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.

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.

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.

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.

Insights from the supplementary motor area syndrome in balancing movement initiation and inhibition.

The supplementary motor area (SMA) syndrome is a characteristic neurosurgical syndrome that can occur after unilateral resection of the SMA. Clinical symptoms may vary from none to a global akinesia, predominantly on the contralateral side, with preserved muscle strength and mutism. A remarkable feature is that these symptoms completely resolve within weeks to months, leaving only a disturbance in alternating bimanual movements. In this review we give an overview of the old and new insights from the SMA syndrome and extrapolate these findings to seemingly unrelated diseases and symptoms such as Parkinson's disease (PD) and tics. Furthermore, we integrate findings from lesion, stimulation and functional imaging studies to provide insight in the motor function of the SMA.

Different distal-proximal movement balances in right- and left-hand writing may hint at differential premotor cortex involvement.

Right-handed people generally write with their right hand. Language expressed in script is thus performed with the hand also preferred for skilled motor tasks. This may suggest an efficient functional interaction between the language area of Broca and the adjacent ventral premotor cortex (PMv) in the left (dominant) hemisphere. Pilot observations suggested that distal movements are particularly implicated in cursive writing with the right hand and proximal movements in left-hand writing, which generated ideas concerning hemisphere-specific roles of PMv and dorsal premotor cortex (PMd). Now we examined upper-limb movements in 30 right-handed participants during right- and left-hand writing, respectively. Quantitative description of distal and proximal movements demonstrated a significant difference between movements in right- and left-hand writing (p<.001, Wilcoxon signed-rank test). A Distal Movement Excess (DME) characterized writing with the right hand, while proximal and distal movements similarly contributed to left-hand writing. Although differences between non-language drawings were not tested, we propose that the DME in right-hand writing may reflect functional dominance of PMv in the left hemisphere. More proximal movements in left-hand writing might be related to PMd dominance in right-hemisphere motor control, logically implicated in spatial visuomotor transformations as seen in reaching.

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.

Interruption of visually perceived forward motion in depth evokes a cortical activation shift from spatial to intentional motor regions.

Forward locomotion generates a radially expanding flow of visual motion which supports goal-directed walking. In stationary mode, wide-field visual presentation of optic flow stimuli evokes the illusion of forward self-motion. These effects illustrate an intimate relation between visual and motor processing. In the present fMRI study, we applied optic flow to identify distinct interfaces between circuitries implicated in vision and movement. The dorsal premotor cortex (PMd) was expected to contribute to wide-field forward motion flow (FFw), reflecting a pathway for externally triggered motor control. Medial prefrontal activation was expected to follow interrupted optic flow urging internally generated action. Data of 15 healthy subjects were analyzed with Statistical Parametric Mapping and confirmed this hypothesis. Right PMd activation was seen in FFw, together with activations of posterior parietal cortex, ventral V5, and the right fusiform gyrus. Conjunction analysis of the transition from wide to narrow forward flow and reversed wide-field flow revealed selective dorsal medial prefrontal activation. These findings point at equivalent visuomotor transformations in locomotion and goal-directed hand movement, in which parietal-premotor circuitry is crucially implicated. Possible implications of an activation shift from spatial to intentional motor regions for understanding freezing of gait in Parkinson's disease are discussed: impaired medial prefrontal function in Parkinson's disease may reflect an insufficient internal motor drive when visual support from optic flow is reduced at the entrance of a narrow corridor.

Traumatic cervical artery dissection in head injury: the value of follow-up brain imaging.

INTRODUCTION: Traumatic cervical artery dissection (TCAD) is a relative infrequent complication of traumatic brain injury (TBI). Since TCAD is associated with morbidity in a considerable percentage of patients, it is important to obtain clues for recognising TCAD in this category of patients. METHODS: Retrospective case-cohort study in severe TBI patients. RESULTS: Five patients with traumatic cervical artery dissection after severe TBI, leading to ischemic strokes, are described. Secondary deterioration to coma was present in four out of five patients during admission. The diagnosis of TCAD was delayed in most cases because the secondary deterioration was often attributed to multisystem problems related to trauma patients, i.e. shock or hypoxia or medication effects. Local clinical symptoms and signs suggestive of TCAD are difficult to detect in this patient group. In all patients, the CT-scan on admission demonstrated no abnormalities. A follow-up scan at day 2 revealed that in all patients abnormalities in the vascular territories had evolved. CONCLUSION: With this case-cohort study we underline the importance of considering TCAD in severe TBI patients and emphasise the role for standard follow-up brain imaging. Also possible treatment consequences are discussed.

Cerebral consequences of dynamic immobilisation after primary digital flexor tendon repair.

Current treatment protocols for flexor tendon injuries of the hand generally result in an acceptable function, which can be quantified by objective parameters such as range of motion. The latter does not always match the patients' subjective experiences of persisting dysfunction. This raises the question whether changes in the cerebral control of movement might contribute to the perceived deficit. The main objective of the present positron emission tomography (PET) study was to characterise the cerebral responses in movement-associated areas during simple finger flexion immediately after dynamic immobilisation and after a subsequent 6-week period of active training. Ten subjects with flexor tendon injury participated in the PET study. Electromyography (EMG) recordings were made during finger flexion and extension in an additional subject. The main finding was that the (ventral) putamen contralateral to flexor movement was not activated immediately after release from splinting, while such activation reappeared after a period of training. This indicates a temporary loss of efficient motor control of over-learnt movements. The increase of unwanted co-contractions during flexion in a first EMG session, and not during extension, supports a concept of lost skills.

Clinical implications of cerebral reorganisation after primary digital flexor tendon repair.

After flexor tendon injury, most attention is given to the quality of the tendon repair and postoperative early passive dynamic mobilisation. Schemes for active mobilisation have been developed to prevent tendon adhesions and joint stiffness. This paper describes five patients to demonstrate the cerebral consequences of immobilisation allowing only passive movements, which implies a prolonged absence of actual motor commands. At the end of such immobilisation, PET imaging revealed reduced blood flow in specific motor areas, associated with temporary loss of efficient motor control. Effective motor control was regained after active flexion exercises which was reflected in normalised cerebral activations. This suggests that temporary, reversible cerebral dysfunction may affect the outcome of flexor tendon injuries.

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.

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.

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.

Decreased blood-brain barrier P-glycoprotein function in the progression of Parkinson's disease, PSP and MSA.

Decreased blood-brain barrier (BBB) efflux function of the P-glycoprotein (P-gp) transport system could facilitate the accumulation of toxic compounds in the brain, increasing the risk of neurodegenerative pathology such as Parkinson's disease (PD). This study investigated in vivo BBB P-gp function in patients with parkinsonian neurodegenerative syndromes, using [11C]-verapamil PET in PD, PSP and MSA patients. Regional differences in distribution volume were studied using SPM with higher uptake interpreted as reduced P-gp function. Advanced PD patients and PSP patients had increased [11C]-verapamil uptake in frontal white matter regions compared to controls; while de novo PD patients showed lower uptake in midbrain and frontal regions. PSP and MSA patients had increased uptake in the basal ganglia. Decreased BBB P-gp function seems a late event in neurodegenerative disorders, and could enhance continuous neurodegeneration. Lower [11C]-verapamil uptake in midbrain and frontal regions of de novo PD patients could indicate a regional up-regulation of P-gp function.

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.