Functional magnetic resonance brain imaging of executive cognitive performance in young first-episode schizophrenia patients and age-matched long-term cannabis users

Converging evidence from epidemiological, clinical and neuropsychological research suggests a link between cannabis use and increased risk of psychosis. Long-term cannabis use has also been related to deficit-like “negative” symptoms and cognitive impairment that resemble some of the clinical and cognitive features of schizophrenia. The current functional brain imaging study investigated the impact of a history of heavy cannabis use on impaired executive function in first-episode schizophrenia patients. Whilst performing the Tower of London task in a magnetic resonance imaging scanner, event-related blood oxygenation level-dependent (BOLD) brain activation was compared between four age and gender-matched groups: 12 first-episode schizophrenia patients; 17 long-term cannabis users; seven cannabis using first-episode schizophrenia patients; and 17 healthy control subjects. BOLD activation was assessed as a function of increasing task difficulty within and between groups as well as the main effects of cannabis use and the diagnosis of schizophrenia. Cannabis users and non-drug using first-episode schizophrenia patients exhibited equivalently reduced dorsolateral prefrontal activation in response to task difficulty. A trend towards additional prefrontal and left superior parietal cortical activation deficits was observed in cannabis-using first-episode schizophrenia patients while a history of cannabis use accounted for increased activation in the visual cortex. Cannabis users and schizophrenia patients fail to adequately activate the dorsolateral prefrontal cortex, thus pointing to a common working memory impairment which is particularly evident in cannabis-using first-episode schizophrenia patients. A history of heavy cannabis use, on the other hand, accounted for increased primary visual processing, suggesting compensatory imagery processing of the task.

An organization of visual and auditory fear conditioning in the lateral amygdala

Pavlovian fear conditioning is an evolutionary conserved and extensively studied form of associative learning and memory. In mammals, the lateral amygdala (LA) is an essential locus for Pavlovian fear learning and memory. Despite significant progress unraveling the cellular mechanisms responsible for fear conditioning, very little is known about the anatomical organization of neurons encoding fear conditioning in the LA. One key question is how fear conditioning to different sensory stimuli is organized in LA neuronal ensembles. Here we show that Pavlovian fear conditioning, formed through either the auditory or visual sensory modality, activates a similar density of LA neurons expressing a learning-induced phosphorylated extracellular signal-regulated kinase (p-ERK1/2). While the size of the neuron population specific to either memory was similar, the anatomical distribution differed. Several discrete sites in the LA contained a small but significant number of p-ERK1/2-expressing neurons specific to either sensory modality. The sites were anatomically localized to different levels of the longitudinal plane and were independent of both memory strength and the relative size of the activated neuronal population, suggesting some portion of the memory trace for auditory and visually cued fear conditioning is allocated differently in the LA. Presenting the visual stimulus by itself did not activate the same p-ERK1/2 neuron density or pattern, confirming the novelty of light alone cannot account for the specific pattern of activated neurons after visual fear conditioning. Together, these findings reveal an anatomical distribution of visual and auditory fear conditioning at the level of neuronal ensembles in the LA.

A high and low fear phenotype mouse model

Fear-related illnesses such as post-traumatic stress disorder (PTSD) impose a tremendous burden on individual quality of life, families, and the national economy. In the military population, 17-20% of services members returning from deployment are diagnosed with PTSD. While treatments have improved for PTSD and are helpful for some, many people continue to suffer despite therapy. The aim of this research is to examine fear memory behaviourally and at the cellular level in the amygdala by using a unique inter-cross strain of high and low fear phenotype mice. An extended outcross C57BL/6J x DBA/2J (F8) are selected for high or low Pavlovian fear memory to context and cue. On presentation of either the original learning context or the cue (tone) mice display high or low levels of freezing as a behavioural measure of fear. In order to identify key aspects of the cellular basis of this difference in fear memory behaviour we are making measurements of protein levels and neuron numbers of a known pathway involved in the consolidation of a long term fear memory (pMAPK). Ongoing studies aim to determine if high fear behaviour is associated with differential signalling in the lateral amygdala compared to low fear behaviour. Additionally, by blocking this pathway in the lateral amygdala (LA), we aim to reduce fear behaviour following Pavlovian fear conditioning. This research will help to unravel the cellular mechanisms underlying high fear behaviour and advance the field toward targeted treatment and improved outcomes, ultimately improving human quality of life.

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.

Cerebellar grey matter deficits in first-episode schizophrenia mapped using cortical pattern matching

Cerebellar dysfunction has been proposed to lead to “cognitive dysmetria” in schizophrenia via the cortico-cerebellar-thalamic-cortical circuit, contributing to a range of cognitive and clinical symptoms of the disorder. Here we investigated total cerebellar grey and white matter volumes and cerebellar regional grey matter abnormalities in 13 remitted first-episode schizophrenia patients with less than 2 years’ duration of illness. Patient data were compared to 13 pair-wise age, gender, and handedness-matched healthy volunteers using cortical pattern averaging on high-resolution magnetic resonance images. Total cerebellar volume and total grey matter volumes in first-episode schizophrenia patients did not differ from healthy control subjects, but total cerebellar white matter was increased and total grey to white matter ratios were reduced in patients. Four clusters of cerebellar grey matter reduction were identified: (i) in superior vermis; (ii) in the left lobuli VI; (iii) in right-inferior lobule IX, extending into left lobule IX; and (iv) bilaterally in the areas of lobuli III, peduncle and left flocculus. Grey matter deficits were particularly prominent in right lobuli III and IX, left flocculus and bilateral pedunculi. These cerebellar areas have been implicated in attention control, emotional regulation, social functioning, initiation of smooth pursuit eye movements, eye-blink conditioning, language processing, verbal memory, executive function and the processing of spatial and emotional information. Consistent with common clinical, cognitive, and pathophysiological signs of established illness, our findings demonstrate cerebellar pathology as early as in first-episode schizophrenia.

Examining the neural correlates of choice behavior in a gambling task using steady state topography

The present study investigated the behavioral and neuropsychological characteristics of decision-making behavior during a gambling task as well as how these characteristics may relate to the Somatic Marker Hypothesis and the Frequency of Gain model. The applicability to intertemporal choice was also discussed. Patterns of card selection during a computerized interpretation of the Iowa Gambling Task were assessed for 10 men and 10 women. Steady State Topography was employed to assess cortical processing throughout this task. Results supported the hypothesis that patterns of card selection were in line with both theories. As hypothesized, these 2 patterns of card selection were also associated with distinct patterns of cortical activity, suggesting that intertemporal choice may involve the recruitment of right dorsolateral prefrontal cortex for somatic labeling, left fusiform gyrus for object representations, and the left dorsolateral prefrontal cortex for an analysis of the associated frequency of gain or loss. It is suggested that processes contributing to intertemporal choice may include inhibition of negatively valenced options, guiding decisions away from those options, as well as computations favoring frequently rewarded options.

Steady state visually evoked potential correlates of static and dynamic emotional face processing

While the neural regions associated with facial identity recognition are considered to be well defined, the neural correlates of non-moving and moving images of facial emotion processing are less clear. This study examined the brain electrical activity changes in 26 participants (14 males M = 21.64, SD = 3.99; 12 females M = 24.42, SD = 4.36), during a passive face viewing task, a scrambled face task and separate emotion and gender face discrimination tasks. The steady state visual evoked potential (SSVEP) was recorded from 64-electrode sites. Consistent with previous research, face related activity was evidenced at scalp regions over the parieto-temporal region approximately 170 ms after stimulus presentation. Results also identified different SSVEP spatio-temporal changes associated with the processing of static and dynamic facial emotions with respect to gender, with static stimuli predominately associated with an increase in inhibitory processing within the frontal region. Dynamic facial emotions were associated with changes in SSVEP response within the temporal region, which are proposed to index inhibitory processing. It is suggested that static images represent non-canonical stimuli which are processed via different mechanisms to their more ecologically valid dynamic counterparts.

The potential for new understandings of normal and abnormal cognition by integration of neuroimaging and behavioral data : Not an exercise in carrying coals to Newcastle

Discovering the means to prevent and cure schizophrenia is a vision that motivates many scientists. But in order to achieve this goal, we need to understand its neurobiological basis. The emergent metadiscipline of cognitive neuroscience fields an impressive array of tools that can be marshaled towards achieving this goal, including powerful new methods of imaging the brain (both structural and functional) as well as assessments of perceptual and cognitive capacities based on psychophysical procedures, experimental tasks and models developed by cognitive science. We believe that the integration of data from this array of tools offers the greatest possibilities and potential for advancing understanding of the neural basis of not only normal cognition but also the cognitive impairments that are fundamental to schizophrenia. Since sufficient expertise in the application of these tools and methods rarely reside in a single individual, or even a single laboratory, collaboration is a key element in this endeavor. Here, we review some of the products of our integrative efforts in collaboration with our colleagues on the East Coast of Australia and Pacific Rim. This research focuses on the neural basis of executive function deficits and impairments in early auditory processing in patients using various combinations of performance indices (from perceptual and cognitive paradigms), ERPs, fMRI and sMRI. In each case, integration of two or more sources of information provides more information than any one source alone by revealing new insights into structure-function relationships. Furthermore, the addition of other imaging methodologies (such as DTI) and approaches (such as computational models of cognition) offers new horizons in human brain imaging research and in understanding human behavior.

Mirror neuron activation is associated with facial emotion processing

Theoretical accounts suggest that mirror neurons play a crucial role in social cognition. The current study used transcranial-magnetic stimulation (TMS) to investigate the association between mirror neuron activation and facialemotion processing, a fundamental aspect of social cognition, among healthy adults (n = 20). Facial emotion processing of static (but not dynamic) images correlated significantly with an enhanced motor response, proposed to reflect mirror neuron activation. These correlations did not appear to reflect general facial processing or pattern recognition, and provide support to current theoretical accounts linking the mirror neuron system to aspects of social cognition. We discuss the mechanism by which mirror neurons might facilitate facial emotion recognition.

Reduced motor facilitation during action observation in schizophrenia : a mirror neuron deficit?

Impairments in social cognitive functioning are well documented in schizophrenia, however the neural basis of these deficits is unclear. A recent explanatory model of social cognition centers upon the activity of mirror neurons, which are cortical brain cells that become active during both the performance and observation of behavior. Here, we test for the first time whether mirror neuron functioning is reduced in schizophrenia. Fifteen individuals with schizophrenia or schizoaffective disorder and fifteen healthy controls completed a transcranial magnetic stimulation (TMS) experiment designed to assess mirror neuron activation. While patients demonstrated no abnormalities in cortical excitability, motor facilitation during action observation, putatively reflecting mirror neuron activity, was reduced in schizophrenia. Dysfunction within the mirror neuron system may contribute to the pathophysiology of schizophrenia.

The effect of the ecstasy 'come-down' on the diagnosis of ecstasy dependence

Background: The existence of an ecstasy dependence syndrome is controversial. We examined whether the acute after-effects of ecstasy use (i.e., the “come-down”) falsely lead to the identification of ecstasy withdrawal and the subsequent diagnosis of ecstasy dependence. Methods: The Structured Clinical Interview for DSM-IV-TR Disorders: Research Version (SCID-RV) was administered to 214 Australian ecstasy users. Ecstasy withdrawal was operationalized in three contrasting ways: (i) as per DSM-IV criteria; (ii) as the expected after effects of ecstasy (a regular come-down); or (iii) as a substantially greater or longer come-down than on first use (intense come-down). These definitions were validated against frequency of ecstasy use, readiness to change and ability to resist the urge to use ecstasy. Confirmatory factor analyses were used to see how they aligned with the overall dependence syndrome. Results: Come-down symptoms increased the prevalence of withdrawal from 1% (DSM-IV criterion) to 11% (intense come-downs) and 75% (regular come-downs). Past year ecstasy dependence remained at 31% when including the DSM-IV withdrawal criteria and was 32% with intense come-downs, but increased to 45% with regular come-downs. Intense come-downs were associated with lower ability to resist ecstasy use and loaded positively on the dependence syndrome. Regular come-downs did not load positively on the ecstasy dependence syndrome and were not related to other indices of dependence. Conclusion: The acute after-effects of ecstasy should be excluded when assessing ecstasy withdrawal as they can lead to a false diagnosis of ecstasy dependence. Worsening of the ecstasy come-down may be a marker for dependence.

The influence of injury cause, contact-sport participation, and personal knowledge on expectation of outcome from mild traumatic brain injury

Objective: This study investigated the influence of injury cause, contact-sport participation, and prior knowledge of mild traumatic brain injury (mTBI) on injury beliefs and chronic symptom expectations of mTBI. Method: A total of 185 non-contact-sport players (non-CSPs) and 59 contact-sport players (CSPs) with no history of mTBI were randomly allocated to one of two conditions in which they read either a vignette depicting a sport-related mTBI (mTBIsport) or a motor-vehicle-accident-related mTBI (mTBIMVA). The vignettes were otherwise standardized to convey the same injury parameters (e.g., duration of loss of consciousness). After reading a vignette, participants reported their injury beliefs (i.e., perceptions of injury undesirability, chronicity, and consequences) and their expectations of chronic postconcussion syndrome (PCS) and posttraumatic stress disorder (PTSD) symptoms. Results: Non-CSPs held significantly more negative beliefs and expected greater PTSD symptomatology and greater PCS affective symptomatology from an mTBIMVA vignette thann mTBIsport vignette, but this difference was not found for CSPs. Unlike CSPs, non-CSPs who personally knew someone who had sustained an mTBI expected significantly less PCS symptomatology than those who did not. Despite these different results for non-CSPs and CSPs, overall, contact-sport participation did not significantly affect injury beliefs and symptom expectations from an mTBIsport. Conclusions: Expectations of persistent problems after an mTBI are influenced by factors such as injury cause even when injury parameters are held constant. Personal knowledge of mTBI, but not contact sport participation, may account for some variability in mTBI beliefs and expectations. These factors require consideration when assessing mTBI outcome.

A critical evaluation of written discharge advice for people with mild traumatic brain injury : what should we be looking for?

Objective: To formally evaluate the written discharge advice for people with mild traumatic brain injury (mTBI). Methods: Eleven publications met the inclusion criteria: (1) intended for adults; (2) ≤two A4 pages; (3) published in English; (4) freely accessible; and (5) currently used (or suitable for use) in Australian hospital emergency departments or similar settings. Two independent raters evaluated the content and style of each publication against established standards. The readability of the publication, the diagnostic term(s) contained in it and a modified Patient Literature Usefulness Index (mPLUI) were also evaluated. Results: The mean content score was 19.18 ± 8.53 (maximum = 31) and the mean style score was 6.8 ± 1.34 (maximum = 8). The mean Flesch-Kincaid reading ease score was 66.42 ± 4.3. The mean mPLUI score was 65.86 ± 14.97 (maximum = 100). Higher scores on these metrics indicate more desirable properties. Over 80% of the publications used mixed diagnostic terminology. One publication scored optimally on two of the four metrics and highly on the others. Discussion: The content, style, readability and usefulness of written mTBI discharge advice was highly variable. The provision of written information to patients with mTBI is advised, but this variability in materials highlights the need for evaluation before distribution. Areas are identified to guide the improvement of written mTBI discharge advice.

Primary and secondary neural networks of auditory prepulse inhibition: a functional magnetic resonance imaging study of sensorimotor gating of the human acoustic startle response

Feedforward inhibition deficits have been consistently demonstrated in a range of neuropsychiatric conditions using prepulse inhibition (PPI) of the acoustic startle eye-blink reflex when assessing sensorimotor gating. While PPI can be recorded in acutely decerebrated rats, behavioural, pharmacological and psychophysiological studies suggest the involvement of a complex neural network extending from brainstem nuclei to higher order cortical areas. The current functional magnetic resonance imaging study investigated the neural network underlying PPI and its association with electromyographically (EMG) recorded PPI of the acoustic startle eye-blink reflex in 16 healthy volunteers. A sparse imaging design was employed to model signal changes in blood oxygenation level-dependent (BOLD) responses to acoustic startle probes that were preceded by a prepulse at 120 ms or 480 ms stimulus onset asynchrony or without prepulse. Sensorimotor gating was EMG confirmed for the 120-ms prepulse condition, while startle responses in the 480-ms prepulse condition did not differ from startle alone. Multiple regression analysis of BOLD contrasts identified activation in pons, thalamus, caudate nuclei, left angular gyrus and bilaterally in anterior cingulate, associated with EMGrecorded sensorimotor gating. Planned contrasts confirmed increased pons activation for startle alone vs 120-ms prepulse condition, while increased anterior superior frontal gyrus activation was confirmed for the reverse contrast. Our findings are consistent with a primary pontine circuitry of sensorimotor gating that interconnects with inferior parietal, superior temporal, frontal and prefrontal cortices via thalamus and striatum. PPI processes in the prefrontal, frontal and superior temporal cortex were functionally distinct from sensorimotor gating.

Facial emotion processing in schizophrenia : no evidence for a deficit specific to negative emotions in a differential deficit design

People with schizophrenia perform poorly when recognising facial expressions of emotion, particularly negative emotions such as fear. This finding has been taken as evidence of a “negative emotion specific deficit”, putatively associated with a dysfunction in the limbic system, particularly the amygdala. An alternative explanation is that greater difficulty in recognising negative emotions may reflect a priori differences in task difficulty. The present study uses a differential deficit design to test the above argument. Facial emotion recognition accuracy for seven emotion categories was compared across three groups. Eighteen schizophrenia patients and one group of healthy age- and gender-matched controls viewed identical sets of stimuli. A second group of 18 age- and gender-matched controls viewed a degraded version of the same stimuli. The level of stimulus degradation was chosen so as to equate overall level of accuracy to the schizophrenia patients. Both the schizophrenia group and the degraded image control group showed reduced overall recognition accuracy and reduced recognition accuracy for fearful and sad facial stimuli compared with the intact-image control group. There were no differences in recognition accuracy for any emotion category between the schizophrenia group and the degraded image control group. These findings argue against a negative emotion specific deficit in schizophrenia.