Peter Pieperhoff

Analysis of neural mechanisms underlying verbal fluency in cytoarchitectonically defined stereotaxic space—The roles of Brodmann areas 44 and 45

We investigated neural activations underlying a verbal fluency task and cytoarchitectonic probabilistic maps of Brocas speech region (Brodmanns areas 44 and 45). To do so, we reanalyzed data from a previous functional magnetic resonance imaging (fMRI) [Brain 125 (2002) 1024] and from a cytoarchitectonic study [J. Comp. Neurol. 412 (1999) 319] and developed a method to combine both data sets. In the fMRI experiment, verbal fluency was investigated in 11 healthy volunteers, who covertly produced words from predefined categories. A factorial design was used with factors verbal class (semantic vs. overlearned fluency) and switching between categories (no vs. yes). fMRI data analysis employed SPM99 (Statistical Parametric Mapping). Cytoarchitectonic maps of areas 44 and 45 were derived from histologic sections of 10 postmortem brains. Both the in vivo fMRI and postmortem MR data were warped to a common reference brain using a new elastic warping tool. Cytoarchitectonic probability maps with stereotaxic information about intersubject variability were calculated for both areas and superimposed on the functional data, which showed the involvement of left hemisphere areas with verbal fluency relative to the baseline. Semantic relative to overlearned fluency showed greater involvement of left area 45 than of 44. Thus, although both areas participate in verbal fluency, they do so differentially. Left area 45 is more involved in semantic aspects of language processing, while area 44 is probably involved in high-level aspects of programming speech production per se. The combination of functional data analysis with a new elastic warping tool and cytoarchitectonic maps opens new perspectives for analyzing the cortical networks involved in language.

Deformation Field Morphometry Reveals Age-Related Structural Differences between the Brains of Adults up to 51 Years

Age-related differences in the anatomical structure of the brains from 51 healthy male subjects (age: 18–51 years) were analyzed by deformation field morphometry in a cross-sectional study. The magnetic resonance images of the brains were nonlinearly registered onto the image of a reference brain: the registration algorithm simulated an elastic deformation of each brain (source brain) so that the voxelwise intensity differences with the reference brain were minimized. A three-dimensional deformation field was calculated for each source brain that encoded the anatomical differences between the source brain and the reference brain. Maps of voxelwise volume differences between each subjects brain and the reference brain were analyzed. They showed age-related differences in anatomically defined regions of interest. Major volume decreases were found in the white matter and nuclei of the cerebellum, as well as in the ventral thalamic nuclei and the somatosensory and motor cortices, including the underlying white matter. These findings suggest that aging between the second and sixth decade predominantly affects subcortical nuclei and cortical areas of the sensorimotor system, forming the cortico-rubro-cerebello-thalamo-cortical pathway. Additionally, a pronounced age-related decline in volume was observed in the rostral anterior cingulate, orbitofrontal, and lateral prefrontal cortices. Almost no differences were observed in the occipital and temporal lobes. The ventricles showed a pronounced widening. Remarkably, these volume differences occur at a relatively early period of the human life span. It may be speculated that these structural differences accompany or precede differences in sensorimotor functions and behavior.

Dependence of amygdala activation on echo time: Results from olfactory fMRI experiments

Echo time dependence of the BOLD sensitivity is an important topic in fMRI whenever brain regions are considered where the EPI data quality suffers from susceptibility gradients. Here, an fMRI study is presented showing that a reduced echo time EPI sequence significantly enhances the statistical inference in subcortical (limbic) brain regions, with special focus on the amygdala. As a consequence, to facilitate whole-brain fMRI with optimal echo times, a sequence with slice-dependent echo time is demonstrated with a focus on structures suffering from susceptibility changes. The applicability of this method is shown in a second fMRI study aimed at both, cortical, and limbic brain regions. The results are in good agreement with theoretical descriptions of the BOLD sensitivity under the influence of susceptibility gradients.

Structure and spectroscopy of phosphorus cluster anions: Theory (simulated annealing) and experiment (photoelectron detachment)

Photoelectron detachment measurements have been performed on singly charged phosphorus cluster anions with up to nine atoms, generated by a pulsed arc cluster ion source (PACIS). Transitions between the anion ground states and states of the neutral clusters are observed for all clusters, and vibrational fine structure in both dimer and trimer. A comparison with the results of density functional calculations with simulated annealing—an extension to negative ions of earlier work on neutral and positively charged clusters—provides a consistent overall picture for all cluster sizes and the first experimental structural information on several.

Amygdala control of emotion-induced forgetting and remembering: Evidence from Urbach-Wiethe disease

When presented in a neutral context, emotional items interfere with episodic encoding of temporally contiguous non-emotional items, resulting in dissociable valence-dependent retrograde and arousal-dependent anterograde modulatory effects. By studying two rare patients with congenital lipoid proteinosis (Urbach-Wiethe) and a focal disease emphasis on the basolateral amygdala (BLA), we demonstrate that this bidirectional modification of episodic encoding by emotion depends on the integrity of the amygdala, as both retrograde and anterograde modulatory effects are absent. Our findings implicate the amygdala in a neural circuitry that orchestrates rapid retrograde and anterograde regulation of episodic memory access upon criteria of behavioral significance.

Brain morphometry shows effects of long-term musical practice in middle-aged keyboard players

To what extent does musical practice change the structure of the brain? In order to understand how long-lasting musical training changes brain structure, 20 male right-handed, middle-aged professional musicians and 19 matched controls were investigated. Among the musicians, 13 were pianists or organists with intensive practice regimes. The others were either music teachers at schools or string instrumentalists, who had studied the piano at least as a subsidiary subject, and practiced less intensively. The study was based on T1-weighted MR images, which were analyzed using deformation-based morphometry. Cytoarchitectonic probabilistic maps of cortical areas and subcortical nuclei as well as myeloarchitectonic maps of fiber tracts were used as regions of interest to compare volume differences in the brains of musicians and controls. In addition, maps of voxel-wise volume differences were computed and analyzed. Musicians showed a significantly better symmetric motor performance as well as a greater capability of controlling hand independence than controls. Structural MRI-data revealed significant volumetric differences between the brains of keyboard players, who practiced intensively and controls in right sensorimotor areas and the corticospinal tract as well as in the entorhinal cortex and the left superior parietal lobule. Moreover, they showed also larger volumes in a comparable set of regions than the less intensively practicing musicians. The structural changes in the sensory and motor systems correspond well to the behavioral results, and can be interpreted in terms of plasticity as a result of intensive motor training. Areas of the superior parietal lobule and the entorhinal cortex might be enlarged in musicians due to their special skills in sight-playing and memorizing of scores. In conclusion, intensive and specific musical training seems to have an impact on brain structure, not only during the sensitive period of childhood but throughout life.

Studying variability in human brain aging in a population-based German cohort—rationale and design of 1000BRAINS

The ongoing 1000 brains study (1000BRAINS) is an epidemiological and neuroscientific investigation of structural and functional variability in the human brain during aging. The two recruitment sources are the 10-year follow-up cohort of the German Heinz Nixdorf Recall (HNR) Study, and the HNR MultiGeneration Study cohort, which comprises spouses and offspring of HNR subjects. The HNR is a longitudinal epidemiological investigation of cardiovascular risk factors, with a comprehensive collection of clinical, laboratory, socioeconomic, and environmental data from population-based subjects aged 45–75 years on inclusion. HNR subjects underwent detailed assessments in 2000, 2006, and 2011, and completed annual postal questionnaires on health status. 1000BRAINS accesses these HNR data and applies a separate protocol comprising: neuropsychological tests of attention, memory, executive functions and language; examination of motor skills; ratings of personality, life quality, mood and daily activities; analysis of laboratory and genetic data; and state-of-the-art magnetic resonance imaging (MRI, 3 Tesla) of the brain. The latter includes (i) 3D-T1- and 3D-T2-weighted scans for structural analyses and myelin mapping; (ii) three diffusion imaging sequences optimized for diffusion tensor imaging, high-angular resolution diffusion imaging for detailed fiber tracking and for diffusion kurtosis imaging; (iii) resting-state and task-based functional MRI; and (iv) fluid-attenuated inversion recovery and MR angiography for the detection of vascular lesions and the mapping of white matter lesions. The unique design of 1000BRAINS allows: (i) comprehensive investigation of various influences including genetics, environment and health status on variability in brain structure and function during aging; and (ii) identification of the impact of selected influencing factors on specific cognitive subsystems and their anatomical correlates.

Biotin-Responsive Basal Ganglia Disease: A Treatable Differential Diagnosis of Leigh Syndrome

Biotin-responsive basal ganglia disease (BBGD) is an autosomal recessive disorder, which is caused by mutations in the SLC19A3 gene. BBGD typically causes (sub)acute episodes with encephalopathy and subsequent neurological deterioration. If untreated, the clinical course may be fatal. Our report on a 6-year-old child with BBGD highlights that the disease is a crucial differential diagnosis of Leigh syndrome. Therefore, biotin and thiamine treatment is recommended for any patient with symmetrical basal ganglia lesions and neurological symptoms until BBGD is excluded. In addition, we exemplify that deformation-field-based morphometry of brain magnetic resonance images constitutes a novel quantitative tool, which might be very useful to monitor disease course and therapeutic effects in neurometabolic disorders.

Longitudinal Deformation-Based Morphometry Reveals Spatio-Temporal Dynamics of Brain Volume Changes in Patients with Corticobasal Syndrome

Background/Objective Corticobasal syndrome (CBS) is a rare neurodegenerative disorder characterized by a progressive and asymmetric manifestation of cortical and basal-ganglia symptoms of different origin. The spatio-temporal dynamics of cerebral atrophy in CBS is barely known. This study aimed to longitudinally quantify the individual dynamics of brain volume changes in patients with CBS as compared to healthy controls. Methods We used deformation-field-based morphometry (DFM) to study volumetric changes of each individual brain in short intervals of a few months. DFM enabled the quantitative analysis of local volume changes without predefining regions of interest in MR images of 6 patients with CBS and 11 matched healthy controls. A total of 64 whole brain 3D-MR-scans were acquired two to eight times over periods of 14 to 26 months. Based on repeated registrations of MR observations to the initial scan, maps of local volume ratio changes were computed. Results Compared to controls patients showed significant and increasing volume loss over time in premotor and primary-motor-cortices, somatosensory area 3a, superior parietal areas BA 5/7, and corticospinal tract. Furthermore, significant and asymmetric atrophy was identified in the caudate nucleus head, putamen, pallidum, motor-thalamus and substantia nigra. Temporal lobe was affected in those patients who presented progressive cognitive impairment. Conclusions The analysis revealed localized, pathological changes in brains of patients with CBS, which differed significantly from those occurring during aging in healthy controls. As compared to age- and sex-matched controls, brains of CBS patients showed a common degenerating neural network comprising the motor circuit with basal ganglia and motor thalamic nuclei as well as the premotor and primary-motor-cortex.

Longitudinal changes in brains of patients with fluent primary progressive aphasia.

Primary progressive aphasia (PPA) is a rare clinical dementia syndrome with predominant, progressive language impairment. Clinical symptoms, linguistic impairment and the course of the disease may vary considerably between patients. In order to capture these aspects, longitudinal assessments of neurofunctional changes in PPA including their relationship to behaviour and clinical symptoms are mandatory, ideally at intervals shorter than 1 year. Here, we report a longitudinal fMRI study investigating the development of lexical processing and their neural basis in PPA patients over 1year. Four logopenic PPA patients and four matched controls were scanned 3 times (T1, T2, T3, at 6months intervals) while performing a visual lexical decision task on German words and pseudowords. Group differences for the lexicality effect (pseudowords>words) were assessed at time point T1 and its longitudinal changes in the BOLD signal associated with the lexicality effect were analysed. Brain atrophy was assessed with a high-resolution MPRAGE sequence and analysed using deformation based morphometry (DBM). From the very beginning of the study, PPA patients showed reduced left-hemispheric and increased right-hemispheric activations compared to controls. During the progression of the disease, activation increased predominantly in left posterior middle temporal gyrus (pMTG) and inferior frontal junction area, whereas the same regions decreased in activity in control brains. Interestingly, DBM data showed that this increase in activation in PPA patients was accompanied by progressing atrophy in the same regions. At a behavioural level, the accuracy in the lexical decision task was comparably high for both groups during the whole period of examination, despite some large variability between patients. To conclude, the dissociation between (i) maintained high performance, (ii) increased activity in regions involved in lexical access such as pMTG, and (iii) progressive atrophy of the very same regions supports the notion of a compensatory mechanism in brains of PPA patients for maintaining language while brain atrophy is progressing. The activity increase within a left-lateralised fronto-temporal network seems vital for high-level performance, whereas initial right-hemispheric recruitment of homologue language regions, which is reminiscent of that in vascular aphasics, has no continuous impact on lexical performance.