Secondary sensory area SII is crucially involved in the preparation of familiar movements compared to movements never made before.

Secondary sensorimotor regions are involved in sensorimotor integration and movement preparation. These regions take part in parietal-premotor circuitry that is not only active during motor execution but also during movement observation and imagery. This activation particularly occurs when observed movements belong to one's own motor repertoire, consistent with the finding that motor imagery only improves performance when one can actually make such movement. We aimed to investigate whether imagery or observation of a movement that was never made before causes parietal-premotor activation or that the ability to perform this movement is indeed a precondition. Nine subjects [group Already Knowing It (AKI)] could abduct their hallux (moving big toe outward). Seven subjects initially failed to make such movement (Absolute Zero A0 group). They had to imagine, observe, or execute this movement, whereas fMRI data were obtained both before and after training. Contrasting abduction observation between the AKI-group and A0-group showed increased left SII and supplementary motor area activation. Comparing the observation of hallux flexion with abduction showed increased bilateral SII activation in the A0 and not in the AKI group. Prolonged training resulted in equal performance and similar cerebral activation patterns in the two groups. Thereby, conjunction analysis of the correlations on subject's range of abduction during execution, imagery, and observation of hallux abduction showed exclusive bilateral SII activation. The reduced SII involvement in A0 may imply that effective interplay between sensory predictions and feedback does not take place without actual movement experience. However, this can be acquired by training.

Relationship between parental lung function and their children's lung function early in life.

This study investigated the relationship between parental lung function and their children's lung function measured early in life. Infants were participants in the Wheezing Illnesses Study Leidsche Rijn (WHISTLER). Lung function was measured before the age of 2 months using the single occlusion technique. Parental data on lung function (spirometry), medical history and environmental factors were obtained from the linked database of the Utrecht Health Project. Parental data on pulmonary function and covariates were available in 546 infants. Univariate linear regression analysis demonstrated a significant positive relationship between the infant's respiratory compliance and parental forced expiratory flow at 25-75% of forced vital capacity (FEF(25-75%))(,) forced expiratory volume in 1 s (FEV(1)) and forced vital capacity. A significant negative relationship was found between the infant's respiratory resistance and parental FEF(25-75%)and FEV(1). No significant relationship was found between the infant's respiratory time constant and parental lung function. Adjusting for body size partially reduced the significance of the observed relationship; adjusting for shared environmental factors did not change the observed results. Parental lung function levels are predictors of the respiratory mechanics of their newborn infants, which can only partially be explained by familial aggregation of body size. This suggests genetic mechanisms in familial aggregation of lung function, which are already detectable early in life.

Overlap and segregation in predorsal premotor cortex activations related to free selection of self-referenced and target-based finger movements.

In reaching movements, parietal contributions can be distinguished that are based on representations of external space and body scheme. By functional magnetic resonance imaging, we examined 16 healthy subjects to see whether such segregation similarly exists in the frontal lobes when visuomotor actions are not specified but when free choices are allowed. Free selection was button based (target based) or finger based (self-referenced), with invariant instructions as control. To avoid a visual attention bias, instructions were auditory presented. Statistical parametric mapping revealed that free button selection with the same finger was associated with increased activations in the anterior cingulate cortex (ACC), right posterodorsal prefrontal cortex (PFC) including the rostral extension of the dorsal premotor cortex (pre-PMd), and the anterodorsal PFC. Prefrontal activation related to free finger selection (pressing the same button) was restricted to an anteromedial segment of the posterodorsal PFC/pre-PMd. Bilateral inferior parietal activations were present in both free-choice conditions. Pre-PMd and parietal contributions to free selection support concepts on early-stage action selection in dorsal visuomotor pathways. The rostral-caudal segregation in pre-PMd activations reflected that in anterior direction, frontal processing is gradually less involved in selection of environmental information but increasingly committed to self-referenced selection. ACC particularly contributes to free selection between external goals.

Cerebral representations of space and time.

A link between perception of time and spatial change is particularly revealed in dynamic conditions. By fMRI, we identified regional segregation as well as overlap in activations related to spatial and temporal processing. Using spatial and temporal anticipation concerning movements of a ball provided a balanced paradigm for contrasting spatial and temporal conditions. In addition, momentary judgments were assessed. Subjects watched a monitor-display with a moving ball that repeatedly disappeared. Ordered in 4 conditions, they indicated either where or when the ball would hit the screen bottom, where it actually disappeared or what its speed was. Analysis with SPM showed posterior parietal activations related to both spatial- and temporal predictions. After directly contrasting these two conditions, parietal activations remained robust in spatial prediction but virtually disappeared in temporal prediction, while additional left cerebellar-right prefrontal and pre-SMA activations in temporal prediction remained unchanged. Speed contrasted to the location of disappearance showed similar parietal decrease with maintained cerebellar-prefrontal activations, but also increased caudate activation. From these results we inferred that parietal-based spatial information was a prerequisite for temporal processing, while prefrontal-cerebellar activations subsequently reflected working memory and feedforward processing for the assessment of differences between past and future spatial states. We propose that a temporal component was extracted from speed, i.e. approximated momentary time, which demarcated minimal intervals of spatial change (defined by neuronal processing time). The caudate association with such interval demarcation provided an argument to integrate concepts of space-referenced time processing and a clock-like processing model.

Changes in striatal dopamine D2 receptor binding in pre-clinical Huntington's disease.

BACKGROUND: Carriers of the Huntington disease (HD) mutation develop a progressive neurodegenerative disorder after a pre-clinical phase. We examined the value of (11)C-raclopride PET (RAC) as a biomarker for pre-clinical HD pathophysiology. METHODS: In a prospective cohort study with clinical and neuropsychological assessment we collected complete RAC data in 18 pre-clinical mutation carriers (HD-PMC) and 11 controls. Follow-up was 2 years. We calculated striatal RAC binding potential (BP) to measure dopamine D2 receptor availability. RESULTS: No HD-PMC had overt neuropsychological dysfunction. RAC-BP in putamen was abnormal in up to 44% of HD-PMC. The rate of RAC-BP decline (2.6% per year) was not significantly higher than in controls. Follow-up putaminal BP correlated weakly with predicted distance to onset of clinical HD (P = 0.034), but the rate of decline did not. Three HD-PMC developed motor abnormalities suspect for HD but did not show an increased rate of decline of putaminal BP. CONCLUSIONS: Many HD-PMC have striatal abnormalities but we found no clearly increased rate of D2 receptor changes around the onset of clinical HD. A longer follow-up of the present study cohort is needed to establish the value of RAC-BP in assessing the risk of clinical conversion from striatal D2 binding data.

Lateral parietal cortex in the generation of behavior: Implications for apathy.

A reduction in goal-directed behavior, or apathy, occurs in neurological and psychiatric disorders, though its neural substrates remain unclear. Deficits in circuits connecting the prefrontal cortex to subcortical regions are considered to underlie apathy. Although apathy is empirically associated with widespread changes in these regions, studies across disorders also link apathy with the lateral parietal cortex. Such variety in regional involvement is consistent with the established role of prefrontal and subcortical regions in models of goal-directed behavior, and with the suggestion of subtypes of apathy. However, these models do not provide a basis for the involvement of the lateral parietal cortex with apathy. Here, we review the association between lateral parietal cortex dysfunction and apathy across disorders and analyze the putative cognitive functions that may link this region with goal-directed behavior. We suggest that neural processes in the angular and supramarginal gyri of the inferior parietal lobule may provide an interface enabling the transformation of internal goals to external actions through intentional initiation of action interrelated with mechanisms of primary sensorimotor transformation. Consequently, we propose that impairment in this process of embedding intended action in a 'body schema' facilitating adequate recruitment of an effector system, is the likely mechanism underlying the association between the lateral parietal cortex and apathy. Considering the evidence, we propose a revised neurocognitive model of apathy where deficient internal initiation of behavior mediated by the inferior parietal lobule may be sufficient, though not necessary, to reduce goal-directed behavior, and may constitute a volitional subtype of apathy.

Cortico-thalamic activation in generalized status epilepticus, a PET study.

In a patient with a refractory generalized convulsive status epilepticus, the ictal distribution of regional cerebral glucose was assessed with positron emission tomography (PET). Synchronized seizure activity in the EEG was associated with bilateral metabolic activation of medial sensorimotor regions, anterior cingulate cortex, striatum and thalamus. This pattern with focal cortical activation supports the concept that a cortical focus may drive epilepsy, while the thalamus mediates synchronization of neuronal activity as reflected in the EEG.

Crossed Cerebellar Diaschisis in Alzheimer's Disease.

BACKGROUND: We describe the phenomenon of crossed cerebellar diaschisis (CCD) in four subjects diagnosed with Alzheimer's disease (AD) according to the National Institute on Aging - Alzheimer Association (NIA-AA) criteria, in combination with 18F-FDG PET and 11C-PiB PET imaging. METHODS: 18F-FDG PET showed a pattern of cerebral metabolism with relative decrease most prominent in the frontal-parietal cortex of the left hemisphere and crossed hypometabolism of the right cerebellum. 11C-PiB PET showed symmetrical amyloid accumulation, but a lower relative tracer delivery (a surrogate of relative cerebral blood flow) in the left hemisphere. CCD is the phenomenon of unilateral cerebellar hypometabolism as a remote effect of supratentorial dysfunction of the brain in the contralateral hemisphere. The mechanism implies the involvement of the cortico-ponto-cerebellar fibers. The pathophysiology is thought to have a functional or reversible basis but can also reflect in secondary morphologic change. CCD is a well-recognized phenomenon, since the development of new imaging techniques, although scarcely described in neurodegenerative dementias. RESULTS: To our knowledge this is the first report describing CCD in AD subjects with documentation of both 18F-FDG PET and 11C-PiB PET imaging. CCD in our subjects was explained on a functional basis due to neurodegenerative pathology in the left hemisphere. There was no structural lesion and the symmetric amyloid accumulation did not correspond with the unilateral metabolic impairment. CONCLUSION: This suggests that CCD might be caused by non-amyloid neurodegeneration. The pathophysiological mechanism, clinical relevance and therapeutic implications of CCD and the role of the cerebellum in AD need further investigation.

Medial versus lateral prefrontal dissociation in movement selection and inhibitory control.

We aimed to test the hypothesis that the cerebral selection of movement includes active suppression of unwanted movements. To that end, a cerebral activation paradigm was used in which index finger flexion was compared with similar movement, made together with fingers 3, 4, 5. Cerebral activations were assessed by positron emission tomography (PET) measurements of cerebral perfusion in 10 healthy subjects, during the two motor tasks and rest. Statistical parametric mapping (SPM) revealed significant increase of (antero)medial prefrontal activity and subtle changes in pallidum and thalamus in the condition of less movement, i.e. isolated index finger flexion contrasted to full-hand flexion. These increases indicated a mechanism of selection mediated by active suppression of unwanted movements. Suppression of all motor responses was inferred from anterolateral prefrontal activation related to rest (with only auditory cues), contrasted to both motor conditions. This segregation of inhibitory functions specifies the complementary character of response selection and inhibitory control, in such a way, that towards the medial prefrontal surface, a transition from general to increasingly selective inhibition allows the internal ordering of action.

Abnormal surface EMG during clinically normal wrist movement in cervical dystonia.

We investigated whether patients with cervical dystonia (CD) have abnormal muscle activation in non-dystonic body parts. Eight healthy controls and eight CD patients performed a flexion-extension movement of the right wrist. Movement execution was recorded by surface electromyography (EMG) from forearm muscles. Although patients had no complaints concerning wrist movement and had no apparent difficulty in executing the task, they demonstrated lower mean EMG amplitude (flexor: 0.32 mV and extensor: 0.61 mV) than controls (flexor: 0.67 mV; P = 0.021 and extensor: 1.18 mV; P = 0.068; borderline significant). Mean extensor muscle contraction was prolonged in patients (1860 ms) compared with controls (1334 ms; P = 0.026). Variation in mean EMG amplitude over movements tended to be higher in patients (flexor: 43% and extensor: 35%) than controls (flexor: 34%; P = 0.072 and extensor: 26%; P = 0.073). These results suggest that CD patients also have abnormal muscle activation in non-dystonic body parts at a subclinical level. This would support the concept that in dystonia, non-dystonic limbs are in a 'pre-dystonic state'.

Cerebral activation related to implicit sequence learning in a Double Serial Reaction Time task.

Using functional magnetic resonance imaging (fMRI), we examined the distribution of cerebral activations related to implicitly learning a series of fixed stimulus-response combinations. In a novel - bimanual - variant of the Serial Reaction Time task (SRT), simultaneous finger movements of the two hands were made in response to pairs of visual stimuli that were presented in a fixed order (Double SRT). Paired stimulus presentation prevented explicit sequence knowledge occurring during task practice, which implied that a dual task paradigm could be avoided. Extensive prescanning training on randomly ordered stimulus pairs allowed us to focus on the acquisition of implicit sequence knowledge. Activation specifically related to the acquisition of fixed sequence knowledge was highly significant in the right ventrolateral prefrontal cortex. The medial prefrontal and right ventral premotor cortex were more indirectly related with such procedural learning. We conclude that this set of activations reflects a stage of implicit sequence learning constituted by components of (i) spatial working memory (right ventral prefrontal cortex), (ii) response monitoring and selection (medial prefrontal cortex), and (iii) facilitated linkage of visuospatial cues to compatible responses (right ventral premotor). Comparing the random-order stimulus-response actions with fixed sequences showed activations in dorsal premotor and posterior parietal cortices, consistent with a dorsal pathway dominance in real-time visuomotor control. The relative long time during which performance improves in the DoSRT provides an opportunity for future study of various stages in both general skill and fixed sequence learning.

Passive respiratory mechanics measured during natural sleep in healthy term neonates and infants up to 8 weeks of life.

The single occlusion technique (SOT) is a simple and noninvasive technique for measurement of passive respiratory mechanics in infants. Reference values based on measurements of a large population of healthy infants performed outside specialized research laboratories are lacking. The aim of this study was to present reference values for passive respiratory mechanics based on a large population of healthy term neonates and infants measured during natural sleep in routine care. As part of the ongoing Wheezing Illnesses Study Leidsche Rijn (WHISTLER), the compliance (C(rs)) and resistance (R(rs)) of the respiratory system were measured in 450 healthy unsedated neonates and infants with a mean age of 4.6 +/- 1.3 weeks. Multivariable regression analysis, with gestational age, age at measurement, body size, sex, and ethnicity as possible predictors, was carried out to estimate prediction equations for mean C(rs) and R(rs) values. Technically acceptable lung function measurements could be performed in 328 (73%) neonates and infants. Median C(rs) was 39.5 (range 14.8-79.1) ml/kPa and median R(rs) was 7.4 (range 3.8-19.5) kPa/L/sec. The following regression equations for C(rs) and R(rs) were obtained: ln C(rs) = 1.677 + 1.3 x 10(-4) x birth weight (g) + 0.030 x birth length (cm) and ln R(rs) = 2.496-3.1 x 10(-6) x birth length(3) (cm(3)) - 0.114 x sex. We provided reference values for passive respiratory mechanics using the SOT in a large population of healthy term neonates and infants measured during natural sleep. These data provide a frame of reference for assessing the normality of SOT measurements performed in routine care.

Hippocampus activation related to 'real-time' processing of visuospatial change.

The delay associated with cerebral processing time implies a lack of real-time representation of changes in the observed environment. To bridge this gap for motor actions in a dynamical environment, the brain uses predictions of the most plausible future reality based on previously provided information. To optimise these predictions, adjustments to actual experiences are necessary. This requires a perceptual memory buffer. In our study we gained more insight how the brain treats (real-time) information by comparing cerebral activations related to judging past-, present- and future locations of a moving ball, respectively. Eighteen healthy subjects made these estimations while fMRI data was obtained. All three conditions evoked bilateral dorsal-parietal and premotor activations, while judgment of the location of the ball at the moment of judgment showed increased bilateral posterior hippocampus activation relative to making both future and past judgments at the one-second time-sale. Since the condition of such 'real-time' judgments implied undistracted observation of the ball's actual movements, the associated hippocampal activation is consistent with the concept that the hippocampus participates in a top-down exerted sensory gating mechanism. In this way, it may play a role in novelty (saliency) detection.

[Localisation of brain function, 125 years after the thesis of Aletta Jacobs, the first Dutch female physician]. / Lokalisatie van hersenfuncties, 125 jaar na het proefschrift van de eerste Nederlandse vrouwelijke arts, Aletta Jacobs.

Aletta H. Jacobs was the first female physician in the Netherlands. In 1879, she defended her thesis which addressed the subject of localising brain functions. In it she described three neurological patients using systematic conventions highly resembling those in use today. Moreover, she discussed whether or not functions were regionally represented. Her discussion concluded in favour of localisation. These days, the concept of distributed networks goes beyond simple topographical representation. This is illustrated in the cerebral organisation of vision. It is possible to discern visual centres that are specialised in processing specific qualities such as colour or visual motion. An additional feature of such segregated processing streams is the presence of underlying connections to specific brain areas at a distance. Functioning as a node in multiple networks, one single brain region may potentially be involved in multiple functions. This depends on the interactions with other regions and on the actual dominance of information processing within such networks.

Muscle co-activity tuning in Parkinsonian hand movement: disease-specific changes at behavioral and cerebral level.

We investigated simple directional hand movements based on different degrees of muscle co-activity, at behavioral and cerebral level in healthy subjects and Parkinson's disease (PD) patients. We compared "singular" movements, dominated by the activity of one agonist muscle, to "composite" movements, requiring conjoint activity of multiple muscles, in a center-out (right hand) step-tracking task. Behavioral parameters were obtained by EMG and kinematic recordings. fMRI was used to investigate differences in underlying brain activations between PD patients (N = 12) and healthy (age-matched) subjects (N = 18). In healthy subjects, composite movements recruited the striatum and cortical areas comprising bilaterally the supplementary motor area and premotor cortex, contralateral medial prefrontal cortex, primary motor cortex, primary visual cortex, and ipsilateral superior parietal cortex. Contrarily, the ipsilateral cerebellum was more involved in singular movements. This striking dichotomy between striatal and cortical recruitment vs. cerebellar involvement was considered to reflect the complementary roles of these areas in motor control, in which the basal ganglia are involved in movement selection and the cerebellum in movement optimization. Compared to healthy subjects, PD patients showed decreased activation of the striatum and cortical areas in composite movement, while performing worse at behavioral level. This implies that PD patients are especially impaired on tasks requiring highly tuned muscle co-activity. Singular movement, on the other hand, was characterized by a combination of increased activation of the ipsilateral parietal cortex and left cerebellum. As singular movement performance was only slightly compromised, we interpret this as a reflection of increased visuospatial processing, possibly as a compensational mechanism.

Parkinson bradykinesia correlates with EEG background frequency and perceptual forward projection.

BACKGROUND: To deal with processing-time in the nervous system, visuomotor control requires anticipation. An index for such anticipation is provided by the 'flash-lag illusion' in which moving objects are perceived ahead of static objects while actually being in the same place. We investigated the neurophysiological relation between visuomotor anticipation and motor velocity in Parkinson's disease (PD) and controls. METHODS: Motor velocity was assessed by the number of keystrokes in 30s ('kinesia score') and visuomotor anticipation in a behavioural flash-lag paradigm while electroencephalography data was obtained. PD patients (n = 24) were divided in a 'PDslow' and a 'PDfast' group based on kinesia score. RESULTS: The PDslow group had a lower kinesia score than controls (resp. 40.3 ± 1.7 and 64.9 ± 4.6, p < 0.001). The flash-lag illusion was weaker in the PDslow group than in controls (resp. fractions 0.32 ± 0.04 and 0.50 ± 0.09 of the responses indicating perceived lagging, p = 0.03). Furthermore, the magnitude of the flash-lag illusion correlated with the kinesia score (cc = 0.45, p = 0.02). Finally, electroencephalography background frequency was lower in the PDslow group than in controls (resp 8.24 ± 0.24 and 9.1 ± 0.32 Hz, p = 0.01) and background frequency correlated with the kinesia score (cc = 0.58, p = 0.001). CONCLUSIONS: The decreased flash-lag illusion and lower electroencephalography background frequency in more bradykinetic PD patients provides support for disturbed visuomotor anticipations, putatively caused by reduced, sub-cortically mediated, network efficiency. This suggests a link between anticipation in early-stage visual motion processing and motor preparation.

Visualization of damaged brain tissue after ischemic stroke with cobalt-55 positron emission tomography.

UNLABELLED: In animal experiments, the radionuclide 55Co2+ has been shown to accumulate in degenerating cerebral tissue similar to Ca2+. METHODS: The potential role of 55Co2+ for in vivo brain PET imaging was investigated in four patients after ischemic stroke. RESULTS: PET showed uptake of 55Co2+ in damaged brain tissue irrespective of blood-brain barrier integrity, as affirmed by CT and MRI. CONCLUSION: Our preliminary results indicate that 55CoCl2 may prove to be a useful and relatively inexpensive PET radiopharmaceutical for visualization of degenerative processes in brain tissue.

The distribution of cerebral activity related to visuomotor coordination indicating perceptual and executional specialization.

The distribution of increased regional cerebral blood flow (rCBF) related to visuomotor coordination was studied by means of positron emission tomography (PET) in normal subjects. An experimental condition, in which a vertically presented zigzag figure had to be copied in a horizontal orientation, was compared with a control condition in which the same horizontal drawing was made, guided by a horizontally presented example. Cognitive components dealing with the mismatch in visual orientation resulted in activation of (i) right dorsal premotor cortex, (ii) right posterior parietal cortex, (iii) visual cortex (area V1) and (iv) left fusiform gyrus. In a second experiment, conditions were compared in which the same horizontal zigzag figure was copied in either a vertical or a horizontal orientation. Now, the motor components of the transformation of orientation appeared to be associated only with left premotor cortex activation. The differential distribution of activations is regarded to reflect the selective effort to cope with either the visual or the motor component of spatial incongruity, and indicates specialization for perceptual and executive components in visuomotor control. We propose that the perceptual component of visuomotor transformation in our experiment relates to a realignment of the coordinates of a percept to an internally defined coordinate system. The executive component relates to guidance of movement within an internal representation of space. In a preceding behavioural experiment, a majority of patients with Parkinson's disease (PD) failed on the task in which they had to make a horizontal copy of a vertically presented picture. This finding may suggest a deficit in the maintenance of an internal spatial representation to guide movement.

Cerebral activation related to skills practice in a double serial reaction time task: striatal involvement in random-order sequence learning.

We used functional Magnetic Resonance Imaging (fMRI) to examine the distribution of cerebral activation related to prolonged skill practice. In a bimanual variant of the Serial Reaction Time Task (SRT), simultaneous finger movements of the two hands were made in response to randomly ordered pairs of visual stimuli (Double SRT, DoSRT). Extended practice by a week of daily performance resulted in gradual decrease of reaction times, associated with an increased involvement of the ventral putamen and globus pallidus, reaching statistical significance only on the left side (Statistical Parametric Mapping, SPM99). This increase was complementary to a decrease of cortical activations. The striatal activation after training on random order stimuli indicates that the striatum is not exclusively involved in sequence learning. This extended function implies a role in the acquisition of basic visuomotor skills that includes the specific selection of the appropriate muscles in response to independent stimuli.