Enrico Simonotto

The functional anatomy of inspection time: an event-related fMRI study.

Twenty healthy young adults underwent functional magnetic resonance imaging (fMRI) of the brain while performing a visual inspection time task. Inspection time is a forced-choice, two-alternative visual backward-masking task in which the subject is briefly shown two parallel vertical lines of markedly different lengths and must decide which is longer. As stimulus duration decreases, performance declines to chance levels. Individual differences in inspection time correlate with higher cognitive functions. An event-related design was used. The hemodynamic (blood oxygenation level-dependent; BOLD) response was computed as both a function of the eight levels of stimulus duration, from 6 ms (where performance is almost at chance) to 150 ms (where performance is nearly perfect), and a function of the behavioral responses. Random effects analysis showed that the difficulty of the visual discrimination was related to bilateral activation in the inferior fronto-opercular cortex, superior/medial frontal gyrus, and anterior cingulate gyrus, and bilateral deactivation in the posterior cingulate gyrus and precuneus. Examination of the time courses of BOLD responses showed that activation was related specifically to the more difficult, briefer stimuli and that deactivation was found across most stimulus levels. Functional connectivity suggested the existence of two networks. One comprised the fronto-opercular area, intrasylvian area, medial frontal gyrus, and the anterior cingulate cortex (ACC), possibly associated with processing of visually degraded percepts. A posterior network of sensory-related and associative regions might subserve processing of a visual discrimination task that has high processing demands and combines several fundamental cognitive domains. fMRI can thus reveal information about the neural correlates of mental events which occur over very short durations.

A visual joke fMRI investigation into Theory of Mind and enhanced risk of schizophrenia

Theory of Mind (ToM) or mentalizing is the ability of individuals to determine the intentions and behavior of others. This ability is known to be compromised in schizophrenia and has been shown to fluctuate with symptom severity. Neuropsychological investigations into relatives of individuals with schizophrenia have shown that some relatives also show a deficit in this area of social cognition. In order to address this state and trait issue, we investigated the performance of high-risk relatives of individuals with schizophrenia to those of a matched control group (n = 13) on a blocked design visual joke fMRI paradigm. The task involved looking at two sets of cartoon jokes, one set which required mentalizing abilities to understand the jokes and another set that did not require such abilities. Relatives were divided into two groups based on the presence (HR+, n = 12) or absence (HR-, n = 12) of positive symptoms. The task provided robust activations across the groups in areas previously associated with mentalizing abilities, such as the PFC, precuneus, and temporal lobes. Significant between-group activations were observed in the PFC (primarily BA6, 8, and 9) with the HR- activating significantly greater than the HR+ in these regions. Both a secondary state-specific analysis and a third post hoc analysis further investigating state effects showed significant PFC between-group differences. This study is the first time relatives of individuals with schizophrenia have been imaged using a ToM paradigm, and the results provide evidence of both a state and state-mediated trait effect.

fMRI in patients with motor conversion symptoms and controls with simulated weakness

Background: Conversion disorder (motor type) describes weakness that is not due to recognized disease or conscious simulation but instead is thought to be a “psychogenic” phenomenon. It is a common clinical problem in neurology but its neural correlates remain poorly understood. Objective: To compare the neural correlates of unilateral functional weakness in conversion disorder with those in healthy controls asked to simulate unilateral weakness. Methods: Functional magnetic resonance imaging (fMRI) was used to examine whole brain activations during ankle plantarflexion in four patients with unilateral ankle weakness due to conversion disorder and four healthy controls simulating unilateral weakness. Group data were analyzed separately for patients and controls. Results: Both patients and controls activated the motor cortex (paracentral lobule) contralateral to the “weak” limb less strongly and more diffusely than the motor cortex contralateral to the normally moving leg. Patients with conversion disorder activated a network of areas including the putamen and lingual gyri bilaterally, left inferior frontal gyrus, left insula, and deactivated right middle frontal and orbitofrontal cortices. Controls simulating weakness, but not cases, activated the contralateral supplementary motor area. Conclusions: Unilateral weakness in established conversion disorder is associated with a distinctive pattern of activation, which overlaps with but is different from the activation pattern associated with simulated weakness. The overall pattern suggests more complex mental activity in patients with conversion disorder than in controls. BA = Brodmann area; DLPFC = dorsolateral prefrontal cortex; DSM-IV = Diagnostic and Statistical Manual of Diseases, fourth revision; EPI = echo planar imaging; fMRI = functional magnetic resonance imaging; ICD-10 = International Classification of Diseases, version 10; MNI = Montreal Neurological Institute; MRI = magnetic resonance imaging; NCS = nerve conduction studies; PET = positron emission tomography; SMA = supplementary motor area; SPECT = single photon emission computed tomography; SPM99 = statistical parametric mapping software.

Limbic over-activity in depression during preserved performance on the n-back task.

The profile of cognitive dysfunction observed in patients with major depressive disorder (MDD) may be partially attributed to a deficit in the central executive component of working memory (WM). This could be the consequence of a functional deficit in regions of cortex that are associated with WM function in healthy adults. In order to investigate this assertion, ten patients with a diagnosis of MDD and ten matched healthy controls undertook a parametric WM task (i.e. the n-back task) during the acquisition of blood oxygen level dependent echo planar magnetic resonance images (BOLD EPI fMRI). There was no significant difference in the behavioral performance of depressed patients and controls. This was true for both accuracy and reaction time on the n-back task. Random effects analysis of the functional imaging data (using SPM99) revealed a significant difference in load-dependent activation in the medial orbitofrontal cortex/rostral anterior cingulate between patients and controls (cluster size (K(E))/volume = 128/1024 mm3, P(corrected) = 0.025). While both participant groups exhibited a significant decrease in activation in this region with increased task difficulty, the magnitude of this decrease was smaller in patients with MDD than in controls. Therefore, this study implies that the performance of WM tasks is associated with a dysfunctional activation of the medial orbitofrontal and rostral anterior cingulate cortex in MDD. The study thus offers a rationale for explaining depressive cognitive impairment by the abnormal fronto-limbic activation found in clinical depression.

Functional Imaging as a Predictor of Schizophrenia

BACKGROUND Prospective studies of young individuals at high risk of schizophrenia allow the investigation of whether neural abnormalities predate development of illness and, if present, have the potential to identify those who may become ill. METHODS We studied young individuals with at least two relatives with the disorder. At baseline functional magnetic resonance imaging (fMRI) scan, none met criteria for any psychiatric disorder, but four subjects subsequently developed schizophrenia. We report the baseline functional imaging findings in these subjects performing a sentence completion task compared with normal control subjects (n = 21) and those at high risk with (n = 21) and without (n = 41) psychotic symptoms who have not developed the disorder. RESULTS High-risk subjects who became ill demonstrated increased activation of the parietal lobe, decreased activation of the anterior cingulate, and smaller increases in activation with increasing task difficulty in the right lingual gyrus and bilateral temporal regions. The hypothesized predictive power of parietal activation was supported only in combination with lingual gyrus activity, which gave a positive predictive value in this sample of .80. CONCLUSIONS Although these findings should be considered cautiously, as only four subjects who had an fMRI scan subsequently became ill, they suggest functional abnormalities are present in high-risk subjects who later became ill, which distinguish them not only from normal control subjects but also those at high risk who had not developed the disorder. These differences are detectable with fMRI and may have clinical utility.

Correlations between fMRI activation and individual psychotic symptoms in un-medicated subjects at high genetic risk of schizophrenia

Background:It has been proposed that different types of psychopathology in schizophrenia may reflect distinguishable pathological processes. In the current study we aimed to address such associations in the absence of confounders such as medication and disease chronicity by examining specific relationships between fMRI activation and individual symptom severity scores in un-medicated subjects at high genetic risk of schizophrenia.Methods:Associations were examined across two functional imaging paradigms: the Hayling sentence completion task, and an encoding/retrieval task, comprising encoding (at word classification) and retrieval (old word/new word judgement). Symptom severity was assessed using the positive and negative syndrome scale (PANSS). Items examined were hallucinations, delusions, and suspiciousness/persecution.Results:Associations were seen in the anterior middle temporal gyrus in relation to hallucination scores during the sentence completion task, and in the medial temporal lobe in association with suspiciousness/persecution scores in the encoding/retrieval task. Cerebellar activation was associated with delusions and suspiciousness/persecution scores across both tasks with differing patterns of laterality.Conclusion:These results support a role for the lateral temporal cortex in hallucinations and medial temporal lobe in positive psychotic symptoms. They also highlight the potential role of the cerebellum in the formation of delusions. That the current results are seen in un-medicated high risk subjects indicates these associations are not specific to the established illness and are not related to medication effects.

Episodic and semantic memory tasks activate different brain regions in Alzheimer disease.

Objective: To compare brain activity identified by fMRI in subjects with Alzheimer disease (AD) and older healthy controls (HCs) performing an episodic/working memory (EWM) and semantic memory (SM) task. Methods: Nine AD (mean age 73.6) and 10 HC (mean age 71.8) subjects underwent an fMRI memory paradigm. Tasks comprised 1) baseline (recognizing a single digit presented for 1 second), 2) SM (addition of two single digits, always producing a single digit answer), and 3) EWM (recall of the previous single digit on the stimulus of the next digit). Each condition was presented in 2-minute blocks with a shorter and longer time interval for the first and second minute within blocks. Results: Comparing AD and HC subjects, there were no activated brain regions in common for EWM > SM, but left anterior cingulate (Brodmann area [BA] 24, 0, 31, 4) and left medial frontal lobe gyrus (BA 25, -6, 23, -15) were activated by both groups for SM > EWM. Key differences were that for EWM > SM, HC subjects activated the right parahippocampal gyrus, whereas subjects with AD activated the right superior frontal gyrus and left uncus. Conclusions: Subjects with Alzheimer disease (AD) recruited brain regions for easier episodic/working memory (EWM) tasks used by healthy controls (HCs) for more difficult EWM tasks. AD subjects recruited brain regions for semantic memory tasks used by HCs for more difficult EWM tasks. The authors propose a functional “memory reserve” model of compensatory recruitment according to task difficulty and underlying neuropathology.

fMRI changes over time and reproducibility in unmedicated subjects at high genetic risk of schizophrenia.

BACKGROUND Functional brain abnormalities have been repeatedly demonstrated in schizophrenia but there is little data concerning their progression. For such studies to have credibility it is first important to establish the reproducibility of functional imaging techniques. The current study aimed to examine these factors in healthy controls and in unmedicated subjects at high genetic risk of the disorder: (i) to examine the reproducibility of task-related activation patterns, (ii) to determine if there were any progressive functional changes in high-risk subjects versus controls reflecting inheritance of the schizophrenic trait, and (iii) to examine changes over time in relation to fluctuating positive psychotic symptoms (i.e. state effects). METHOD Subjects were scanned performing the Hayling sentence completion test on two occasions 18 months apart. Changes in activation were examined in controls and high-risk subjects (n=16, n=63). Reproducibility was assessed for controls and high-risk subjects who remained asymptomatic at both time points (n=16, n=32). RESULTS Intra-class correlation values indicated good agreement between scanning sessions. No significant differences over time were seen between the high-risk and control group; however, comparison of high-risk subjects who developed symptoms versus those who remained asymptomatic revealed activation increases in the left middle temporal gyrus (p=0.026). CONCLUSIONS The current results suggest that functional changes over time occur in the lateral temporal cortex as high genetic risk subjects become symptomatic, further, they indicate the usefulness of functional imaging tools for investigating progressive changes associated with state and trait effects in schizophrenia.

The functional anatomy of inspection time: a pilot fMRI study

Seven healthy subjects underwent functional magnetic resonance imaging (fMRI) of the brain while performing an inspection time task. Employing a block-type design, the task had three difficulty levels: a control condition, an easy (200 ms stimulus duration), and a more difficult (40 ms) discrimination. Based on group results, there were widespread significant areas of difference in brain activation and deactivation when pairwise comparisons were conducted among the three task conditions. When the difficult condition was compared with the easy condition, there was relative activation in areas of the following brain regions: cingulate gyrus and some frontal and parietal lobe areas. Areas within the following regions showed relative deactivation (greater blood oxygenation level-dependent, BOLD, signal in the easy condition): frontal, temporal, and parietal lobe. There were overlaps between these areas and those found to be active while performing higher cognitive tasks in other functional brain imaging studies. These pilot data encourage future studies of the functional anatomy of inspection time and its relevance to psychometric intelligence.