Characterization of Cerebellar Atrophy and Resting State Functional Connectivity Patterns in Sporadic Adult-Onset Ataxia of Unknown Etiology (SAOA).

Sporadic adult-onset ataxia of unknown etiology (SAOA) is a non-genetic neurodegenerative disorder of the cerebellum of unknown cause which manifests with progressive ataxia without severe autonomic failure. Although SAOA is associated with cerebellar degeneration, little is known about the specific cerebellar atrophy pattern in SAOA. Thirty-seven SAOA patients and 49 healthy controls (HCs) were included at two centers. We investigated the structural and functional characteristics of SAOA brains using voxel-based morphometry (VBM) and resting-state functional imaging (rs-fMRI). In order to examine the functional consequence of structural cerebellar alterations, the amplitude of low-frequency fluctuation (ALFF) and degree centrality (DC) were analyzed, and then assessed their relation with disease severity, disease duration, and age of onset within these regions. Group differences were investigated using two-sample t tests, controlling for age, gender, site, and the total intracranial volume. The VBM analysis revealed a significant, mostly bilateral reduction of local gray matter (GM) volume in lobules I-V, V, VI, IX, X, and vermis VIII a/b in SAOA patients, compared with HCs. The GM volume loss in these regions was significantly associated with disease severity, disease duration, and age of onset. The disease-related atrophy regions did not show any functional alternations compared with HCs but were functionally characterized by high ALFF and poor DC compared with intact cerebellar regions. Our data revealed volume reduction in SAOA in cerebellar regions that are known to be involved in motor and somatosensory processing, corresponding with the clinical phenotype of SAOA. Our data suggest that the atrophy occurs in those cerebellar regions which are characterized by high ALFF and poor DC. Further studies have to show if these findings are specific for SAOA, and if they can be used to predict disease progression.

The role of muscle strength on tendon adaptability in old age.

PURPOSE: The purpose of the study was to determine: (1) the relationship between ankle plantarflexor muscle strength and Achilles tendon (AT) biomechanical properties in older female adults, and (2) whether muscle strength asymmetries between the individually dominant and non-dominant legs in the above subject group were accompanied by inter-limb AT size differences. METHODS: The maximal generated AT force, AT stiffness, AT Young's modulus, and AT cross-sectional area (CSA) along its length were determined for both legs in 30 women (65 ± 7 years) using dynamometry, ultrasonography, and magnetic resonance imaging. RESULTS: No between-leg differences in triceps surae muscle strength were identified between dominant (2798 ± 566 N) and non-dominant limb (2667 ± 512 N). The AT CSA increased gradually in the proximo-distal direction, with no differences between the legs. There was a significant correlation (P < 0.05) of maximal AT force with AT stiffness (r = 0.500) and Young's modulus (r = 0.414), but only a tendency with the mean AT CSA. However, region-specific analysis revealed a significant relationship between maximal AT force and the proximal part of the AT, indicating that this region is more likely to display morphological adaptations following an increase in muscle strength in older adults. CONCLUSIONS: These findings demonstrate that maximal force-generation capabilities play a more important role in the variation of AT stiffness and material properties than in tendon CSA, suggesting that exercise-induced increases in muscle strength in older adults may lead to changes in tendon stiffness foremost due to alterations in material rather than in its size.

Executive control processes are associated with individual fitness outcomes following regular exercise training: blood lactate profile curves and neuroimaging findings.

Cardiovascular training has been associated with neuroimaging correlates of executive control functions (ECF) in seniors and children/adolescents, while complementary studies in middle-aged populations are lacking. Ascribing a prominent role to cardiorespiratory fitness improvements, most studies concentrated on training-induced gains in maximal oxygen uptake (VO2max), although other fitness indices may provide complementary information. Here, we investigated the impact of long-term sub-maximal exercise training on interference control, considering individual training-induced shifts in blood lactate profile curves (BLC) and VO2max. Twenty-three middle-aged sedentary males (M = 49 years) underwent a six-month exercise program (intervention group, IG). Additionally, 14 individuals without exercise training were recruited (control group, CG, M = 52 years). Interference control was assessed before and after the intervention, using a functional magnetic resonance imaging (fMRI) flanker paradigm. Task performance and brain activations showed no significant group-by-time interactions. However, regression analyses in the IG revealed significant associations between individual fitness gains and brain activation changes in frontal regions, which were not evident for VO2max, but for BLC. In conclusion, training-induced plasticity of ECF-related brain activity can be observed in late middle adulthood, but depends on individual fitness gains. For moderate training intensities, BLC shifts may provide sensitive markers for training-induced adaptations linked to ECF-related brain function.

The association of children's mathematic abilities with both adults' cognitive abilities and intrinsic fronto-parietal networks is altered in preterm-born individuals.

Mathematic abilities in childhood are highly predictive for long-term neurocognitive outcomes. Preterm-born individuals have an increased risk for both persistent cognitive impairments and long-term changes in macroscopic brain organization. We hypothesized that the association of childhood mathematic abilities with both adulthood general cognitive abilities and associated fronto-parietal intrinsic networks is altered after preterm delivery. 72 preterm- and 71 term-born individuals underwent standardized mathematic and IQ testing at 8 years and resting-state fMRI and full-scale IQ testing at 26 years of age. Outcome measure for intrinsic networks was intrinsic functional connectivity (iFC). Controlling for IQ at age eight, mathematic abilities in childhood were significantly stronger positively associated with adults' IQ in preterm compared with term-born individuals. In preterm-born individuals, the association of children's mathematic abilities and adults' fronto-parietal iFC was altered. Likewise, fronto-parietal iFC was distinctively linked with preterm- and term-born adults' IQ. Results provide evidence that preterm birth alters the link of mathematic abilities in childhood and general cognitive abilities and fronto-parietal intrinsic networks in adulthood. Data suggest a distinct functional role of intrinsic fronto-parietal networks for preterm individuals with respect to mathematic abilities and that these networks together with associated children's mathematic abilities may represent potential neurocognitive targets for early intervention.

Extensive and interrelated subcortical white and gray matter alterations in preterm-born adults.

Preterm birth is a leading cause for impaired neurocognitive development with an increased risk for persistent cognitive deficits in adulthood. In newborns, preterm birth is associated with interrelated white matter (WM) alterations and deep gray matter (GM) loss; however, little is known about the persistence and relevance of these subcortical brain changes. We tested the hypothesis that the pattern of correspondent subcortical WM and GM changes is present in preterm-born adults and has a brain-injury-like nature, i.e., it predicts lowered general cognitive performance. Eighty-five preterm-born and 69 matched term-born adults were assessed by diffusion- and T1-weighted MRI and cognitive testing. Main outcome measures were fractional anisotropy of water diffusion for WM property, GM volume for GM property, and full-scale IQ for cognitive performance. In preterm-born adults, reduced fractional anisotropy was widely distributed ranging from cerebellum to brainstem to hemispheres. GM volume was reduced in the thalamus, striatum, temporal cortices, and increased in the cingulate cortices. Fractional anisotropy reductions were specifically associated with GM loss in thalamus and striatum, with correlation patterns for both regions extensively overlapping in the WM of brainstem and hemispheres. For overlap regions, fractional anisotropy was positively related with both gestational age and full-scale IQ. Results provide evidence for extensive, interrelated, and adverse WM and GM subcortical changes in preterm-born adults. Data suggest persistent brain-injury-like changes of subcortical-cortical connectivity after preterm delivery.

[German guidelines for brain tumour imaging by PET and SPECT using labelled amino acids]. / PET- und SPECT-Untersuchungen von Hirntumoren mit radioaktiv markierten Aminosäuren.

For the primary diagnosis of brain tumours, morphological imaging by means of magnetic resonance imaging (MRI) is the current method of choice. The complementary use of functional imaging by positron emitting tomography (PET) and single photon emitting computerized tomography (SPECT) with labelled amino acids can provide significant information on some clinically relevant questions, which are beyond the capacity of MRI. These diagnostic issues affect in particular the improvement of biopsy targeting and tumour delineation for surgery and radiotherapy planning. In addition, amino acid labelled PET and SPECT tracers are helpful for the differentiation between tumour recurrence and non-specific post-therapeutic tissue changes, in predicting prognosis of low grade gliomas, and for metabolic monitoring of treatment response. The application of dynamic PET examination protocols for the assessment of amino acid kinetics has been shown to enable an improved non-invasive tumour grading. The purpose of this guideline is to provide practical assistance for indication, examination procedure and image analysis of brain PET/SPECT with labelled amino acids in order to allow for a high quality standard of the method. After a short introduction on pathobiochemistry and radiopharmacy of amino acid labelled tracers, concrete and detailed information is given on the several indications, patient preparation and examination protocols as well as on data reconstruction, visual and quantitative image analysis and interpretation. In addition, possible pitfalls are described, and the relevant original publications are listed for further information.

[Cerebral MRI of preterm neonates at term equivalent age at 3 Tesla: hints at white matter damage on T2- and diffusion weighted images]. / Erfahrungen mit der MRT des Hirns bei Frühgeborenen--Hinweise auf Schädigung der weißen Substanz in T2- und Diffusionswichtung bei 3 Tesla.

BACKGROUND: MRI of the brain is reported to be very sensitive in the detection of diffuse white matter damage in preterm neonates. AIM: To review 3 Tesla-MRI studies of 21 preterm neonates at term equivalent age with regard to safety and detection of white matter changes. PATIENTS: In 21 preterm neonates (9 female, 12 male, mean age 96 days) an MRI of the brain was performed for clinical reasons with oral sedation. All examinations could be performed at 3 Tesla without any complication. In 7 of 21 noncystic periventricular white matter lesions could be found and in 14 hyperintensity of white matter (DEHSI) was observed. ADC-values of the white matter were considerably higher than reported for healthy children in literature. CONCLUSION: MRI at 3 Tesla can be performed safely in oral sedation at term equivalent age at 3 Tesla. T2-weighted and diffusion-weighted imaging is very sensitive for white matter changes.

Distinct striatal regions for planning and executing novel and automated movement sequences.

The basal ganglia-thalamo-cortical circuits are viewed as segregated parallel feed back loops crucially involved in motor control, cognition, and emotional processing. Their role in planning novel, as compared to overlearned movement patterns is as yet not well defined. We tested for the involvement of the associative striatum (caudate/anterior putamen) in the generation of novel movement patterns, which is a critical cognitive requirement for non-routine motor behavior. Using event related functional MRI in 14 right-handed male subjects, we analyzed brain activity in the planning phase of four digit finger sequences. Subjects either executed a single overlearned four digit sequence (RECALL), or self-determined four digit sequences of varying order (GENERATE). In both conditions, RECALL and GENERATE, planning was associated with activation in mesial/lateral premotor cortices, motor cingulate cortex, superior parietal cortex, basal ganglia, insula, thalamus, and midbrain nuclei. When contrasting the planning phase of GENERATE with the planning phase of RECALL, there was significantly higher activation within this distributed network. At the level of the basal ganglia, the planning phase of GENERATE was associated with differentially higher activation located specifically within the associative striatum bilaterally. On the other hand, the execution phase during both conditions was associated with a shift of activity towards the posterior part of the putamen. Our data show the specific involvement of the associative striatum during the planning of non-routine movement patterns and illustrate the propagation of activity from rostral to dorsal basal ganglia sites during different stages of motor processing.

[Current stage of fMRI applications in newborns and children during the first year of life]. / Gegenwärtiger Stand der funktionellen MRT bei Neugeborenen und Kindern im ersten Lebensjahr.

Currently, a paradigm shift towards expanded early use of cranial MRI in newborns at risk and infants in the first year of life can be observed in neonatology. Beyond clinical MRI applications, there is progressive use of functional MRI (fMRI) in this age group. On the one hand, fMRI allows monitoring of functional developmental processes depending on maturational stage; on the other hand, this technique may provide the basis for early detection of pathophysiological processes as a prerequisite for functionally guided therapeutic interventions. This article provides a comprehensive review of current fMRI applications in neonates and infants during the first year of life and focuses on the associated methodological issues (e. g. signal physiology, sedation, safety aspects).

A role of the basal ganglia and midbrain nuclei for initiation of motor sequences.

The mesial premotor cortex is crucial for planning sequential procedures and movement initiation. With event-related (ER) functional magnetic resonance imaging (fMRI) it has been possible to separate mesial premotor activation before, during, and after self-initiated movements and, thereby, to distinguish advance planning from execution. The mesial premotor cortex is part of distributed cortico-basal ganglia-thalamo-cortical networks but, to date, the subcortical contributions to self-initiated movements are far less well understood. Using ER fMRI at 3T in 12 right-handed male volunteers, we studied the subcortical activation preceding an automated four-digit finger sequence that was either self-initiated or triggered externally by a visual cue. Beyond typical cortical activation increases in fronto-parietal regions, both initiation modes induced consistent subcortical activation in basal ganglia, midbrain (substantia nigra), and ipsilateral cerebellum. The planning phase of the internally initiated condition, when contrasted with the externally triggered condition, was associated with enhanced activity in frontal regions (mesial premotor cortex/rostral cingulate zone, dorsolateral prefrontal cortex), parietal regions (precuneus, inferior parietal cortex, encroaching onto V5/MT), insula, contralateral anterior putamen and midbrain (bilateral red nucleus/subthalamic nucleus). These data demonstrate the impact of initiation mode on planning-related activity in the ventral basal ganglia and interconnected midbrain nuclei, thereby stressing the crucial role of distributed cortico-basal ganglia-thalamo-cortical networks for self-initiated automated motor repertoires. Involvement of the substantia nigra during planning, as shown here, indicates dopaminergic gating of motor sequences.

Altered metabolism in frontal brain circuits in cluster headache.

Neuroimaging studies have explored cerebral activation patterns in patients with cluster headache (CH) during attacks and have revealed activation of multiple brain areas known to belong to the general pain-processing network. However, it is still unclear which changes in brain metabolism are inherent to the shift from the 'in bout' to the 'out of bout' period. We measured cerebral glucose metabolism in 11 episodic CH patients during the cluster and again during the remission period with (18)F-fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) and compared these data with 11 healthy controls. 'In bout' compared with 'out of bout' scans were associated with increases of metabolism in the perigenual anterior cingulate cortex (ACC), posterior cingulate cortex, prefrontal cortex, insula, thalamus and temporal cortex. Decreases in metabolism were observed in the cerebellopontine area. Compared with healthy volunteers, hypometabolism in the patient group ('in bout' and 'out of bout') was found in the perigenual ACC, prefrontal and orbitofrontal cortex. Thus, FDG-PET in CH patients revealed 'in bout' activation of brain structures which are involved in descending pain control. Compared with controls, the regional brain metabolism was constitutively decreased in most of these structures, irrespective of the bout. This finding indicates a deficient top-down modulation of antinociceptive circuits in CH patients. We suggest that trigger mechanisms of CH are insufficiently controlled and thus promote the initiation of the bout period and acute attack.

[Methodological aspects of functional neuroimaging at high field strength: a critical review]. / Methodische Aspekte der funktionellen Neurobildgebung im MRT-Hochfeldbereich: eine kritische Ubersicht.

The last few years have proven that high field magnetic resonance imaging (MRI) is superior in nearly every way to conventional equipment up to 1.5 tesla (T). Following the global success of 3T-scanners in research institutes and medical practices, a new generation of MRI devices with field strengths of 7T and higher is now on the horizon. The introduction of ultra high fields has brought MRI technology closer to the physical limitations and increasingly greater costs are required to achieve this goal. This article provides a critical overview of the advantages and problems of functional neuroimaging using ultra high field strengths. This review is principally limited to T2*-based functional imaging techniques not dependent on contrast agents. The main issues include the significance of high field technology with respect to SNR, CNR, resolution, and sequences, as well as artifacts, noise exposure, and SAR. Of great relevance is the discussion of parallel imaging, which will presumably determine the further development of high and ultra high field strengths. Finally, the importance of high field strengths for functional neuroimaging is explained by selected publications.

Gender dependent rate of metabolism of the opioid receptor-PET ligand [18F]fluoroethyldiprenorphine.

AIM: The morphinane-derivate 6-O-(2-[(18)F]fluoroethyl)-6-O-desmethyldiprenorphine ([(18)F]FDPN) is a nonselective opioid receptor ligand currently used in positron emission tomography (PET). Correction for plasma metabolites of the arterial input function is necessary for quantitative measurements of [(18)F]FDPN binding. A study was undertaken to investigate if there are gender dependent differences in the rate of metabolism of [(18)F]FDPN. METHODS: The rate of metabolism of [(18)F]FDPN was mathematically quantified by fitting a bi-exponential function to each individual's dynamic metabolite data. RESULTS: No statistically significant gender differences were found for age, weight, body mass index or dose. However, significant differences (p < 0.01) in two of the four kinetic parameters describing the rate of metabolism were found between the two groups, with women metabolizing [(18)F]FDPN faster than men. These differences were found in the contribution of the fast and slow kinetic components of the model describing the distribution of radioactive species in plasma, indicating a higher rate of enzyme-dependent degradation of [(18)F]FDPN in women than in men. CONCLUSION: The findings reinforce the need for individualized metabolite correction during [(18)F]FDPN-PET scans and also indicate that in certain cases, grouping according to gender could be performed in order to minimize methodological errors of the input function prior to kinetic analyses.

Transmodal sensorimotor networks during action observation in professional pianists.

Audiovisual perception and imitation are essential for musical learning and skill acquisition. We compared professional pianists to musically naive controls with fMRI while observing piano playing finger-hand movements and serial finger-thumb opposition movements both with and without synchronous piano sound. Pianists showed stronger activations within a fronto-parieto-temporal network while observing piano playing compared to controls and contrasted to perception of serial finger-thumb opposition movements. Observation of silent piano playing additionally recruited auditory areas in pianists. Perception of piano sounds coupled with serial finger-thumb opposition movements evoked increased activation within the sensorimotor network. This indicates specialization of multimodal auditory-sensorimotor systems within a fronto-parieto-temporal network by professional musical training. Musical ''language,'' which is acquired by observation and imitation, seems to be tightly coupled to this network in accord with an observation-execution system linking visual and auditory perception to motor performance.

Force level independent representations of predictive grip force-load force coupling: a PET activation study.

The existence of forward internal models is a fundamental principle in theories of predictive motor control. There are indications that internal models are represented in the cerebellum. So far, no conclusive data exist on automated procedures involving predictive motor behavior. In particular, it is unknown whether single or multiple task-specific internal models handle the broad range of behavioral situations in which they occur. Using H2(15)O PET in eight subjects, we examined predictive motor control in an automated grip force-load force coupling task at three differing load force levels. In the experimental condition, subjects pulled a grasped object against an isometric resistance while simultaneously producing anticipatory grip forces. There were three control conditions (pull force isolated; grip force isolated; motor rest). A 2 x 2 factorial design was chosen to reveal the interaction effect of grip force-pull force coupling. The factors were pull force (with/without) and grip force (with/without). Grip and load forces were well matched between experimental and control conditions. Conjunction inference and interaction analyses identified force coupling related activity in the ipsilateral posterior cerebellum that was independent of force levels. Interaction effects were also identified in the anterior cingulate and frontal association regions, the right caudate nucleus, and the left lingual gyrus. These data demonstrate the existence of modular representations for predictive force coupling, with the ipsilateral cerebellum playing a major role. Moreover, the data implicate that the representations for predictive force control are applicable to a range of different environmental affordances.

Differential modulation of subcortical target and cortex during deep brain stimulation.

The combination of electrical deep brain stimulation (DBS) with functional imaging offers a unique model for tracing brain circuitry and for testing the modulatory potential of electrical stimulation on a neuronal network in vivo. We therefore applied parametric positron emission tomography (PET) analyses that allow characterization of rCBF responses as linear and nonlinear functions of the experimentally modulated stimulus (variable stimulator setting). In patients with electrodes in the thalamic ventrointermediate nucleus (VIM) for the treatment of essential tremor (ET) here we show that variations in voltage and frequency of thalamic stimulation have differential effects in a thalamo-cortical circuitry. Increasing stimulation amplitude was associated with a linear raise in rCBF at the thalamic stimulation site, but with a nonlinear rCBF response in the primary sensorimotor cortex (M1/S1). The reverse pattern in rCBF changes was observed with increasing stimulation frequency. These results indicate close connectivity between the stimulated nucleus (VIM) and primary sensorimotor cortex. Likewise, stimulation parameter-specific modulation occurs at this simple interface between an electrical and a cerebral system and suggests that the scope of DBS extends beyond an ablation-like on-off effect: DBS could rather allow a gradual tuning of activity within a neuronal circuit.

A H(2)(15)O positron emission tomography study on mental imagery of movement sequences--the effect of modulating sequence length and direction.

Motor imagery is a state of mental rehearsal of single movements or movement patterns and has been shown to recruit motor networks overlapping with those activated during movement execution. We wished to examine whether the brain areas subserving control of sequential processes could be delineated by pure mental imagery, their activation levels reflecting the processing demands of a sequential task. We studied six right-handed volunteers (39.0 +/- 14 years) with H(2)(15)O positron emission tomography (PET) while they continuously mentally pursued with their right hand one of five sequences differing in complexity (i.e., increases in sequence length, single-finger repetitions, and reversals). Conditions were repeated twice, alternating with two rest scans. Each imagined single motor element was paced at a frequency of 1 Hz. Significant activation increases (P < 0.05, corrected) associated with imagination of right finger movement sequences (conditions I to V combined)--compared to the rest condition--were observed in left sensorimotor cortex (M1/S1) and the adjacent inferior parietal cortex. Further activation increases (P < 0.001, uncorrected) occurred in bilateral dorsal premotor (PMd) cortex, left caudal supplementary motor area, bilateral ventral premotor cortex, right M1, left superior parietal cortex, left putamen, and right cerebellum. Activation decreases occurred in bilateral prefrontal and right temporo-occipital cortex. Activation increases that correlated with sequence complexity were observed only in specific areas of the activated network, notably in left PMd, right superior parietal cortex, and right cerebellar vermis (P < 0.05, corrected). In conclusion, our study, by varying the sequence structure of imagined finger movements, identified task-related activity changes in parietopremotor-cerebellar structures, reflecting their role in mediating sequence control.

Subthalamic nucleus stimulation affects striato-anterior cingulate cortex circuit in a response conflict task: a PET study.

The subthalamic nucleus (STN) has generally been considered as a relay station within frontal-subcortical motor control circuitry. Little is known about the influence of the STN on cognitive networks. Clinical observations and studies in animals suggest that the STN participates in non-motor functions which can now be probed in Parkinson's disease patients with deep brain stimulation of the STN, allowing selective and reversible modulation of this nucleus. Using PET, we studied changes in regional cerebral blood flow (rCBF) associated with a response conflict task (Stroop task) in Parkinson's disease patients ON and OFF bilateral STN stimulation. The Stroop task requires subjects to name the font colour of colour words (e.g. "blue") printed in an incongruent colour ink (e.g. yellow). During STN stimulation, impaired task performance (prolonged reaction times) was associated with decreased activation in both right anterior cingulate cortex (ACC) and right ventral striatum. Concomitant increased activation in left angular gyrus indicative of ongoing word processing during stimulation is consistent with an impairment to inhibit habitual responses. ACC and ventral striatum are part of the ACC circuit associated with response conflict tasks. The decreased activation during STN stimulation in the ACC circuit, while response conflict processing worsened, provides direct evidence of STN modulating non-motor basal ganglia-thalamocortical circuitry. Impairment in ACC circuit function could account for the subtle negative effects on cognition induced by STN stimulation.