Altered hierarchical auditory predictive processing after lesions to the orbitofrontal cortex.

Orbitofrontal cortex (OFC) is classically linked to inhibitory control, emotion regulation, and reward processing. Recent perspectives propose that the OFC also generates predictions about perceptual events, actions, and their outcomes. We tested the role of the OFC in detecting violations of prediction at two levels of abstraction (i.e., hierarchical predictive processing) by studying the event-related potentials (ERPs) of patients with focal OFC lesions (n = 12) and healthy controls (n = 14) while they detected deviant sequences of tones in a local-global paradigm. The structural regularities of the tones were controlled at two hierarchical levels by rules defined at a local (i.e., between tones within sequences) and at a global (i.e., between sequences) level. In OFC patients, ERPs elicited by standard tones were unaffected at both local and global levels compared to controls. However, patients showed an attenuated mismatch negativity (MMN) and P3a to local prediction violation, as well as a diminished MMN followed by a delayed P3a to the combined local and global level prediction violation. The subsequent P3b component to conditions involving violations of prediction at the level of global rules was preserved in the OFC group. Comparable effects were absent in patients with lesions restricted to the lateral PFC, which lends a degree of anatomical specificity to the altered predictive processing resulting from OFC lesion. Overall, the altered magnitudes and time courses of MMN/P3a responses after lesions to the OFC indicate that the neural correlates of detection of auditory regularity violation are impacted at two hierarchical levels of rule abstraction.

Lesions to the Fronto-Parietal Network Impact Alpha-Band Phase Synchrony and Cognitive Control.

Long-range phase synchrony in the α-oscillation band (near 10 Hz) has been proposed to facilitate information integration across anatomically segregated regions. Which areas may top-down regulate such cross-regional integration is largely unknown. We previously found that the moment-to-moment strength of high-α band (10-12 Hz) phase synchrony co-varies with activity in a fronto-parietal (FP) network. This network is critical for adaptive cognitive control functions such as cognitive flexibility required during set-shifting. Using electroencephalography (EEG) in 23 patients with focal frontal lobe lesions (resected tumors), we tested the hypothesis that the FP network is necessary for modulation of high-α band phase synchrony. Global phase-synchrony was measured using an adaptation of the phase-locking value (PLV) in a sliding window procedure, which allowed for measurement of changes in EEG-based resting-state functional connectivity across time. As hypothesized, the temporal modulation (range and standard deviation) of high-α phase synchrony was reduced as a function of FP network lesion extent, mostly due to dorsolateral prefrontal cortex (dlPFC) lesions. Furthermore, patients with dlPFC lesions exhibited reduced cognitive flexibility as measured by the Trail-Making Test (set-shifting). Our findings provide evidence that the FP network is necessary for modulatory control of high-α band long-range phase synchrony, and linked to cognitive flexibility.

Lateral prefrontal cortex lesion impairs regulation of internally and externally directed attention.

Our capacity to flexibly shift between internally and externally directed attention is crucial for successful performance of activities in our daily lives. Neuroimaging studies have implicated the lateral prefrontal cortex (LPFC) in both internally directed processes, including autobiographical memory retrieval and future planning, and externally directed processes, including cognitive control and selective attention. However, the causal involvement of the LPFC in regulating internally directed attention states is unknown. The current study recorded scalp EEG from patients with LPFC lesions and healthy controls as they performed an attention task that instructed them to direct their attention either to the external environment or their internal milieu. We compared frontocentral midline theta and posterior alpha between externally and internally directed attention states. While healthy controls showed increased theta power during externally directed attention and increased alpha power during internally directed attention, LPFC patients revealed no differences between the two attention states in either electrophysiological measure in the analyzed time windows. These findings provide evidence that damage to the LPFC leads to dysregulation of both types of attention, establishing the important role of LPFC in supporting sustained periods of internally and externally directed attention.

Effects of prefrontal cortex damage on emotion understanding: EEG and behavioural evidence.

Humans are highly social beings that interact with each other on a daily basis. In these complex interactions, we get along by being able to identify others' actions and infer their intentions, thoughts and feelings. One of the major theories accounting for this critical ability assumes that the understanding of social signals is based on a primordial tendency to simulate observed actions by activating a mirror neuron system. If mirror neuron regions are important for action and emotion recognition, damage to regions in this network should lead to deficits in these domains. In the current behavioural and EEG study, we focused on the lateral prefrontal cortex including dorsal and ventral prefrontal cortex and utilized a series of task paradigms, each measuring a different aspect of recognizing others' actions or emotions from body cues. We examined 17 patients with lesions including (n = 8) or not including (n = 9) the inferior frontal gyrus, a core mirror neuron system region, and compared their performance to matched healthy control subjects (n = 18), in behavioural tasks and in an EEG observation-execution task measuring mu suppression. Our results provide support for the role of the lateral prefrontal cortex in understanding others' emotions, by showing that even unilateral lesions result in deficits in both accuracy and reaction time in tasks involving the recognition of others' emotions. In tasks involving the recognition of actions, patients showed a general increase in reaction time, but not a reduction in accuracy. Deficits in emotion recognition can be seen by either direct damage to the inferior frontal gyrus, or via damage to dorsal lateral prefrontal cortex regions, resulting in deteriorated performance and less EEG mu suppression over sensorimotor cortex.

Self-Reported Executive Functioning in Everyday Life in Parkinson's Disease after Three Months of Subthalamic Deep Brain Stimulation.

Objective. Studies on the effect of subthalamic deep brain stimulation (STN-DBS) on executive functioning in Parkinson's disease (PD) are still controversial. In this study we compared self-reported daily executive functioning in PD patients before and after three months of STN-DBS. We also examined whether executive functioning in everyday life was associated with motor symptoms, apathy, and psychiatric symptoms. Method. 40 PD patients were examined with the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A), the Symptom Checklist 90-Revised (SCL-90-R), and the Apathy Evaluation Scale (AES-S). Results. PD patients reported significant improvement in daily life executive functioning after 3 months of STN-DBS. Anxiety scores significantly declined, while other psychiatric symptoms remained unchanged. The improvement of self-reported executive functioning did not correlate with motor improvement after STN-DBS. Apathy scores remained unchanged after surgery. Only preoperative depressed mood had predictive value to the improvement of executive function and appears to prevent potentially favorable outcomes from STN-DBS on some aspects of executive function. Conclusion. PD patients being screened for STN-DBS surgery should be evaluated with regard to self-reported executive functioning. Depressive symptoms in presurgical PD patients should be treated. Complementary information about daily life executive functioning in PD patients might enhance further treatment planning of STN-DBS.

Personality changes after deep brain stimulation in Parkinson's disease.

Objectives. Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a recognized therapy that improves motor symptoms in advanced Parkinson's disease (PD). However, little is known about its impact on personality. To address this topic, we have assessed personality traits before and after STN-DBS in PD patients. Methods. Forty patients with advanced PD were assessed with the Temperament and Character Inventory (TCI): the Urgency, Premeditation, Perseverance, Sensation Seeking impulsive behaviour scale (UPPS), and the Neuroticism and Lie subscales of the Eysenck Personality Questionnaire (EPQ-N, EPQ-L) before surgery and after three months of STN-DBS. Collateral information obtained from the UPPS was also reported. Results. Despite improvement in motor function and reduction in dopaminergic dosage patients reported lower score on the TCI Persistence and Self-Transcendence scales, after three months of STN-DBS, compared to baseline (P = 0.006; P = 0.024). Relatives reported significantly increased scores on the UPPS Lack of Premeditation scale at follow-up (P = 0.027). Conclusion. STN-DBS in PD patients is associated with personality changes in the direction of increased impulsivity.

Effects of inhibition of gonadotropin releasing hormone secretion on the response to novel objects in young male and female sheep.

This study investigated the actions of blocking the GnRH receptor using a specific agonist on the response of male and female sheep to a novel object placed in their pen. The study is part of a series performed on 46 same sex twin animals. One of the pair received a subcutaneous implant of the GnRH agonist Goserelin acetate every four weeks while the other remained untreated. Implantation began immediately prior to puberty; at 8 weeks in the males and 28 weeks in the females (as timing of puberty is sex specific). To determine the effects of agonist treatment on the reproductive axis blood samples were collected for measurement of testosterone in the males and progesterone in the females. In addition the volume of the scrotum was determined. The present study aimed to determine whether there are sexually differentiated behavioural responses to a novel object at different stages of brain development (8, 28 and 48 weeks of age) and whether these responses are altered by GnRHa treatment. Approach behaviour towards and interactions with the novel object were monitored as was the number of vocalisations per unit time during the test period. GnRHa treatment suppressed testosterone concentrations and testicular growth in the males and progesterone release in the females. Sheep vocalised significantly more prior to weaning (8 weeks of age) than post weaning (28 and 48 weeks of age) suggesting stress on separation from their dams. Our current study shows that males are more likely to leave their conspecifics to approach a novel object than females. As this behaviour was not altered by suppression of the reproductive axis we suggest that, although sex differences are more obviously expressed in the phenotype after puberty, these may be developed during adolescence but not primarily altered during puberty by sex hormones.

Impact of orbitofrontal lesions on electrophysiological signals in a stop signal task.

Behavioral inhibition and performance monitoring are critical cognitive functions supported by distributed neural networks including the pFC. We examined neurophysiological correlates of motor response inhibition and action monitoring in patients with focal orbitofrontal (OFC) lesions (n = 12) after resection of a primary intracranial tumor or contusion because of traumatic brain injury. Healthy participants served as controls (n = 14). Participants performed a visual stop signal task. We analyzed behavioral performance as well as event-related brain potentials and oscillations. Inhibition difficulty was adjusted individually to yield an equal amount of successful inhibitions across participants. RTs of patients and controls did not differ significantly in go trials or in failed stop trials, and no differences were observed in estimated stop signal RT. However, electrophysiological response patterns during task performance distinguished the groups. Patients with OFC lesions had enhanced P3 amplitudes to congruent condition go signals and to stop signals. In stop trials, patients had attenuated N2 and error-related negativity, but enhanced error positivity. Patients also showed enhanced and prolonged post-error beta band increases for stop errors. This effect was particularly evident in patients whose lesion extended to the subgenual cingulate cortex. In summary, although response inhibition was not impaired, the diminished stop N2 and ERN support a critical role of the OFC in action monitoring. Moreover, the increased stop P3, error positivity, and post-error beta response indicate that OFC injury affected action outcome evaluation and support the notion that the OFC is relevant for the processing of abstract reinforcers such as performing correctly in the task.

Sex-specific development of spatial orientation is independent of peripubertal gonadal steroids.

Prenatal exposure to androgens has been shown to modulate brain development, resulting in changed behavioral attitudes, sexual orientation and cognitive functions, including processing of spatial information. Whether later changes in gonadotropic hormones during puberty induce further organizational effects within the brain is still insufficiently understood. The purpose of this study was to assess development of spatial orientation before and after the time of normal pubertal development, in an ovine model where half of the animals did not undergo typical reproductive maturation due to the pharmacological blockade of gonadotropin releasing hormone receptor (GnRHR) signaling. The study formed part of a larger trial and utilized 46 pairs of same sex Scottish Mule Texel Cross twins (22 female and 24 male). One twin remained untreated throughout (control) while the other received a subcutaneous GnRH agonist (GnRHa: Goserelin-Acetate) implant every fourth week. GnRHa treatment began at eight and 28 weeks of age, in males and females respectively, because the timing of the pubertal transition is sexually differentiated in sheep as it is in humans. Spatial orientation was assessed at three different time points: eight weeks of age, before puberty and treatment in both sexes; 28 weeks of age, after 20 weeks GnRHa treatment in males and before puberty and GnRHa treatment in females; and at 48 weeks of age, which is after the normal time of the pubertal transition in both sexes. Spatial orientation was tested in a spatial maze with traverse time as the main outcome measure. GnRHa treatment did not affect spatial maze performance as no significant differences in traverse time between treated and untreated animals were observed at any time-point. Adolescent females (48 weeks of age) traversed the maze significantly faster than adolescent males, whereas no sex differences in traverse time were seen at earlier developmental stages (eight and 28 weeks). Development of sex differences in spatial orientation was independent of exposure to pubertal hormones since puberty-blocked and control animals both showed the same pattern of spatial maze performance. This result demonstrates the prenatal nature of spatial orientation development. Furthermore, the unexpected finding that female animals outperformed males in the spatial orientation task, underscores the importance of the testing context in spatial orientation experiments.

Peri-pubertal gonadotropin-releasing hormone analog treatment affects hippocampus gene expression without changing spatial orientation in young sheep.

BACKGROUND: Normal brain maturation is the result of molecular changes that can be modulated by endocrine variables associated with brain plasticity and results in sex- and age specific changes in cognitive performance. Using a sheep model, we have previously shown that peri-pubertal pharmacological blockade of gonadotropin releasing hormone (GnRH) receptors results in increased sex-differences in cognitive executive function and emotional control. In this study we explore effects of this treatment regime on hippocampal gene expression and spatial orientation. METHODS: The study was conducted with 30 same-sex twin lambs, half of which were treated with the GnRH analog (GnRHa) goserelin acetate every 4th week, beginning before puberty, until 50 weeks of age. Animals were tested in their spatial orientation ability at 48 weeks of age. Quantitative real time PCR analysis was conducted to examine effects of treatment on the expression of genes associated with synaptic plasticity and endocrine signaling. RESULTS: GnRHa treatment was associated with significant sex- and hemisphere specific changes in mRNA expression for some of the genes studied. The treatment had no significant effect on spatial orientation. However, there was a tendency that females performed better than males in spatial orientation. CONCLUSION: Our results indicate that GnRH directly and/or indirectly, is involved in the regulation of sex- and side-specific expression patterns of genes. Hence, these results should be considered when long-term peri-pubertal GnRHa treatment is used in children.