Martin Peller

A functional endophenotype for sexual orientation in humans

Sexually arousing visual stimuli activate the human reward system and trigger sexual behavior. Here we performed event-related fMRI during visual processing of sexual core stimuli to pinpoint a neuronal correlate of sexual preference in humans. To dissociate gender of the stimulus from sexual preference, we studied male and female heterosexual and homosexual volunteers while they viewed sexual and nonsexual control stimuli. In contrast to previous work, we used core single-sex stimuli displaying male and female sexually aroused genitals. Since stimuli lacked any additional contextual information, they evoked no activity related to neuronal processing of faces, gestures or social interactions. Our prediction was that the sexual preference of the observer determines the neuronal responsiveness to pure male or female sexual stimuli in the human reward and motor system. Consistent with our prediction, the ventral striatum and the centromedian thalamus, showed a stronger neuronal response to preferred relative to non-preferred stimuli. Likewise, the ventral premotor cortex which is a key structure for imitative (mirror neurons) and tool-related (canonical neurons) actions showed a bilateral sexual preference-specific activation, suggesting that viewing sexually aroused genitals of the preferred sex triggers action representations of sexual behavior. The neuronal response of the ventral striatum, centromedian thalamus and ventral premotor cortex to preferred sexual stimuli was consistent across all groups. We propose that this invariant response pattern in core regions of the human reward and motor system represents a functional endophenotype for sexual orientation independent of the gender of the observer and gender of the stimulus.

Manual activity shapes structure and function in contralateral human motor hand area

From longitudinal voxel-based morphometry (VBM) studies we know that relatively short periods of training can increase regional grey matter volume in trained cortical areas. In 14 right-handed patients with writers cramp, we employed VBM to test whether suppression (i.e., immobilization) or enhancement (i.e., training) of manual activity lead to opposing changes in grey matter in the contralateral primary motor hand area (M1(HAND)). We additionally used transcranial magnetic stimulation (TMS) to evaluate concurrent changes in regional excitability. Patients were recruited from a clinical trial which was designed to improve handwriting-associated dystonia. Initially the dystonic hand was immobilized for 4 weeks with the intention to reverse faulty plasticity. After immobilization, patients accomplished a motor re-training for 8 weeks. T1-weighted MRIs of the whole brain and single-pulse TMS measurements of the resting motor threshold (RMT) were performed every 4 weeks. Immobilization of the right hand resulted in a relative grey matter decrease in the contralateral left M1(HAND) along with a decrease in corticomotor excitability as indexed by an increase in RMT. Subsequent training reversed the effects of immobilization, causing an increase in regional grey matter density and excitability of left M1(HAND). The relative changes in grey matter correlated with the relative shifts in RMT. This prospective within-subject VBM study in task-specific hand dystonia shows that the grey matter density of M1(HAND) is dynamically shaped by the level of manual activity. This bi-directional structural plasticity is functionally relevant as local grey matter changes are mirrored by changes in regional excitability.

How to assess motor impairment in writer's cramp

Writers cramp is a task‐specific hand dystonia affecting handwriting. Clinical scores such as the Arm Dystonia Disability Scale (ADDS) or Writers Cramp Rating Scale (WCRS) as well as kinematic analysis of handwriting movements have been used to assess functional impairment in affected patients. In 21 patients with writers cramp and healthy controls, we analyzed the kinematics of writing and cyclic drawing movements. We rated the severity of dystonia using the ADDS and WCRS and correlated the clinical scores with movement kinematics. Mean stroke frequency was significantly reduced in dystonic patients. Drawing movements showed more frequently a decrease in stroke frequency than handwriting movements. During circle drawing, mean vertical peak velocity was more variable in patients relative to controls, indicating an impaired ability to reproduce the same kinematic pattern over time. An increase in vertical writing pressure was only observed during handwriting but not during circle drawing and may reflect a compensatory effort to stabilize the pencil. Kinematic measures and individual ADDS and WCRS scores did not correlate with each other. The lack of correlation is not surprising as ADDS, WCRS, and kinematic analysis probe different aspects of motor impairment. The ADDS characterizes how dystonia affects a set of fine manual tasks, whereas the WCRS scores the manifestation of dystonia during handwriting. Therefore, the clinical scores and kinematic analysis of handwriting provide complementary insights into motor impairment. Future studies need to address which combination of clinical scores and kinematic measures are most appropriate to quantify impairment in writers cramp.

Impaired cross-modal inhibition in Alzheimer disease.

Background Successful cognitive performance depends not only on the activation of specific neuronal networks but also on selective suppression of task-irrelevant modalities, i.e., deactivation of non-required cerebral regions. This ability to suppress the activation of specific brain regions has, to our knowledge, never been systematically evaluated in patients with Alzheimer disease (AD). The aim of the current study was to evaluate both cerebral activation and deactivation in (1) healthy volunteers, (2) patients with mild cognitive impairment (MCI) who are at risk for AD, and (3) patients with moderate AD during active navigation, representing a cognitive task typically affected in AD. Methods and Findings Changes in regional cerebral blood flow (rCBF) were assessed with PET imaging during an active navigation task in a 3D virtual-reality environment. The task was based on visual cues exclusively; no auditory cues were provided. Age-matched groups of healthy individuals, patients with MCI, and patients with AD were examined. Specific differences in the activation patterns were observed in the three groups, with stronger activation of cerebellar portions and visual association cortex in controls and stronger activation of primary visual and frontal cortical areas in patients with MCI and AD. Highly significant bilateral decrease of rCBF in task-irrelevant auditory cortical regions was detected in healthy individuals during performance of the task. This rCBF decrease was interpreted as a cross-modal inhibitory effect. It was diminished in patients with MCI and completely absent in patients with AD. A regression analysis across all individuals revealed a clear positive relation between cognitive status (mini mental state examination score) and the extent of auditory cortical deactivation. Conclusion During active navigation, a high level of movement automation and an involvement of higher-order cerebral association functions were observed in healthy controls. Conversely, in patients with MCI and AD, increased cognitive effort and attention towards movement planning, as well as stronger involvement of lower-order cerebral systems, was found. Successful cognitive performance in healthy individuals is associated with deactivation of task-irrelevant cerebral regions, whereas the development of AD appears to be characterized by a progressive impairment of cross-modal cerebral deactivation functions. These changes may cause the generally decreased ability of patients with AD to direct attention primarily to the relevant cognitive modality.

Motor re‐training does not need to be task specific to improve writer's cramp

Previous studies showed a beneficial effect of motor re‐training in task‐specific hand dystonia. Here we examined whether re‐training needs to specifically focus on the task affected by dystonia. 21 patients with writers cramp were randomly assigned to two types of re‐training: One group of patients trained drawing and writing movements using a pen attached to the bottom of a finger splint. The second group used therapeutic putty to train finger movements without exercises of drawing and writing movements. Training lasted for 8 weeks. Before re‐training, affected hand and forearm were immobilized for 4 weeks to facilitate the responsiveness to re‐training. Dystonia was assessed during handwriting using the Writers Cramp Rating Scale. Although no clinical improvement was observed immediately after immobilization, 8 weeks of re‐training improved task‐specific dystonia relative to baseline (P = 0.005). Both training modalities were equally effective. More severely affected patients benefited most. There was no correlation between disease duration and the individual treatment response. Re‐training also improved hand function as indexed by the Arm Dystonia Disability Scale (P = 0.008). Kinematic handwriting analysis showed that re‐training lowered vertical force level and enhanced the fluency of handwriting. We conclude that re‐training does not need to specifically focus on the task affected by dystonia to be clinically effective.

Rotated alphanumeric characters do not automatically activate frontoparietal areas subserving mental rotation.

Functional neuroimaging studies have identified a set of areas in the intraparietal sulcus and dorsal precentral cortex which show a linear increase in activity with the angle of rotation across a variety of mental rotation tasks. This linear increase in activity with angular disparity suggests that these frontoparietal regions compute rotational transformations. An open question is whether rotated target stimuli automatically activate these frontoparietal regions, even if the task does not require rotational transformations. To address this question, we performed functional MRI while healthy male volunteers made two-choice reaction-time judgements on canonical or mirror images of two-dimensional alphanumeric characters presented at various angles of rotation. Participants had either to decide whether characters were normal or mirror-reversed (i.e., mental rotation) or judge whether the stimulus was a letter or a number (i.e., stimulus categorization). Reaction times and error rates linearly increased with the angle of rotation for mirror-reversed judgements but not for number-letter judgements, showing that only the mental rotation task required rotational transformations of the characters. The mental rotation task was associated with a linear increase in neuronal activity with angular disparity in a bilateral set of frontoparietal areas, comprising the rostral dorsal premotor cortex, frontal eye field, ventral and medial intraparietal sulcus. Neuronal activity in these regions was neither increased nor modulated by angular disparity during the stimulus categorization task. These results suggest that at least for alphanumerical characters, areas implicated in mental rotation will only be called into action if the task requires a rotational transformation.

Chapter 7 Applications of combined TMS-PET studies in clinical and basic research

Publisher Summary This chapter focuses on the combination of transcranial magnetic stimulation (TMS) with positron emission tomography (PET) imaging of regional cerebral blood flow (rCBF) and regional cerebral metabolic rate of glucose (rCMRglc). Despite limited temporal and spatial resolution, the combination of PET with TMS offers some methodological advantages over combined TMS–fMRI studies. Compared with TMS in the MRI scanner, the prerequisites for applying TMS in the PET scanner are relatively easy to establish. PET measurements give an estimate of regional synaptic activity over several tens of seconds or minutes. Combined TMS–PET studies can use the limited temporal resolution of PET as an advantage because a single PET scan will represent the summation of the effects of individual stimuli on regional synaptic activity. The major advantage of PET is that it is possible to make direct comparisons of synaptic activity among different scanning sessions. This makes PET ideally suited to comparing changes in activity because of different TMS paradigms performed on separate days.

Slow pre-movement cortical potentials do not reflect individual response to therapy in writer’s cramp

OBJECTIVE To investigate whether movement-related cortical potentials (MRCP) provide a physiological correlate that indicates the response to treatment in patients with writers cramp. METHODS In 21 patients with writers cramp, who underwent 4 weeks of limb immobilization followed by re-training for 8 weeks, we recorded MRCPs preceding a self-initiated brisk finger abduction movement. MRCP measurements of pre-movement activity were performed at baseline, after the end of immobilization and four and 8 weeks of re-training. We examined 12 controls, who received no intervention, twice 4 weeks apart. RESULTS Patients benefited from the therapeutical intervention (Zeuner et al., 2008). They showed no abnormalities of the MRCPs at baseline. In controls, MRCPs did not significantly change after 4 weeks. In patients, immobilization and re-training had no effect on MRCPs. There was no correlation between the severity of dystonic symptoms or the individual treatment response and MRCPs. CONCLUSION MRCPs are stable measures for interventional studies. However, they do not reflect clinical severity of dystonic symptoms or improvement after therapeutic interventions. SIGNIFICANCE This is the first study to investigate MRCPs in a large cohort of patients with writers cramp compared to a control group at different time points. These potentials do not reflect the motor control disorder in patients with writers cramp.