In your eyes only: deficits in executive functioning after frontal TMS reflect in eye movements

This study investigated the roles of the right and left dorsolateral prefrontal (rDLPFC, lDLPFC) and the medial frontal cortex (MFC) in executive functioning using a theta burst transcranial magnetic stimulation (TMS) approach. Healthy subjects solved two visual search tasks: a number search task with low cognitive demands, and a number and letter search task with high cognitive demands. To observe how subjects solved the tasks, we assessed their behavior with and without TMS using eye movements when subjects were confronted with specific executive demands. To observe executive functions, we were particularly interested in TMS-induced changes in visual exploration strategies found to be associated with good or bad performance in a control condition without TMS stimulation. TMS left processing time unchanged in both tasks. Inhibition of the rDLPFC resulted in a decrease in anticipatory fixations in the number search task, i.e., a decrease in a good strategy in this low demand task. This was paired with a decrease in stimulus fixations. Together, these results point to a role of the rDLPFC in planning and response selection. Inhibition of the lDLPFC and the MFC resulted in an increase in anticipatory fixations in the number and letter search task, i.e., an increase in the application of a good strategy in this task. We interpret these results as a compensatory strategy to account for TMS-induced deficits in attentional switching when faced with high switching demands. After inhibition of the lDLPFC, an increase in regressive fixations was found in the number and letter search task. In the context of high working memory demands, this strategy appears to support TMS-induced working memory deficits. Combining an experimental TMS approach with the recording of eye movements proved sensitive to discrete decrements of executive functions and allows pinpointing the functional organization of the frontal lobes.

Virtual reality and the role of the prefrontal cortex in adults and children

In this review, the neural underpinnings of the experience of presence are outlined. Firstly, it is shown that presence is associated with activation of a distributed network, which includes the dorsal and ventral visual stream, the parietal cortex, the premotor cortex, mesial temporal areas, the brainstem and the thalamus. Secondly, the dorsolateral prefrontal cortex (DLPFC) is identified as a key node of the network as it modulates the activity of the network and the associated experience of presence. Thirdly, children lack the strong modulatory influence of the DLPFC on the network due to their unmatured frontal cortex. Fourthly, it is shown that presence-related measures are influenced by manipulating the activation in the DLPFC using transcranial direct current stimulation (tDCS) while participants are exposed to the virtual roller coaster ride. Finally, the findings are discussed in the context of current models explaining the experience of presence, the rubber hand illusion, and out-of-body experiences.

Differences in frontal cortical activation by a working memory task after substitution of risperidone for typical antipsychotic drugs in patients with schizophrenia

Antipsychotic drug treatment of schizophrenia may be complicated by side effects of widespread dopaminergic antagonism, including exacerbation of negative and cognitive symptoms due to frontal cortical hypodopaminergia. Atypical antipsychotics have been shown to enhance frontal dopaminergic activity in animal models. We predicted that substitution of risperidone for typical antipsychotic drugs in the treatment of schizophrenia would be associated with enhanced functional activation of frontal cortex. We measured cerebral blood oxygenation changes during periodic performance of a verbal working memory task, using functional MRI, on two occasions (baseline and 6 weeks later) in two cohorts of schizophrenic patients. One cohort (n = 10) was treated with typical antipsychotic drugs throughout the study. Risperidone was substituted for typical antipsychotics after baseline assessment in the second cohort (n = 10). A matched group of healthy volunteers (n = 10) was also studied on a single occasion. A network comprising bilateral dorsolateral prefrontal and lateral premotor cortex, the supplementary motor area, and posterior parietal cortex was activated by working memory task performance in both the patients and comparison subjects. A two-way analysis of covariance was used to estimate the effect of substituting risperidone for typical antipsychotics on power of functional response in the patient group. Substitution of risperidone increased functional activation in right prefrontal cortex, supplementary motor area, and posterior parietal cortex at both voxel and regional levels of analysis. This study provides direct evidence for significantly enhanced frontal function in schizophrenic patients after substitution of risperidone for typical antipsychotic drugs, and it indicates the potential value of functional MRI as a tool for longitudinal assessment of psychopharmacological effects on cerebral physiology.

Pain perception: Is there a role for primary somatosensory cortex?

Anatomical, physiological, and lesion data implicate multiple cortical regions in the complex experience of pain. These regions include primary and secondary somatosensory cortices, anterior cingulate cortex, insular cortex, and regions of the frontal cortex. Nevertheless, the role of different cortical areas in pain processing is controversial, particularly that of primary somatosensory cortex (S1). Human brain-imaging studies do not consistently reveal pain-related activation of S1, and older studies of cortical lesions and cortical stimulation in humans did not uncover a clear role of S1 in the pain experience. Whereas studies from a number of laboratories show that S1 is activated during the presentation of noxious stimuli as well as in association with some pathological pain states, others do not report such activation. Several factors may contribute to the different results among studies. First, we have evidence demonstrating that S1 activation is highly modulated by cognitive factors that alter pain perception, including attention and previous experience. Second, the precise somatotopic organization of S1 may lead to small focal activations, which are degraded by sulcal anatomical variability when averaging data across subjects. Third, the probable mixed excitatory and inhibitory effects of nociceptive input to S1 could be disparately represented in different experimental paradigms. Finally, statistical considerations are important in interpreting negative findings in S1. We conclude that, when these factors are taken into account, the bulk of the evidence now strongly supports a prominent and highly modulated role for S1 cortex in the sensory aspects of pain, including localization and discrimination of pain intensity.

Pyramidal neurons of granular prefrontal cortex of the galago: Complexity in evolution of the psychic cell in primates

Typically, cognitive abilities of humans have been attributed to their greatly expanded cortical mantle, granular prefrontal cortex (gPFC) in particular. Recently we have demonstrated systematic differences in microstructure of gPFC in different species. Specifically, pyramidal cells in adult human gPFC are considerably more spinous than those in the gPFC of the macaque monkey, which are more spinous than those in the gPFC of marmoset and owl monkeys. As most cortical dendritic spines receive at least one excitatory input, pyramidal cells in these different species putatively receive different numbers of inputs. These differences in the gPFC pyramidal cell phenotype may be of fundamental importance in determining the functional characteristics of prefrontal circuitry and hence the cognitive styles of the different species. However, it remains unknown as to why the gPFC pyramidal cell phenotype differs between species. Differences could be attributed to, among other things, brain size, relative size of gPFC, or the lineage to which the species belong. Here we investigated pyramidal cells in the dorsolateral gPFC of the prosimian galago to extend the basis for comparison. We found these cells to be less spinous than those in human, macaque, and marmoset. (c) 2005 Wiley-Liss, Inc.

Chronic smoking and alcoholism change expression of selective genes in the human prefrontal cortex

Background: Alcoholism is commonly associated with chronic smoking. A number of gene expression profiles of regions within the human mesocorticolimbic system have identified potential alcohol-sensitive genes; however, the influence of smoking on these changes was not taken into account. This study addressed the impact of alcohol and smoking on the expression of 4 genes, previously identified as alcoholism-sensitive. in the human prefrontal cortex (PFC). Methods: mRNA expression of apolipoprotein D, tissue inhibitor of the metalloproteinase 3, high-affinity glial glutamate transporter and midkine, was measured in the PFC of alcoholic Subjects and controls with and without smoking comorbidity using real-time polymerase chain reaction. Results: The results show that alcohol affects transcription of some of these genes. Additionally, smoking has a marked influence on gene expression. Conclusion: This study emphasizes the need for careful case selection in future gene expression studies to delineate the adaptive molecular process associated with smoking and alcohol.

Quantification of pathological lesions in the frontal and temporal lobe of ten patients diagnosed with Pick's disease

The densities of Pick bodies (PB), Pick cells (PC), senile plaques (SP) and neurofibrillary tangles (NFT) in the frontal and temporal lobe were determined in ten patients diagnosed with Pick's disease (PD). The density of PB was significantly higher in the dentate gyrus granule cells compared with the cortex and the CA sectors of the hippocampus. Within the hippocampus, the highest densities of PB were observed in sector CA1. PC were absent in the dentate gyrus and no significant differences in PC density were observed in the remaining brain regions. With the exception of two patients, the densities of SP and NFT were low with no significant differences in mean densities between cortical regions. In the hippocampus, the density of NFT was greatest in sector CA1. PB and PC densities were positively correlated in the frontal cortex but no correlations were observed between the PD and AD lesions. A principal components analysis (PCA) of the neuropathological variables suggested that variations in the densities of SP in the frontal cortex, temporal cortex and hippocampus were the most important sources of heterogeneity within the patient group. Variations in the densities of PB and NFT in the temporal cortex and hippocampus were of secondary importance. In addition, the PCA suggested that two of the ten patients were atypical. One patient had a higher than average density of SP and one familial patient had a higher density of NFT but few SP.

TRANSFORMATIONS OF TASK-DEPENDENT PLASTICITY FROM A1 TO HIGHER-ORDER AUDITORY CORTEX

Everyday, humans and animals navigate complex acoustic environments, where multiple sound sources overlap. Somehow, they effortlessly perform an acoustic scene analysis and extract relevant signals from background noise. Constant updating of the behavioral relevance of ambient sounds requires the representation and integration of incoming acoustical information with internal representations such as behavioral goals, expectations and memories of previous sound-meaning associations. Rapid plasticity of auditory representations may contribute to our ability to attend and focus on relevant sounds. In order to better understand how auditory representations are transformed in the brain to incorporate behavioral contextual information, we explored task-dependent plasticity in neural responses recorded at four levels of the auditory cortical processing hierarchy of ferrets: the primary auditory cortex (A1), two higher-order auditory areas (dorsal PEG and ventral-anterior PEG) and dorso-lateral frontal cortex. In one study we explored the laminar profile of rapid-task related plasticity in A1 and found that plasticity occurred at all depths, but was greatest in supragranular layers. This result suggests that rapid task-related plasticity in A1 derives primarily from intracortical modulation of neural selectivity. In two other studies we explored task-dependent plasticity in two higher-order areas of the ferret auditory cortex that may correspond to belt (secondary) and parabelt (tertiary) auditory areas. We found that representations of behaviorally-relevant sounds are progressively enhanced during performance of auditory tasks. These selective enhancement effects became progressively larger as you ascend the auditory cortical hierarchy. We also observed neuronal responses to non-auditory, task-related information (reward timing, expectations) in the parabelt area that were very similar to responses previously described in frontal cortex. These results suggests that auditory representations in the brain are transformed from the more veridical spectrotemporal information encoded in earlier auditory stages to a more abstract representation encoding sound behavioral meaning in higher-order auditory areas and dorso-lateral frontal cortex.

Increased premotor cortex activation in high functioning autism during action observation

The mirror neuron (MN) hypothesis of autism has received considerable attention, but to date has produced inconsistent findings. Using functional MRI, participants with high functioning autism or Asperger's syndrome were compared to typically developing individuals (n=12 in each group). Participants passively observed hand gestures that included waving, pointing, and grasping. Concerning the MN network, both groups activated similar regions including prefrontal, inferior parietal and superior temporal regions, with the autism group demonstrating significantly greater activation in the dorsal premotor cortex. Concerning other regions, participants with autism demonstrated increased activity in the anterior cingulate and medial frontal gyrus, and reduced activation in calcarine, cuneus, and middle temporal gyrus. These results suggest that during observation of hand gestures, frontal cortex activation is affected in autism, which we suggest may be linked to abnormal functioning of the MN system.

Different cognitive profiles for single compared with recurrent fallers without Dementia

Relationships between self-reported retrospective falls and cognitive measures (executive function, reaction time, processing speed, working memory, visual attention) were examined in a population based sample of older adults (n = 658). Two of the choice reaction time tests involved inhibiting responses to either targets of a specific color or location with hand and foot responses. Potentially confounding demographic variables, medical conditions and postural sway were controlled for in logistic regression models, excluding participants with possible cognitive impairment. A factor analysis of cognitive measures extracted factors measuring reaction time, accuracy and inhibition, and visual search. Single fallers did not differ from non-fallers in terms of health, sway or cognitive function, except that they performed worse on accuracy and inhibition. In contrast, recurrent fallers performed worse than non-fallers on all measures. Results suggest that occasional falls in late life may be associated with subtle age-related changes in the pre-frontal cortex leading to failures of executive control, whereas recurrent falling may result from more advanced brain ageing that is associated with generalized cognitive decline.

Mismatch negativity in recent-onset and chronic schizophrenia : a current source density analysis

Mismatch negativity (MMN) is a component of the event-related potential elicited by deviant auditory stimuli. It is presumed to index pre-attentive monitoring of changes in the auditory environment. MMN amplitude is smaller in groups of individuals with schizophrenia compared to healthy controls. We compared duration-deviant MMN in 16 recent-onset and 19 chronic schizophrenia patients versus age- and sex-matched controls. Reduced frontal MMN was found in both patient groups, involved reduced hemispheric asymmetry, and was correlated with Global Assessment of Functioning (GAF) and negative symptom ratings. A cortically-constrained LORETA analysis, incorporating anatomical data from each individual's MRI, was performed to generate a current source density model of the MMN response over time. This model suggested MMN generation within a temporal, parietal and frontal network, which was right hemisphere dominant only in controls. An exploratory analysis revealed reduced CSD in patients in superior and middle temporal cortex, inferior and superior parietal cortex, precuneus, anterior cingulate, and superior and middle frontal cortex. A region of interest (ROI) analysis was performed. For the early phase of the MMN, patients had reduced bilateral temporal and parietal response and no lateralisation in frontal ROIs. For late MMN, patients had reduced bilateral parietal response and no lateralisation in temporal ROIs. In patients, correlations revealed a link between GAF and the MMN response in parietal cortex. In controls, the frontal response onset was 17 ms later than the temporal and parietal response. In patients, onset latency of the MMN response was delayed in secondary, but not primary, auditory cortex. However amplitude reductions were observed in both primary and secondary auditory cortex. These latency delays may indicate relatively intact information processing upstream of the primary auditory cortex, but impaired primary auditory cortex or cortico-cortical or thalamo-cortical communication with higher auditory cortices as a core deficit in schizophrenia.

Brain networks subserving the evaluation of static and dynamic facial expressions

Because moving depictions of face emotion have greater ecological validity than their static counterparts, it has been suggested that still photographs may not engage ‘authentic’ mechanisms used to recognize facial expressions in everyday life. To date, however, no neuroimaging studies have adequately addressed the question of whether the processing of static and dynamic expressions rely upon different brain substrates. To address this, we performed an functional magnetic resonance imaging (fMRI) experiment wherein participants made emotional expression discrimination and Sex discrimination judgements to static and moving face images. Compared to Sex discrimination, Emotion discrimination was associated with widespread increased activation in regions of occipito-temporal, parietal and frontal cortex. These regions were activated both by moving and by static emotional stimuli, indicating a general role in the interpretation of emotion. However, portions of the inferior frontal gyri and supplementary/pre-supplementary motor area showed task by motion interaction. These regions were most active during emotion judgements to static faces. Our results demonstrate a common neural substrate for recognizing static and moving facial expressions, but suggest a role for the inferior frontal gyrus in supporting simulation processes that are invoked more strongly to disambiguate static emotional cues.

Gray matter deficits, mismatch negativity, and outcomes in schizophrenia

Reduced mismatch negativity (MMN) in response to auditory change is a well-established finding in schizophrenia and has been shown to be correlated with impaired daily functioning, rather than with hallmark signs and symptoms of the disorder. In this study, we investigated (1) whether the relationship between reduced MMN and impaired daily functioning is mediated by cortical volume loss in temporal and frontal brain regions in schizophrenia and (2) whether this relationship varies with the type of auditory deviant generating MMN. MMN in response to duration, frequency, and intensity deviants was recorded from 18 schizophrenia subjects and 18 pairwise age- and gender-matched healthy subjects. Patients’ levels of global functioning were rated on the Social and Occupational Functioning Assessment Scale. High-resolution structural magnetic resonance scans were acquired to generate average cerebral cortex and temporal lobe models using cortical pattern matching. This technique allows accurate statistical comparison and averaging of cortical measures across subjects, despite wide variations in gyral patterns. MMN amplitude was reduced in schizophrenia patients and correlated with their impaired day-to-day function level. Only in patients, bilateral gray matter reduction in Heschl’s gyrus, as well as motor and executive regions of the frontal cortex, correlated with reduced MMN amplitude in response to frequency deviants, while reduced gray matter in right Heschl’s gyrus also correlated with reduced MMN to duration deviants. Our findings further support the importance of MMN reduction in schizophrenia by linking frontotemporal cerebral gray matter pathology to an automatically generated event-related potential index of daily functioning.

Hemi-orolingual angioedema and ACE inhibition after alteplase treatment of stroke

One hundred seventy-six consecutive patients treated with IV tissue plasminogen activator (tPA) for acute ischemic stroke were examined prospectively, and orolingual angioedema was found in nine (5.1%; 95% CI 2.3 to 9.5). The reaction was typically mild, transient, and contralateral to the ischemic hemisphere. Risk of angioedema was associated with angiotensin-converting enzyme inhibitors (relative risk [RR] 13.6; 95% CI 3.0 to 62.7) and signs on initial CT of ischemia in the insular and frontal cortex (RR 9.1; 95% CI 1.4 to 30.0).

Deficits on self ordered tasks associated with hyperostosis frontalis interna

A 74 year old patient, EW, with dorsolateral frontal cortical compression due to hyperostosis frontalis interna, in the absence of the Morgagni or Stewart-Morel syndromes, is described. In addition to conventional neuropsychological measures EW was administered one nonspatial and two spatial self ordered working memory tasks, as well as a standard measure of fluid intelligence or g. She showed impaired performance on all three self ordered working memory tasks compared with a normal control group of 10 subjects matched for age, education, sex, and IQ. By contrast, her performance on the fluid intelligence test was comparable with that of the controls. It is concluded that the compression of dorsolateral frontal cortex accompanying hyperostosis frontalis interna may produce selective cognitive impairment.