and motor examination by 3 independent movement disorder specialists, including blinded video rating. SETTINGS: University of Lübeck. PARTICIPANTS: Twenty family members. MAIN OUTCOME MEASURES: The PINK1 genotype and PD status of all family members. RESULTS: The index patient of family W carried a homozygous nonsense mutation (c.1366C>T; p.Q456X) and presented with a phenotype closely resembling idiopathic PD but with an onset at 39 years of age. The family included a total of 4 affected homozygous members (age, 60-71 years; age at onset, 39-61 years), 6 members with slight or mild signs of PD (affected) and a heterozygous mutation (age, 31-49 years), and 5 unaffected heterozygous mutation carriers (age, 34-44 years). Although none of the heterozygous affected family members was aware of their signs (asymptomatic), the clinical findings were unequivocal and predominantly or exclusively present on their dominant right-hand side, eg, unilaterally reduced or absent arm swing and unilateral rigidity. The heterozygous members were all considerably younger than the affected homozygous mutation carriers. CONCLUSIONS: Heterozygous PINK1 mutations may predispose to PD, as was previously suggested by the presence of dopamine hypometabolism in asymptomatic mutation carriers. Long-term follow-up of our large family W provides an excellent opportunity to further evaluate the role of single heterozygous PINK1 mutations later in life, which will have major implications on genetic counseling.

Adult↗
PubMed2005

Parametric modulation of cortical activation during smooth pursuit with and without target blanking. an fMRI study.

Smooth pursuit eye movements (SPEM) are performed to track slowly moving visual targets and are accompanied by saccades whenever foveal representation is lost. In the present study, we correlated the cerebral activation as assessed by functional magnetic resonance imaging with parameters of eye movement performance in order to determine the cortical areas involved in the retinal and extraretinal processing of maintaining smooth pursuit velocity (SPV) and generating saccades in 16 healthy males. The stimulus consisted of a target moving at a constant velocity of 10 degrees/s with and without target blanking. During constant target presentation, SPV was positively correlated with the BOLD signal in the right V5 complex and negatively correlated with the BOLD response in the left dorsolateral prefrontal cortex (DLPFC). In the condition with target blanking, additional negative correlations with SPV were found in the left frontal eye field (FEF), the left parietoinsular vestibular cortex (PIVC) and the left angular gyrus. Saccadic frequency was negatively correlated with activations of the right mesial intraparietal sulcus (IPS) during both conditions and the right premotor area during continuous target presentation. We conclude that V5 is directly related to the maintenance of an optimal smooth pursuit velocity during visual feedback, whereas the FEF, PFC, angular gyrus and PIVC are involved in reconstitution and prediction whenever SPV decreases, especially during maintenance of smooth pursuit in the absence of a visual target. Furthermore, we suggest that parietal areas are related to the suppression of saccades during smooth pursuit.

Adult↗
PubMed2004

Reduced neuronal activity in the V5 complex underlies smooth-pursuit deficit in schizophrenia: evidence from an fMRI study.

Smooth-pursuit eye movements are the essential tool for a clear and stable visual perception of our environment by matching eye velocity to the velocity of moving objects. However, in about 50% of schizophrenic patients, this ability is disturbed. To reveal the cortical mechanisms that underlie this deficit, eye velocity-related neuronal activity was analyzed by functional magnetic resonance imaging (fMRI). Blocks of constant velocity ramps (10 degrees/s) were presented to 17 patients with schizophrenia and 16 matched controls while assessing smooth-pursuit velocity (SPV) during scanning sessions. Using random-effects analysis, the parametric modulation of brain hemodynamic responses related to SPV was compared between both groups. In schizophrenic patients, reduced SPV was significantly correlated with a focal decrease of the hemodynamic response in the V5 complex (t = 4.21, P(FWE-corrected) = 0.005). Our results provide direct evidence for reduced neuronal activity in V5 as one major factor underlying abnormal SPV in schizophrenia and suggest impaired motion perception. They confirm hypotheses about a V5 deficit derived from psychophysiological studies with schizophrenic patients in which deficient motion perception (especially velocity discrimination) was associated with impaired smooth-pursuit performance.

Adult↗
PubMed2004

Modulation of the BOLD-response in early recovery from sensorimotor stroke.

BACKGROUND: The BOLD signal in functional MRI (fMRI) is closely related to neural activity. OBJECTIVE: To investigate if this relationship is disrupted after ischemic stroke. METHODS: BOLD activity during tactile exploration of objects was measured with fMRI at 1 week (subacute), 2 to 4 weeks (early chronic), and after 1 month (chronic) after the first completed brain infarction affecting the sensorimotor cortex in eight patients. Functional integrity of the motor cortical output system was assessed with transcranial magnetic stimulation (TMS). RESULTS: Early after infarction the BOLD-response occurred in the adjacent cortical vicinity related to finger movements of the affected hand. However, during the early chronic stage there was a transient lack of this activation despite clinical improvement of hand function and preserved motor evoked potentials. The BOLD activity reappeared after further improvement in the chronic stage. CONCLUSIONS: Our findings suggest a transient hemodynamic-electrical decoupling in the post-ischemic cerebral cortex during the early phase of spontaneous clinical recovery.

Aged↗
PubMed2004

Activation of cerebellar hemispheres in spatial memorization of saccadic eye movements: an fMRI study.

What mechanisms allow us to direct a precise saccade to a remembered target position in space? The cerebellum has been proposed to be involved not only in motor and oculomotor control, but also in perceptual and cognitive functions. We used functional MRI (Echoplanar imaging at 1.5 T) to investigate the role of the cerebellum in the control of externally triggered and internally generated saccadic eye movements of high and low memory impact, in six healthy volunteers. Memory-guided saccades to remembered locations of 3 targets (triple-step saccades) in contrast to either central fixation or to visually guided saccades activated the cerebellar hemispheres predominantly within lobuli VI-crus I. The same areas were activated when an analogous visuospatial working memory task was contrasted to the triple-step saccades. Visually guided saccades activated the posterior vermis and the triple-step saccades, contrasted to the working memory task, activated predominantly the posterior vermis and paravermal regions. Our data confirm the primary involvement of the posterior vermis for visually-triggered saccadic eye movements and present novel evidence for a role of the cerebellar hemispheres in the mnemonic and visuospatial control of memory-guided saccades.

Adult↗
PubMed2004

The mirror neuron system and action recognition.

Mirror neurons, first described in the rostral part of monkey ventral premotor cortex (area F5), discharge both when the animal performs a goal-directed hand action and when it observes another individual performing the same or a similar action. More recently, in the same area mirror neurons responding to the observation of mouth actions have been also found. In humans, through an fMRI study, it has been shown that the observation of actions performed with the hand, the mouth and the foot leads to the activation of different sectors of Broca's area and premotor cortex, according to the effector involved in the observed action, following a somatotopic pattern which resembles the classical motor cortex homunculus. These results strongly support the existence of an execution-observation matching system (mirror neuron system). It has been proposed that this system is involved in action recognition. Experimental evidence in favor of this hypothesis both in the monkey and humans are shortly reviewed.

Animals↗
PubMed2004

Motor functions of the Broca's region.

Broca's region in the dominant cerebral hemisphere is known to mediate the production of language but also contributes to comprehension. This region evolved only in humans and is constituted of Brodmann's areas 44 and 45 in the inferior frontal gyrus. There is, however, evidence that Broca's region overlaps, at least in part, with the ventral premotor cortex. We summarize the evidence that the motor related part of Broca's area is localized in the opercular portion of the inferior frontal cortex, mainly in area 44 of Brodmann. According to our own data, there seems to be a homology between Brodmann area 44 in humans and the monkey area F5. The non-language related motor functions of Broca's region comprise complex hand movements, associative sensorimotor learning and sensorimotor integration. Brodmann's area 44 is also a part of a specialized parieto-premotor network and interacts significantly with the neighboring premotor areas.

Animals↗
PubMed2004

Cortical mechanisms of smooth pursuit eye movements with target blanking. An fMRI study.

Smooth pursuit eye movements are evoked by retinal image motion of visible moving objects and can also be driven by the internal representation of a target due to extraretinal mechanisms (e.g. efference copy). To delineate the corresponding neuronal correlates, functional magnetic resonance imaging at 1.5 T was applied during smooth pursuit at 10 degrees /s with continuous target presentation and target blanking for 1 s to 16 right-handed healthy males. Eye movements were assessed during scanning sessions by infra-red reflection oculography. Smooth pursuit performance was optimal when the target was visible but decreased to a residual velocity of about 30% of the velocity observed during continuous target presentation. Random effects analysis of the imaging data yielded an activation pattern for smooth pursuit in the absence of a visual target (in contrast to continuous target presentation) which included a number of cortical areas in which extraretinal information is available such as the frontal eye field, the superior parietal lobe, the anterior and the posterior intraparietal sulcus and the premotor cortex, and also the supplementary and the presupplementary eye field, the supramarginal gyrus, the dorsolateral prefrontal cortex, cerebellar areas and the basal ganglia. We suggest that cortical mechanisms such as prediction, visuo-spatial attention and transformation, multimodal visuomotor control and working memory are of special importance for maintaining smooth pursuit eye movements in the absence of a visible target.

Adult↗
PubMed2003

Mirror apraxia affects the peripersonal mirror space. A combined lesion and cerebral activation study.

Mirror apraxia is a condition in which patients with lesions of the posterior parietal cortex have deficits in reaching to objects presented through a mirror. The aim of the present study was to investigate possible mechanisms underlying this disorder. First, we addressed the question of whether mirror apraxia is exhibited to the same extent in peripersonal and in body space. Four patients with lesions of the posterior parietal lobe on either side and with marked mirror apraxia were required to reach for objects that were presented to them through a mirror and located either in body space (i.e. on the body surface) or in peripersonal space (i.e. in the reaching distance). Whereas reaching for objects located in body space was flawless in all patients, the performance deteriorated when the same objects were transferred to the peripersonal space. Although the objects were located only a few centimetres above the body surface, the patients reached towards the virtual object in the mirror. Based on these results we suggest that mirror apraxia may originate from a dissociation between the representations of body schema and peripersonal space and that objects located on the body surface become integrated into the body schema. In the second part of the study, using positron emission tomography study (PET), we studied the cerebral activation pattern during reaching to objects presented through a mirror in the peripersonal space in healthy subjects. The results show that increased neural activity in the anterior part of the intraparietal sulcus and in the dorsal premotor cortex was bound to the transformation of the target position from the mirror space to the real space. In contrast, the activity related to object localization in the mirror occurred at the parieto-occipital junction. Both mirror and arm transformation involved the medial posterior part of the superior parietal lobule, putatively area V6a. The results demonstrate that acting through a mirror is processed in a number of cortical areas of the dorsal stream.

Aged↗
PubMed2003

A fronto-parietal circuit for tactile object discrimination: an event-related fMRI study.

Previous studies of somatosensory object discrimination have been focused on the primary and secondary sensorimotor cortices. However, we expected the prefrontal cortex to also become involved in sequential tactile discrimination on the basis of its role in working memory and stimulus discrimination as established in other domains. To investigate the contributions of the different cerebral structures to tactile discrimination of sequentially presented objects, we obtained event-related functional magnetic resonance images from seven healthy volunteers. Our results show that right hand object exploration involved left sensorimotor cortices, bilateral premotor, parietal and temporal cortex, putamen, thalamus, and cerebellum. Tactile exploration of parallelepipeds for subsequent object discrimination activated further areas in the dorsal and ventral portions of the premotor cortex, as well as parietal, midtemporal, and occipital areas of both cerebral hemispheres. Discriminating a parallelepiped from the preceding one involved a bilateral prefrontal-anterior cingulate-superior temporal-posterior parietal circuit. While the prefrontal cortex was active with right hemisphere dominance during discrimination, there was left hemispheric prefrontal activation during the delay period between object presentations. Delay related activity was further seen in the anterior intraparietal area and the fusiform gyrus. The results reveal a prominent role of the human prefrontal cortex for somatosensory object discrimination in correspondence with recent models on stimulus discrimination and working memory.

Adult↗
PubMed2003

Functional properties and interaction of the anterior and posterior intraparietal areas in humans.

In the monkey the lateral bank of the anterior part of the intraparietal sulcus (area AIP), contains neurons that are involved in visually guided, object-related hand movements. It has also been shown that neurons in the caudal part of the intraparietal sulcus (area CIP) preferentially respond to 3D surface orientation. According to these results, it has been hypothesized that neurons in area CIP primarily encode the 3D features of an object and forwards this information to area AIP. AIP then utilizes this information for appropriate hand actions towards the object. Based on analogies to these primate studies, recent neuroimaging studies have suggested human homologues of areas AIP and CIP, however, the functional interaction between these areas remains unclear. Our event related fMRI study was designed to address specifically the question, how CIP and AIP interact in the process of adjustment of hand orientation towards objects. Volunteers were asked to perform three tasks: discrimination of surface orientation, imaging of visually guided hand movements and execution of visually guided hand movements. Our data show that the human AIP was activated both during discrimination of surface orientation and during the subsequent spatial adjustment of the thumb and index finger position towards the surface orientation. In contrast, human CIP was activated by the surface orientation but not by spatial adjustment of finger position. These data clearly indicate that the function of human CIP is more involved in coding 3D features of the objects, whereas human AIP is more involved in visually guided hand movements, similar to its role in the monkey.

Adult↗
PubMed2003

The role of the fastigial nucleus in saccadic eye oscillations.

For the first time, we provide functional magnetic resonance imaging evidence for a recent hypothesis that saccadic oscillations in opsoclonus may result from a disinhibition of the cerebellar fastigial nuclei. Two patients with severe opsoclonus were examined during fixation in the light and during eye closure and in darkness where opsoclonus disappeared. Their activation during opsoclonus was compared with 10 healthy subjects performing visually guided and self-paced saccades in the light and darkness. In contrast to the control subjects, the patients showed a strong bilateral midline cerebellar activation that involved the deep cerebellar nuclei. This is probably not just a secondary finding in the fastigial nuclei due to the high frequent saccadic activity because there was, concomitantly, no oculomotor vermal activation, which is normally seen in healthy subjects. We propose that cerebellar activation of the fastigial nuclei may cause opsoclonus via their projections to the brainstem saccadic generator.

Adult↗