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A universal allometric scaling law has been proposed to describe cortical folding of the mammalian brain as a function of the product of cortical surface area and the square root of cortical thickness across different mammalian species, including humans. Since these cortical properties are vulnerable to developmental disturbances caused by preterm birth in humans and since these alterations are related to cognitive impairments, we tested (i) whether cortical folding in preterm-born adults follows this cortical scaling law and (ii) the functional relevance of potential scaling aberrances. We analysed the cortical scaling relationship in a large and prospectively collected cohort of 91 very premature-born adults (<32 weeks of gestation and/or birthweight <1500 g, very preterm and/or very low birth weight) and 105 full-term controls at 26 years of age based on the total surface area, exposed surface area and average cortical thickness measured with structural magnetic resonance imaging and surface-based morphometry. We found that the slope of the log-transformed cortical scaling relationship was significantly altered in adults (very preterm and/or very low birth weight: 1.24, full-term: 1.14, P = 0.018). More specifically, the slope was significantly altered in male adults (very preterm and/or very low birth weight: 1.24, full-term: 1.00, P = 0.031), while there was no significant difference in the slope of female adults (very preterm and/or very low birth weight: 1.27, full-term: 1.12, P = 0.225). Furthermore, offset was significantly lower compared with full-term controls in both male (very preterm and/or very low birth weight: -0.546, full-term: -0.538, P = 0.001) and female adults (very preterm and/or very low birth weight: -0.545, full-term: -0.538, P = 0.023), indicating a systematic shift of the regression line after preterm birth. Gestational age had a significant effect on the slope in very preterm and/or very low birth weight adults and more specifically in male very preterm and/or very low birth weight adults, indicating that the difference in slope is specifically related to preterm birth. The shape or tension term of the scaling law had no significant effect on cognitive performance, while the size of the cortex did. Results demonstrate altered scaling of cortical surface and cortical thickness in very premature-born adults. Data suggest altered mechanical forces acting on the cortex after preterm birth., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Several observations suggest an impact of prematurity on the claustrum. First, the claustrum's development appears to depend on transient subplate neurons of intra-uterine brain development, which are affected by prematurity. Second, the claustrum is the most densely connected region of the mammalian forebrain relative to its volume; due to its effect on pre-oligodendrocytes, prematurity impacts white matter connections and thereby the development of sources and targets of such connections, potentially including the claustrum. Third, due to its high connection degree, the claustrum contributes to general cognitive functioning (e.g., selective attention and task switching/maintaining); general cognitive functioning, however, is at risk in prematurity. Thus, we hypothesized altered claustrum structure after premature birth, with these alterations being associated with impaired general cognitive performance in premature born persons. Using T1-weighted and diffusion-weighted magnetic resonance imaging in 70 very preterm/very low-birth-weight (VP/VLBW) born adults and 87 term-born adults, we found specifically increased mean diffusivity in the claustrum of VP/VLBW adults, associated both with low birth weight and at-trend with reduced IQ. This result demonstrates altered claustrum microstructure after premature birth. Data suggest aberrant claustrum development, which is potentially related with aberrant subplate neuron and forebrain connection development of prematurity., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Gyrification is a hallmark of human brain development, starting in the second half of gestation in primary cortices, followed by unimodal and then transmodal associative cortices. Alterations in gyrification have been noted in premature-born newborns and children, suggesting abnormal cortical folding to be a permanent feature of prematurity. Furthermore, both gyrification and prematurity are tightly linked with cognitive performance, indicating a link between prematurity, gyrification, and cognitive performance. To investigate this triangular relation, we tested the following two hypotheses: (i) gyrification is aberrant in premature-born adults; and (ii) aberrant gyrification contributes to the impact of prematurity on adult cognitive performance. One hundred and one very premature-born adults (i.e. adults born before 32 weeks of gestation, and/or with birth weight <1500 g) and 111 mature-born adults were assessed by structural MRI and cognitive testing at 27 years of age. Gyrification was measured by local cortical absolute mean curvature (AMC), evaluated through structural MRI. Cognitive performance was assessed by the Wechsler Adult Intelligence Scale, full-scale IQ test. Two-sample t-tests, regression and mediation analyses were used to assess AMC group differences and the relation between AMC, birth-related variables, and full-scale IQ. Three key findings were identified. First, local AMC was widely increased in fronto-temporo-parietal primary and associative cortices of very premature-born adults. Increase of AMC was inversely associated with gestational age and birth weight and positively associated with medical complications at birth, respectively. Second, increased AMC of temporal associative cortices specifically contributed to the association between prematurity and reduced adult IQ (two-path mediation), indicating that aberrant gyrification of temporal associative cortices is critical for impaired cognitive performance after premature birth. Finally, further investigation of the relationship of gyrification between the early folding postcentral cortices and associative temporal cortices, folding later during neurodevelopment, revealed that the effect of gyrification abnormalities in associative temporal cortices on adult IQ is influenced itself by gyrification abnormalities occurring in the early folding postcentral cortices (three-path mediation). These results indicate that gyrification development across cortical areas in the brain conveys prematurity effects on adult IQ. Overall, these results provide evidence that premature birth leads to permanently aberrant gyrification patterns suggesting an altered neurodevelopmental trajectory. Statistical mediation modelling suggests that both aberrant gyrification itself as well as its propagation across the cortex express aspects of impaired neurodevelopment after premature birth and lead to reduced cognitive performance in adulthood. Thus, markers of gyrification appear as potential candidates for prognosis and treatment of prematurity effects., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Patients with Alzheimer's disease vary in their ability to sustain cognitive abilities in the presence of brain pathology. A major open question is which brain mechanisms may support higher reserve capacity, i.e. relatively high cognitive performance at a given level of Alzheimer's pathology. Higher functional MRI-assessed functional connectivity of a hub in the left frontal cortex is a core candidate brain mechanism underlying reserve as it is associated with education (i.e. a protective factor often associated with higher reserve) and attenuated cognitive impairment in prodromal Alzheimer's disease. However, no study has yet assessed whether such hub connectivity of the left frontal cortex supports reserve throughout the evolution of pathological brain changes in Alzheimer's disease, including the presymptomatic stage when cognitive decline is subtle. To address this research gap, we obtained cross-sectional resting state functional MRI in 74 participants with autosomal dominant Alzheimer's disease, 55 controls from the Dominantly Inherited Alzheimer's Network and 75 amyloid-positive elderly participants, as well as 41 amyloid-negative cognitively normal elderly subjects from the German Center of Neurodegenerative Diseases multicentre study on biomarkers in sporadic Alzheimer's disease. For each participant, global left frontal cortex connectivity was computed as the average resting state functional connectivity between the left frontal cortex (seed) and each voxel in the grey matter. As a marker of disease stage, we applied estimated years from symptom onset in autosomal dominantly inherited Alzheimer's disease and cerebrospinal fluid tau levels in sporadic Alzheimer's disease cases. In both autosomal dominant and sporadic Alzheimer's disease patients, higher levels of left frontal cortex connectivity were correlated with greater education. For autosomal dominant Alzheimer's disease, a significant left frontal cortex connectivity × estimated years of onset interaction was found, indicating slower decline of memory and global cognition at higher levels of connectivity. Similarly, in sporadic amyloid-positive elderly subjects, the effect of tau on cognition was attenuated at higher levels of left frontal cortex connectivity. Polynomial regression analysis showed that the trajectory of cognitive decline was shifted towards a later stage of Alzheimer's disease in patients with higher levels of left frontal cortex connectivity. Together, our findings suggest that higher resilience against the development of cognitive impairment throughout the early stages of Alzheimer's disease is at least partially attributable to higher left frontal cortex-hub connectivity.

Widespread brain changes are present in preterm born infants, adolescents, and even adults. While neurobiological models of prematurity facilitate powerful explanations for the adverse effects of preterm birth on the developing brain at microscale, convincing linking principles at large-scale level to explain the widespread nature of brain changes are still missing. We investigated effects of preterm birth on the brain's large-scale intrinsic networks and their relation to brain structure in preterm born adults. In 95 preterm and 83 full-term born adults, structural and functional magnetic resonance imaging at-rest was used to analyze both voxel-based morphometry and spatial patterns of functional connectivity in ongoing blood oxygenation level-dependent activity. Differences in intrinsic functional connectivity (iFC) were found in cortical and subcortical networks. Structural differences were located in subcortical, temporal, and cingulate areas. Critically, for preterm born adults, iFC-network differences were overlapping and correlating with aberrant regional gray-matter (GM) volume specifically in subcortical and temporal areas. Overlapping changes were predicted by prematurity and in particular by neonatal medical complications. These results provide evidence that preterm birth has long-lasting effects on functional connectivity of intrinsic networks, and these changes are specifically related to structural alterations in ventral brain GM., (© The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The runner's high describes a euphoric state resulting from long-distance running. The cerebral neurochemical correlates of exercise-induced mood changes have been barely investigated so far. We aimed to unravel the opioidergic mechanisms of the runner's high in the human brain and to identify the relationship to perceived euphoria. We performed a positron emission tomography "ligand activation" study with the nonselective opioidergic ligand 6-O-(2-[(18)F]fluoroethyl)-6-O-desmethyldiprenorphine ([(18)F]FDPN). Ten athletes were scanned at 2 separate occasions in random order, at rest and after 2 h of endurance running (21.5 +/- 4.7 km). Binding kinetics of [(18)F]FDPN were quantified by basis pursuit denoising (DEPICT software). Statistical parametric mapping (SPM2) was used for voxelwise analyses to determine relative changes in ligand binding after running and correlations of opioid binding with euphoria ratings. Reductions in opioid receptor availability were identified preferentially in prefrontal and limbic/paralimbic brain structures. The level of euphoria was significantly increased after running and was inversely correlated with opioid binding in prefrontal/orbitofrontal cortices, the anterior cingulate cortex, bilateral insula, parainsular cortex, and temporoparietal regions. These findings support the "opioid theory" of the runner's high and suggest region-specific effects in frontolimbic brain areas that are involved in the processing of affective states and mood.

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.

Previous work has identified the prefrontal cortex (PFC) and striatum as participating in the planning and selection of movements. We compared the brain activation patterns during planning in Parkinson's disease patients and age-matched controls using H(2)(15)O-PET and the Tower of London (TOL) task. In this study, our mildly affected Parkinson's disease group performed as well as the control group but showed a different pattern of neuronal activation. In the two groups, overlapping areas of the PFC were activated but, whereas the right caudate nucleus was activated in the control group, this was not evident in the Parkinson's disease patients. This suggests that normal normal frontal lobe activation can occur in Parkinson's disease despite abnormal processing within the basal ganglia. Moreover, right hippocampus activity was suppressed in the controls and enhanced in the Parkinson's disease patients. This could represent a shift to the declarative memory system in Parkinson's disease during performance of the TOL task, possibly resulting from insufficient working memory capacity within the frontostriatal system.

Event-related functional MRI (fMRI) was used to study blood oxygen level dependent cortical signal changes associated with volitional limb movements off and on levodopa in Parkinson's disease. Eight patients with early stage akinetic Parkinson's disease and eight healthy volunteers underwent three functional imaging runs (high speed echo planar imaging with 600 scans/run) while performing paced single joystick movements in a freely chosen direction every 7-15 s. The non-magnetic joystick was linked to a monitoring system for on-line registration of performance parameters along with timing of the pacing tones and fMRI-scan acquisition parameters. This allowed correlation of movement onset, i.e. event-onset, to scanning time. We repeated the scanning procedure in the Parkinson's disease patients when akinesia improved 30 min after oral levodopa. Compared with the control group, patients both off and on levodopa showed movement-related impaired activation in the rostral supplementary motor area and increased activation in primary motor cortex (M1) and the lateral premotor cortex bilaterally. Levodopa led to a relative normalization of the impaired activation in the mesial premotor cortex and decreased signal levels in M1, lateral premotor and superior parietal cortex. We conclude that levodopa improves impaired motor initiation in the supplementary motor area and decreases hyperfunction of lateral premotor and M1 associated with Parkinson's disease during simple volitional movements.

We used the Tower of London task (TOL) and H(2)(15)O-PET to map the network of brain structures involved in planning. Six healthy right-handed subjects had 12 measurements of relative regional cerebral blood flow (rrCBF) during six conditions, each performed twice. There was one rest condition, and five sets of TOL problems at different complexity levels, performed on a touch-sensitive computer monitor with the right arm. Complexity was defined as the number of moves required to solve each problem. Activation was analysed in two ways: a category analysis comparing levels of rrCBF during rest and task was done to identify all structures involved in performance of the TOL; and a correlation analysis was carried out to delineate a subset of structures where the levels of rrCBF correlated with task complexity. Activated brain areas in which rrCBF increases did not correlate with complexity could be grouped into: (i) regions belonging to the dorsal stream of visual input processing, namely visual cortical areas 17, 18 and 19, and posterior parietal cortical areas 7 and 40; and (ii) regions involved in the execution and sequencing of arm movements (right cerebellum, left primary motor cortex and supplementary motor area). Brain regions where levels of rrCBF correlated with task complexity included lateral premotor cortex (area 6), rostral anterior cingulate cortex (areas 32 and 24), dorsolateral prefrontal cortex (areas 9 and 46) bilaterally, and right dorsal caudate nucleus. We propose that dorsolateral prefrontal, lateral premotor, anterior cingulate and caudate areas form a network for the planning of movement that interacts with brain areas primarily involved in visual processing and movement execution.

There is conjoining experimental and clinical evidence supporting a fundamental role of the basal ganglia as a sensory analyser engaged in central somatosensory control. This study was aimed at investigating the functional anatomy of sensory processing in two clinical conditions characterized by basal ganglia dysfunction, i.e. Parkinson's and Huntington's disease. Based on previously recorded data of somatosensory evoked potentials, we expected deficient sensory-evoked activation in cortical areas that receive modulatory somatosensory input via the basal ganglia. Eight Parkinson's disease patients, eight Huntington's disease patients and eight healthy controls underwent repetitive H(2)(15)O-PET activation scans during two experimental conditions in random order: (i) continuous unilateral high-frequency vibratory stimulation applied to the immobilized metacarpal joint of the index finger and (ii) rest (no vibratory stimulus). In the control cohort, the activation pattern was lateralized to the side opposite to stimulus presentation, including cortical [primary sensory cortex (S1); secondary sensory cortex (S2)] and subcortical (globus pallidus, ventrolateral thalamus) regional cerebral blood flow (rCBF) increases (P < 0.001). Between-group comparisons (P < 0.01) of vibration-induced rCBF changes between patients and controls revealed differences in central sensory processing: (i) in Parkinson's disease, decreased activation of contralateral sensorimotor (S1/M1) and lateral premotor cortex, contralateral S2, contralateral posterior cingulate, bilateral prefrontal cortex (Brodmann area 10) and contralateral basal ganglia; (ii) in Huntington's disease, decreased activation of contralateral S2, parietal areas 39 and 40, and lingual gyrus, bilateral prefrontal cortex (Brodmann areas 8, 9, 10 and 44), S1 (trend only) and contralateral basal ganglia; (iii) in both clinical conditions relative enhanced activation of ipsilateral sensory cortical areas, notably caudal S1, S2 and insular cortex. Our data show that Parkinson's disease and Huntington's disease, beyond well-established deficits in central motor control, are characterized by abnormal cortical and subcortical activation on passive sensory stimulation. Furthermore, the finding that activation increases in ipsilateral sensory cortical areas may be interpreted as an indication of either altered central focusing and gating of sensory impulses, or enhanced compensatory recruitment of associative sensory areas in the presence of basal ganglia dysfunction. Altered sensory processing is thought to contribute to pertinent motor deficits in both conditions.

Repeated PET cerebral blood flow measurements using H2(15)O were performed in 13 patients with confirmed Huntington's disease and nine age-matched controls. The activation paradigm consisted of an externally triggered finger opposition task (1.5 Hz) with the dominant hand, the control condition being the auditory input. In the patients with Huntington's disease, impaired activity of the striatum and its frontal motor projection areas (rostral supplementary motor area, anterior cingulate and premotor cortex) could be demonstrated along with enhanced activity mainly in parietal areas during movement. The results suggest that the pathology of Huntington's disease causes impairment of the output part of the basal ganglia-thalamo-cortical motor circuit and may induce a compensatory recruitment of additional accessory motor pathways involving the parietal cortex.

Regional cerebral blood flow was measured with H2(15)O PET in seven patients with choreic Huntington's disease and seven age-matched control subjects. Subjects were scanned at rest and when performing paced joystick movements, in freely chosen directions, with the dominant arm. During movement, the patients showed impaired activation of contralateral primary motor, medial premotor, bilateral parietal and bilateral prefrontal areas along with increased activation of bilateral insular areas. The underactivity of frontal areas in Huntington's disease is similar to the pattern of impaired activation in Parkinson's disease and is likely to result from degeneration of basal ganglia to frontal projections. Primary motor underactivity may explain the bradykinesia that these patients exhibit and, if inhibitory neurons are involved, also their chorea.

Supplementary motor area and right dorsal prefrontal cortex activation in Parkinson's disease is selectively impaired during volitional limb movements. Since posteroventral pallidotomy improves motor performance in Parkinson's disease patients 'off' medication (i.e. off medication for 9-12 h), we hypothesized that it would also concomitantly increase supplementary motor area and dorsal prefrontal cortex activation. Six Parkinson's disease patients with a median total motor Unified Parkinson's Disease Rating Scale (UPDRS) of 52.5 (range 34-66) 'off' medication underwent unilateral right posteroventral pallidotomy. The patients had H2(15)O PET when 'off' medication before and 3-4 months after surgery. Each PET study comprised four to six measurements of regional cerebral blood flow either at rest or while performing regularly paced joystick movements in freely selected directions (forward, backward, left or right) using the left hand. Pre- and postoperative scans were performed in an identical manner and the associated levels of activation were compared using statistical parametric mapping. After pallidotomy, the median total motor UPDRS score 'off' medication decreased by 34.7% (P = 0.03) and mean response times of joystick movements following the pacing tones improved by 13.8% (P = 0.08). Relative increases in activation of the supplementary motor area and right dorsal prefrontal cortex were observed during joystick movements (P < 0.001). Decreased activation was seen in the region of the right pallidum (P = 0.001). We conclude that pallidotomy reduces pallidal inhibition of thalamocortical circuits and reverses, at least partially, the impairment of supplementary motor area and dorsal prefrontal cortex activation associated with Parkinson's disease.

Patients with Parkinson's disease have great difficulty in performing sequential and bimanual movements. We used H2(15)O PET to study the regional cerebral blood flow associated with performance of sequential finger movements made unimanually and bimanually in a group of Parkinson's disease patients and a group of control volunteers. In controls, sequential finger movements led to activation of the contralateral motor cortex and inferior parietal cortex (Brodmann area 40), the lateral premotor cortex and bilateral supplementary motor area. No prefrontal activation was seen. Sequential finger movements in the Parkinson's disease group were associated with a similar pattern of activation but there was relative impairment of activation in the mesial frontal and prefrontal areas. A novel finding was the presence of relative overactivity in the lateral premotor and inferolateral parietal regions. We conclude that in Parkinson's disease there is a switch from the use of striato-mesial frontal to parietal-lateral premotor circuits in order to facilitate performance of complex finger movements.

Magnetic resonance imaging of changes in cerebral blood oxygenation (CBO) delineated areas of neural activation during self-paced unilateral middle finger tapping in five normal volunteers. Four contiguous imaging sections parallel to the bicommissural plane covered the hand area of the primary sensori-motor cortex bilaterally. All measurements were performed at 2.0 T using rapid gradient-echo sequences (TR/TE = 63/30 ms) with high spatial resolution (0.8 x 1.6 x 4 mm) and both strong (40 degrees flip angle) and weak (10 degrees) radiofrequency excitation pulses. This allows differentiation of flow and CBO contributions to the observed signal alterations. Functional cooperativity was analysed by a pixel-by-pixel correlation of signal intensity time courses with the stimulus protocol. Areas of activation included the contralateral primary motor cortex, the homologue part of the primary sensory cortex, the supplementary motor area (SMA) and the lateral premotor areas in all volunteers. Task-related activation of ipsilateral primary motor cortex above a threshold correlation coefficient of 0.5 was seen in two out of five volunteers (at 40 degrees) and one out of five (at 10 degrees) when performing the right-hand task. The present MRI findings readily demonstrate in single subjects that the SMA is involved in self-paced finger tapping. Only sparse activation in the ipsilateral primary motor cortex is consistent with the motor paradigm used.