Contrasting Frontoparietal Network Connectivity in Antipsychotic Medication-Naive First-Episode Psychosis Patients Who Do and Do Not Display Features of the Deficit Syndrome.

BACKGROUND: The deficit syndrome is a clinical subtype of schizophrenia that is characterized by enduring negative symptoms. Several lines of evidence point to frontoparietal involvement, but the frontoparietal control network (FPCN) and its subsystems (FPCNA and FPCNB) proposed by Yeo et al. have not been systematically characterized at rest in patients with the deficit syndrome. METHODS: We used resting-state fMRI to investigate the FPCN and its subnetworks in 72 healthy controls and 65 antipsychotic medication-naive, first-episode psychosis patients (22 displayed deficit syndrome features, 43 did not). To assess whole-brain FPCN connectivity, we used the right posterior parietal cortex as the seed region. We then performed region of interest analyses in FPCN subsystems. RESULTS: We found that patterns of FPCN dysconnectivity to the whole brain differed in patients who displayed deficit syndrome features compared with those who did not. Examining the FPCN on a more granular level revealed reduced within-FPCN(A) connectivity only in patients displaying deficit features. FPCNB connectivity did not differ between patient groups. DISCUSSION: Here, we describe a neurobiological signature of aberrant FPCN connectivity in antipsychotic-naive, first-episode patients who display clinical features of the deficit syndrome. Importantly, frontoparietal subnetwork connectivity differentiated subgroups, where the FPCNA is selectively involved in patients with deficit features. Our findings add to the growing body of literature supporting a neurobiological distinction between two clinical subtypes of schizophrenia, which has the potential to be leveraged for patient stratification in clinical trials and the development of novel treatments.

Hippocampal Dysconnectivity and Altered Glutamatergic Modulation of the Default Mode Network: A Combined Resting-State Connectivity and Magnetic Resonance Spectroscopy Study in Schizophrenia.

BACKGROUND: Converging lines of evidence point to hippocampal dysfunction in schizophrenia. It is thought that hippocampal dysfunction spreads across hippocampal subfields and to cortical regions by way of long-range efferent projections. Importantly, abnormalities in the excitation/inhibition balance could impair the long-range modulation of neural networks. The goal of this project was twofold. First, we sought to identify replicable patterns of hippocampal dysconnectivity in patients with a psychosis spectrum disorder. Second, we aimed to investigate a putative link between glutamatergic metabolism and hippocampal connectivity alterations. METHODS: We evaluated resting-state hippocampal functional connectivity alterations in two cohorts of patients with a psychosis spectrum disorder. The first cohort consisted of 55 medication-naïve patients with first-episode psychosis and 41 matched healthy control subjects, and the second cohort consisted of 42 unmedicated patients with schizophrenia and 41 matched control subjects. We also acquired measurements of glutamate + glutamine in the left hippocampus using magnetic resonance spectroscopy for 42 patients with first-episode psychosis and 37 healthy control subjects from our first cohort. RESULTS: We observed a pattern of hippocampal functional hypoconnectivity to regions of the default mode network and hyperconnectivity to the lateral occipital cortex in both cohorts. We also show that in healthy control subjects, greater hippocampal glutamate + glutamine levels predicted greater hippocampal functional connectivity to the anterior default mode network. Furthermore, this relationship was reversed in medication-naïve subjects with first-episode psychosis. CONCLUSIONS: These results suggest that an alteration in the relationship between glutamate and functional connectivity may disrupt the dynamic of major neural networks.

White matter and neurite morphology differ in psychogenic nonepileptic seizures.

OBJECTIVE: To further evaluate the relationship between the clinical profiles and limbic and motor brain regions and their connecting pathways in psychogenic nonepileptic seizures (PNES). Neurite Orientation Dispersion and Density Indices (NODDI) multicompartment modeling was used to test the relationships between tissue alterations in patients with traumatic brain injury (TBI) and multiple psychiatric symptoms. METHODS: The sample included participants with prior TBI (TBI; N = 37) but no PNES, and with TBI and PNES (TBI + PNES; N = 34). Participants completed 3T Siemens Prisma MRI high angular resolution imaging diffusion protocol. Statistical maps, including fractional anisotropy (FA), mean diffusivity (MD), neurite dispersion [orientation dispersion index (ODI)] and density [intracellular volume fraction (ICVF), and free water (i.e., isotropic) volume fraction (V-ISO)] signal intensity, were generated for each participant. Linear mixed-effects models identified clusters of between-group differences in indices of white matter changes. Pearson's r correlation tests assessed any relationship between signal intensity and psychiatric symptoms. RESULTS: Compared to TBI, TBI + PNES revealed decreases in FA, ICVF, and V-ISO and increases in MD for clusters within cingulum bundle, uncinate fasciculus, fornix/stria terminalis, and corticospinal tract pathways (cluster threshold α = 0.05). Indices of white matter changes for these clusters correlated with depressive, anxiety, PTSD, psychoticism, and somatization symptom severity (FDR threshold α = 0.05). A follow-up within-group analysis revealed that these correlations failed to reach the criteria for significance in the TBI + PNES group alone. INTERPRETATION: The results expand support for the hypothesis that alterations in pathways comprising the specific PNES network correspond to patient profiles. These findings implicate myelin-specific changes as possible contributors to PNES, thus introducing novel potential treatment targets.

Racial differences in adult-onset MRI-negative temporal lobe epilepsy.

OBJECTIVE: We recently detected a significant racial difference in our population with temporal lobe epilepsy (TLE) at the University of Alabama at Birmingham (UAB) seizure monitoring unit. We found that Black patients were more likely than their White counterparts to carry a TLE diagnosis. Using this same patient population, we focus on the patients with TLE to better describe the relationship between race and epidemiology in this population. METHODS: We analyzed the data from patients diagnosed with TLE admitted to the UAB seizure monitoring unit between January 2000 and December 2011. For patients with a video electroencephalography (EEG) confirmed diagnosis of TLE (n = 385), basic demographic information including race and magnetic resonance imaging (MRI) findings were collected. Descriptive statistics and multivariate logistic regression were used to explore the relationship between MRI findings, demographic data, and race. RESULTS: For Black patients with TLE, we found that they were more likely to be female (odds ratio [OR] = 1.91, 95% confidence interval [CI]: 1.14-3.19), have seizure onset in adulthood (OR = 2.39, 95% CI: 1.43-3.19), and have normal MRIs (OR = 1.69, 95% CI: 1.04-2.77) compared to White counterparts with TLE after adjusting for covariates. CONCLUSIONS: These data suggest that Black race (compared to White) is associated with higher expression of adult-onset MRI-negative TLE, an important subtype of epilepsy with unique implications for evaluation, treatment, and prognosis. If validated in other cohorts, the findings may explain the lower reported rates of epilepsy surgery utilization among Blacks. The racial differences in surgical utilization could be due to a greater prevalence of an epilepsy that is less amenable to surgical resection rather than to cultural differences or access to care.

Cannabidiol improves frequency and severity of seizures and reduces adverse events in an open-label add-on prospective study.

The objective of this study was to characterize the changes in adverse events, seizure severity, and frequency in response to a pharmaceutical formulation of highly purified cannabidiol (CBD; Epidiolex®) in a large, prospective, single-center, open-label study. We initiated CBD in 72 children and 60 adults with treatment-resistant epilepsy (TRE) at 5 mg/kg/day and titrated it up to a maximum dosage of 50 mg/kg/day. At each visit, we monitored treatment adverse events with the adverse events profile (AEP), seizure severity using the Chalfont Seizure Severity Scale (CSSS), and seizure frequency (SF) using seizure calendars. We analyzed data for the enrollment and visits at 12, 24, and 48 weeks. We recorded AEP, CSSS, and SF at each follow-up visit for the weeks preceding the visit (seizures were averaged over 2-week periods). Of the 139 study participants in this ongoing study, at the time of analysis, 132 had 12-week, 88 had 24-week, and 61 had 48-week data. Study retention was 77% at one year. There were no significant differences between participants who contributed all 4 data points and those who contributed 2 or 3 data points in baseline demographic and AEP/SF/CSSS measures. For all participants, AEP decreased between CBD initiation and the 12-week visit (40.8 vs. 33.2; p < 0.0001) with stable AEP scores thereafter (all p ≥ 0.14). Chalfont Seizure Severity Scale scores were 80.7 at baseline, decreasing to 39.2 at 12 weeks (p < 0.0001) and stable CSSS thereafter (all p ≥ 0.19). Bi-weekly SF decreased from a mean of 144.4 at entry to 52.2 at 12 weeks (p = 0.01) and remained stable thereafter (all p ≥ 0.65). Analyses of the pediatric and adult subgroups revealed similar patterns. Most patients were treated with dosages of CBD between 20 and 30 mg/kg/day. For the first time, this prospective, open-label safety study of CBD in TRE provides evidence for significant improvements in AEP, CSSS, and SF at 12 weeks that are sustained over the 48-week duration of treatment.

Racial disparities in temporal lobe epilepsy.

OBJECTIVE: This study reports on epilepsy type period prevalence and black-white racial differences in a large patient population in the Southeastern United States. METHODS: For all patients visiting the University of Alabama at Birmingham's seizure monitoring unit between 2000 and 2011 (n = 3240), video EEG diagnosis was recorded along with basic demographic information. Descriptive statistics and multivariate logistic regression were used to identify factors associated with temporal lobe epilepsy (TLE) diagnosis. RESULTS: The racial distribution was 77.3% white, and 20.0% black (other races were only 2.3% of the population). Most patients had either TLE (n = 630) or PNES (n = 1150) compared to other focal (n = 424) or generalized epilepsies (n = 224). The diagnosis of TLE was significantly greater for blacks than whites (odds ratio [OR] = 1.87, 95% confidence interval [CI] 1.47-2.37). The period prevalence measures for the other conclusively diagnosed epilepsies were not significantly different. Women were disproportionately represented in the study population, and black women carried the most statistical weight for the TLE prevalence difference. INTERPRETATION: The nearly two-fold larger period prevalence of TLE among black patients is a striking finding that merits explanation. Although some selection bias exists due to a moderately lower than expected representation of blacks, socioeconomic status or access to care should not be assumed to be the only factors that might be responsible for the prevalence difference. Rather, all clues for distinct pathophysiological racial differences should be explored.

White Matter Abnormalities in Patients with Treatment-Resistant Genetic Generalized Epilepsies.

BACKGROUND Genetic generalized epilepsies (GGEs) are associated with microstructural brain abnormalities that can be evaluated with diffusion tensor imaging (DTI). Available studies on GGEs have conflicting results. Our primary goal was to compare the white matter structure in a cohort of patients with video/EEG-confirmed GGEs to healthy controls (HCs). Our secondary goal was to assess the potential effect of age at GGE onset on the white matter structure. MATERIAL AND METHODS A convenience sample of 23 patients with well-characterized treatment-resistant GGEs (13 female) was compared to 23 HCs. All participants received MRI at 3T. DTI indices, including fractional anisotropy (FA) and mean diffusivity (MD), were compared between groups using Tract-Based Spatial Statistics (TBSS). RESULTS After controlling for differences between groups, abnormalities in DTI parameters were observed in patients with GGEs, including decreases in functional anisotropy (FA) in the hemispheric (left>right) and brain stem white matter. The examination of the effect of age at GGE onset on the white matter integrity revealed a significant negative correlation in the left parietal white matter region FA (R=-0.504; p=0.017); similar trends were observed in the white matter underlying left motor cortex (R=-0.357; p=0.103) and left posterior limb of the internal capsule (R=-0.319; p=0.148). CONCLUSIONS Our study confirms the presence of widespread white matter abnormalities in patients with GGEs and provides evidence that the age at GGE onset may have an important effect on white matter integrity.

Statistical modeling of ICEEG features that determine resection planning.

OBJECT: The interpretation of intracranial EEG (ICEEG) recordings is a complex balance of the significance of specific rhythms and their relative timing to seizure onset. Ictal and interictal findings are evaluated in light of findings from cortical stimulation of eloquent cortex to determine the area of resection. PATIENTS AND METHODS: Patients with ICEEG electrodes and subsequent surgical resection were retrospectively identified. Only the first 15s of ictal activity, which was divided into five 3-s epochs, was considered. Every electrode in each patient was considered a separate observation in a logistic regression model to predict whether the cortex under a given electrode was included in the planned resection. RESULTS: 19 included patients had a total of 37 unique seizures. Recordings from a total of 1306 electrodes were analyzed. The strongest predictors of resection of cortex underlying a given electrode was the presence of low-voltage fast activity in Epoch 1, rhythmic spikes in Epoch 1, interictal paroxysmal fast activity, and low-voltage fast activity in Epoch 2. High-amplitude beta spikes and rhythmic slow waves were also significant predictors in Epoch 1. Interictal spikes had a higher odds ratio of affecting the planned resection if described as "continuous" or "very frequent". The presence of motor or language cortex were the strongest negative predictors of resecting underlying cortex. CONCLUSIONS: Here we describe a novel model of ictal and interictal patterns significantly associated with the inclusion of cortex underlying a given ICEEG electrode in the surgical resection plan.

Cortical thickness in human V1 associated with central vision loss.

Better understanding of the extent and scope of visual cortex plasticity following central vision loss is essential both for clarifying the mechanisms of brain plasticity and for future development of interventions to retain or restore visual function. This study investigated structural differences in primary visual cortex between normally-sighted controls and participants with central vision loss due to macular degeneration (MD). Ten participants with MD and ten age-, gender-, and education-matched controls with normal vision were included. The thickness of primary visual cortex was assessed using T1-weighted anatomical scans, and central and peripheral cortical regions were carefully compared between well-characterized participants with MD and controls. Results suggest that, compared to controls, participants with MD had significantly thinner cortex in typically centrally-responsive primary visual cortex - the region of cortex that normally receives visual input from the damaged area of the retina. Conversely, peripherally-responsive primary visual cortex demonstrated significantly increased cortical thickness relative to controls. These results suggest that central vision loss may give rise to cortical thinning, while in the same group of people, compensatory recruitment of spared peripheral vision may give rise to cortical thickening. This work furthers our understanding of neural plasticity in the context of adult vision loss.

Controllability modulates the neural response to predictable but not unpredictable threat in humans.

Stress resilience is mediated, in part, by our ability to predict and control threats within our environment. Therefore, determining the neural mechanisms that regulate the emotional response to predictable and controllable threats may provide important new insight into the processes that mediate resilience to emotional dysfunction and guide the future development of interventions for anxiety disorders. To better understand the effect of predictability and controllability on threat-related brain activity in humans, two groups of healthy volunteers participated in a yoked Pavlovian fear conditioning study during functional magnetic resonance imaging (fMRI). Threat predictability was manipulated by presenting an aversive unconditioned stimulus (UCS) that was either preceded by a conditioned stimulus (i.e., predictable) or by presenting the UCS alone (i.e., unpredictable). Similar to animal model research that has employed yoked fear conditioning procedures, one group (controllable condition; CC), but not the other group (uncontrollable condition; UC) was able to terminate the UCS. The fMRI signal response within the dorsolateral prefrontal cortex (PFC), dorsomedial PFC, ventromedial PFC, and posterior cingulate was diminished during predictable compared to unpredictable threat (i.e., UCS). In addition, threat-related activity within the ventromedial PFC and bilateral hippocampus was diminished only to threats that were both predictable and controllable. These findings provide insight into how threat predictability and controllability affects the activity of brain regions (i.e., ventromedial PFC and hippocampus) involved in emotion regulation, and may have important implications for better understanding neural processes that mediate emotional resilience to stress.

White matter diffusion abnormalities in patients with psychogenic non-epileptic seizures.

The purpose of this study was to conduct a preliminary investigation of the white matter characteristics in patients with psychogenic non-epileptic seizures (PNES). Diffusion Tensor Imaging (DTI) data were collected at 3T in 16 patients with PNES and 16 age- and sex-matched healthy controls (HC). All patients with PNES had their diagnosis confirmed via video/EEG monitoring; HCs had no comorbid neurological or psychiatric conditions. DTI indices including fractional anisotropy (FA), and mean diffusivity (MD) were calculated and compared between patients with PNES and HCs using Tract-Based Spatial Statistics (TBSS). Significantly higher FA values were observed in patients with PNES in the left corona radiata, left internal and external capsules, left superior temporal gyrus, as well as left uncinate fasciculus (UF) (P<0.05; corrected for multiple comparisons). There was no significant change in other indices between patients with PNES and HCs. These findings suggest that patients with PNES have significantly altered white matter structural connectivity when compared to age- and sex-matched HCs. These abnormalities are present in left hemispheric regions associated with emotion regulation and motor pathways. While the relationship between the pathophysiology of PNES and these abnormalities is not entirely clear, this work provides an initial basis to guide future prospective studies.

Uncinate fasciculus connectivity in patients with psychogenic nonepileptic seizures: A preliminary diffusion tensor tractography study.

The amygdala, hippocampus, and medial prefrontal cortex are limbic brain regions connected by the uncinate fasciculus (UF) and implicated in emotion regulation. The aim of this study was to assess the connectivity characteristics of the UF in patients with psychogenic nonepileptic seizures (PNES) and matched healthy controls. We hypothesized that white matter connectivity of the UF in patients with PNES would differ from that in healthy controls. Eight patients with PNES and eight age- and sex-matched healthy controls underwent 3T MRI and 32-direction diffusion tensor imaging (DTI). Computation of DTI indices including fractional anisotropy (FA) and diffusion tensor tractography was performed. Two regions of interest were defined to manually trace the UF in each hemisphere for each subject. Fractional anisotropy and the number of reconstructed streamlines for the left and right hemispheres of the UF and the degree of asymmetry for each measure were compared between groups. Correlations between UF measures and clinical variables were also performed. Patients with PNES exhibited a significantly greater number of UF streamlines in the right hemisphere tract than in the left hemisphere (p=0.031), with such difference not observed in controls (p=0.81). This was reflected in a significant group difference in the asymmetry index (AI) for the number of streamlines, with more rightward asymmetry in patients with PNES (p=0.021). Average FA of the UF was similar between groups and between hemispheres for each group (all p>0.05). Age at illness onset was correlated with the AI for FA (r=-0.87; p=0.0045). Previously observed differences in emotion processing between controls and patients with PNES may be related to the differences in the rightward asymmetry in the number of UF streamlines in patients with PNES. Age at PNES onset appears to also have a role in the FA asymmetry of the UF. This is the first study to investigate the structural connectivity in these regions involved in emotional regulation in patients with PNES; further research is necessary to clarify the complex relationships between clinical measures and DTI characteristics.

The amygdala mediates the emotional modulation of threat-elicited skin conductance response.

The ability to respond adaptively to threats in a changing environment is an important emotional function. The amygdala is a critical component of the neural circuit that mediates many emotion-related processes, and thus likely plays an important role in modulating the peripheral emotional response to threat. However, prior research has largely focused on the amygdala's response to stimuli that signal impending threat, giving less attention to the amygdala's response to the threat itself. From a functional perspective, however, it is the response to the threat itself that is most biologically relevant. Thus, understanding the factors that influence the amygdala's response to threat is critical for a complete understanding of adaptive emotional processes. Therefore, we used functional MRI to investigate factors (i.e., valence and arousal of co-occurring visual stimuli) that influence the amygdala's response to threat (loud white noise). We also assessed whether changes in amygdala activity varied with the peripheral expression of emotion (indexed via skin conductance response; SCR). The results showed that threat-elicited amygdala activation varied with the arousal, not valence, of emotional images. More specifically, threat-elicited amygdala activation was larger to the threat when presented during high-arousal (i.e., negative and positive) versus low-arousal (i.e., neutral) images. Further, the threat-elicited amygdala response was positively correlated with threat-elicited SCR. These findings indicate the amygdala's response to threat is modified by the nature (e.g., arousal) of other stimuli in the environment. In turn, the amygdala appears to mediate important aspects of the peripheral emotional response to threat.

Predictive value of hippocampal internal architecture asymmetry in temporal lobe epilepsy.

BACKGROUND: Asymmetry of hippocampal internal architecture (HIA) clarity has been suggested to be a sign of hippocampal sclerosis (HS) and is frequently associated with other MRI findings of HS. The goal of this work is to use a previously developed HIA visual scoring system (Ver Hoef et al., 2013) to quantify HIA asymmetry in a retrospective series of consecutive temporal lobe epilepsy (TLE) patients and evaluate its value in predicting laterality of seizure onset both in patients with other signs of HS (HS+) and those without (HS-). METHODS: The HIA scoring system was used to rate hippocampal asymmetry and to assess the agreement between HIA and seizure lateralization. The median values of the average HIA scores for each hippocampus were compared for HS+ epileptogenic hippocampi, HS- epileptogenic hippocampi, and non-epileptogenic hippocampi with a Kruskal-Wallis one-way analysis of variance by ranks. Pair-wise differences between groups were evaluated with the two-tailed Mann-Whitney U test. A logistic regression model examined the utility of average HIA asymmetry score in predicting the true laterality of seizure onset as determined by video-EEG. Sensitivity and specificity are calculated using various asymmetry thresholds in each patient group. RESULTS: Fifty-five patients were identified who met inclusion criteria. Thirteen patients (24%) were found to have hippocampal atrophy and/or signal abnormality indicative of HS (HS+) and 42 did not (HS-). Significant differences were observed in the distribution of individual and average HIA scores between each of the groups of hippocampi, with HS+ hippocampi having the lowest HIA scores and non-epileptogenic hippocampi having the highest. Logistic regression analysis showed that the average HIA asymmetry score was a strong predictor of the laterality of seizure onset (ß=3.93508, p<0.001). HIA asymmetry remained significant even after adjustment for HS+/HS- status (ß=3.8854, p<0.001). Among HS- patients, when the average HIA asymmetry score was equal to or exceeded a threshold value of 0.5, the specificity for correctly predicting the side of seizure onset was between 95% and 100% with a sensitivity of 40-45%. Among HS+ patients, a threshold of 0.3 yielded a sensitivity of 85% and specificity of 100%. CONCLUSIONS: In this report we show for the first time that HIA asymmetry is a significant predictor of the laterality of seizure onset in TLE patients with otherwise normal MRI findings, and that the proposed HIA scoring system has high specificity and moderate sensitivity for lateralizing seizure onset in patients with TLE.

Evaluating hippocampal internal architecture on MRI: inter-rater reliability of a proposed scoring system.

BACKGROUND: Asymmetry of hippocampal internal architecture (HIA) has been reported to be a frequent imaging finding in epilepsy patients with temporal lobe epilepsy (TLE) who exhibit other signs of hippocampal sclerosis. HIA asymmetry may also be an independent predictor of the side of seizure onset in patients with otherwise normal MRI scans. The study of HIA asymmetry and its relationship to the laterality of TLE would benefit from a reliable method of assessing the clarity of HIA in MRI scans. We propose a visual scoring system that rates HIA clarity from 1 (imperceptible) to 4 (excellent) and report the inter-rater reliability (IRR) of this system. METHODS: In the initial preliminary phase of this study we examined IRR using a kappa statistic (κ) among a mixed group of expert and non-expert reviewers using only a brief description of the scoring system to score single images from a series of patients. In the second phase we explored the effect of training on the use of our HIA scoring system by assessing IRR among neuroimaging experts before and after a brief interactive training session. In this phase, multiple slices from each patient were scored. Separate κ values and intraclass correlation coefficients (ICC) were calculated from the scores given to each hippocampal image and from the asymmetry of scores between left and right for each slice. In the third phase the effect of training on non-expert reviewers was explored using a similar approach as with the expert reviewers. RESULTS: In the preliminary phase of the study, HIA scoring of single images showed substantial agreement among expert reviewers (κHIA=0.65), fair agreement among non-expert reviewers (κHIA=0.27), and a fair to moderate degree of agreement among all the reviewers as a whole (κHIA=0.40). In the second phase, prior to training there was substantial agreement among expert reviewers in regard to the individual HIA scores (κHIA=0.62; ICCHIA=0.81) but only moderate agreement on the degree of asymmetry (κAsym=0.47; ICCAsym=0.71). Training improved agreement on the individual HIA scores (κHIA=0.58-0.72; ICCHIA=0.76-0.84) and on the degree of asymmetry (κAsym=0.61-0.67; ICCAsym=0.81-0.85). Among non-expert reviewers, scores improved from only a fair degree of agreement pre-training (κHIA=0.25, κAsym=0.25; ICCHIA=0.68, ICCAsym=0.66) to a moderate level of agreement after training (κHIA=0.54, κAsym=0.52; ICCHIA=0.78, ICCAsym=0.81). CONCLUSIONS: The proposed HIA scoring system has a substantial degree of inter-rater reliability among experienced neuroimaging reviewers. Training improves the detection of asymmetries in HIA score in particular. Non-expert reviewers can employ the system with a moderate degree of reliability, and training has an even greater impact on the improvement of scoring reliability.

Human trace fear conditioning: right-lateralized cortical activity supports trace-interval processes.

Pavlovian conditioning requires the convergence and simultaneous activation of neural circuitry that supports conditioned stimulus (CS) and unconditioned stimulus (US) processes. However, in trace conditioning, the CS and US are separated by a period of time called the trace interval, and thus do not overlap. Therefore, determining brain regions that support associative learning by maintaining a CS representation during the trace interval is an important issue for conditioning research. Prior functional magnetic resonance imaging (fMRI) research has identified brain regions that support trace-conditioning processes. However, relatively little is known about whether this activity is specific to the trace CS, the trace interval, or both periods of time. The present study was designed to disentangle the hemodynamic response produced by the trace CS from that associated with the trace interval, in order to identify learning-related activation during these distinct components of a trace-conditioning trial. Trace-conditioned activity was observed within dorsomedial prefrontal cortex (PFC), dorsolateral PFC, insula, inferior parietal lobule (IPL), and posterior cingulate (PCC). Each of these regions showed learning-related activity during the trace CS, while trace-interval activity was only observed within a subset of these areas (i.e., dorsomedial PFC, PCC, right dorsolateral PFC, right IPL, right superior/middle temporal gyrus, and bilateral insula). Trace-interval activity was greater in right than in left dorsolateral PFC, IPL, and superior/middle temporal gyrus. These findings indicate that components of the prefrontal, cingulate, insular, and parietal cortices support trace-interval processes, as well as suggesting that a right-lateralized fronto-parietal circuit may play a unique role in trace conditioning.

Neural substrates underlying learning-related changes of the unconditioned fear response.

The ability to predict an impending threat during Pavlovian conditioning diminishes the emotional response that is produced once the threat is encountered. Diminution of the threat response appears to be mediated by somewhat independent associative learning and expectancy-related processes. Therefore, the present study was designed to better understand the neural mechanisms that support associative learning processes, independent of expectancy, that influence the emotional response to a threat. Healthy volunteers took part in a Pavlovian conditioning procedure during which trait anxiety, expectation of the unconditioned stimulus (UCS), skin conductance response (SCR), and functional magnetic resonance imaging (fMRI) signal were assessed. The results showed no evidence for associative learning that was independent of expectation. Threat-related SCR expression was diminished on predictable trials vs. unpredictable trials of the UCS (i.e. conditioned UCR diminution). Similar to SCR, conditioned UCR diminution was observed within the left dorsolateral PFC, dorsomedial PFC, ventromedial PFC, and left anterior insula. In contrast, potentiation of the threat-related fMRI signal response was observed within left dorsolateral PFC, inferior parietal lobule (IPL), and posterior insula. A negative relationship was observed between UCS expectancy and UCR expression within the dorsomedial PFC, ventromedial PFC, and anterior insula. Finally, the anticipatory fMRI signal responses within the PFC, posterior cingulate, and amygdala showed an inverse relationship with threat-related activation within the brain regions that showed UCR diminution. The current findings suggest that the PFC and amygdala support learning-related processes that impact the magnitude of the emotional response to a threat.

"How to do things with words": role of motor cortex in semantic representation of action words.

Language, believed to have originated from actions, not only functions as a medium to access other minds, but it also helps us commit actions and enriches our social life. This fMRI study investigated the semantic and neural representations of actions and mental states. We focused mainly on language semantics (comprehending sentences with action words versus those with mental state words). While in an fMRI scanner, twenty-four healthy, right-handed adult volunteers read a series of sentences with a verb depicting either a mental state (e.g., deceive, persuade) or an action (e.g., punch, kick), and answered a comprehension question that followed. Overall, this task showed brain activation in the left inferior frontal gyrus and in the left posterior superior temporal sulci. While comprehending sentences with mental state terms, participants showed greater activation in left orbitofrontal, and in left precuneus areas. On the other hand, the action sentences recruited more primary motor, left inferior parietal, bilateral occipital, right superior temporal, and right inferior frontal areas. The findings of this study underscore the role of motor and visuospatial involvement in action word representation in the human brain.

Neural mechanisms underlying the conditioned diminution of the unconditioned fear response.

Recognizing cues that predict an aversive event allows one to react more effectively under threatening conditions, and minimizes the reaction to the threat itself. This is demonstrated during Pavlovian fear conditioning when the unconditioned response (UCR) to a predictable unconditioned stimulus (UCS) is diminished compared to the UCR to an unpredictable UCS. The present study investigated the functional magnetic resonance imaging (fMRI) signal response associated with Pavlovian conditioned UCR diminution to better understand the relationship between individual differences in behavior and the neural mechanisms of the threat-related emotional response. Healthy volunteers participated in a fear conditioning study in which trait anxiety, skin conductance response (SCR), UCS expectancy, and the fMRI signal were assessed. During acquisition trials, a tone (CS+) was paired with a white noise UCS and a second tone (CS-) was presented without the UCS. Test trials consisted of the CS+ paired with the UCS, CS- paired with the UCS, and presentations of the UCS alone to assess conditioned UCR diminution. UCR diminution was observed within the dorsolateral PFC, dorsomedial PFC, cingulate cortex, inferior parietal lobule (IPL), anterior insula, and amygdala. The threat-related activity within the dorsolateral PFC, dorsomedial PFC, posterior cingulate cortex, and IPL varied with individual differences in trait anxiety. In addition, anticipatory (i.e. CS elicited) activity within the PFC showed an inverse relationship with threat-related (i.e. UCS elicited) activity within the PFC, IPL, and amygdala. Further, the emotional response (indexed via SCR) elicited by the threat was closely linked to amygdala activity. These findings are consistent with the view that the amygdala and PFC support learning-related processes that influence the emotional response evoked by a threat.

Left mesial temporal sclerosis and verbal memory: a magnetoencephalography study.

The purpose of this study is to examine the pattern of mesial temporal lobe activity in patients with left mesial temporal sclerosis (LMTS) and normal control subjects during a verbal memory task using magnetoencephalography. Six LMTS patients and seven normal control subjects performed a word recognition task while event-related neuromagnetic responses were recorded for 248 trials in each of two runs. An equivalent current dipole model was used to localize activity sources and determine if the right or left mesial temporal lobe was active. All six (100%) LMTS patients but only two (28%) normal control subjects had right mesial temporal activity (P < 0.02). Two (33%) LMTS patients and 6 (86%) normal control subjects had left mesial temporal activity (P = 0.27). No significant differences in latency or duration of activity were seen between left and right sides or between groups. Our data suggest that patients with left hippocampal dysfunction are more likely to recruit the right mesial temporal lobe during verbal memory tasks than normal control subjects. A trend toward less left mesial temporal activity in LMTS patients is seen as well. Further study is needed to determine the predictive value of this technique regarding postresection memory outcome.