Lisa E. Williams

Reduced multisensory integration in patients with schizophrenia on a target detection task

A growing body of literature demonstrates impaired multisensory integration (MSI) in patients with schizophrenia compared to non-psychiatric individuals. One of the most basic measures of MSI is intersensory facilitation of reaction times (RTs), in which bimodal targets, with cues from two sensory modalities, are detected faster than unimodal targets. This RT speeding is generally attributed to super-additive processing of multisensory targets. In order to test whether patients with schizophrenia are impaired on this basic measure of MSI, we assessed the degree of intersensory facilitation for a sample of 20 patients compared to 20 non-psychiatric individuals using a very simple target detection task. RTs were recorded for participants to detect targets that were either unimodal (auditory alone, A; visual alone, V) or bimodal (auditory+visual, AV). RT distributions to detect bimodal targets were compared with predicted RT distributions based on the summed probability distribution of each participants RTs to visual alone and auditory alone targets. Patients with schizophrenia showed less RT facilitation when detecting bimodal targets relative to non-psychiatric individuals, even when groups were matched for unimodal RTs. Within the schizophrenia group, RT benefit was correlated with negative symptoms, such that patients with greater negative symptoms showed the least RT facilitation (r(2)=0.20, p<0.05). Additionally, schizophrenia patients who experienced both auditory and visual hallucinations showed less multisensory benefit compared to patients who experienced only auditory hallucinations, indicating that the presence of hallucinations in two modalities may more strongly impair MSI compared to hallucinations in only one modality.

Electroencephalography (EEG) and Event‐Related Potentials (ERPs) with Human Participants

Understanding the basic neural processes that underlie complex higher‐order cognitive operations and functional domains is a fundamental goal of cognitive neuroscience. Electroencephalography (EEG) is a non‐invasive and relatively inexpensive method for assessing neurophysiological function that can be used to achieve this goal. EEG measures the electrical activity of large, synchronously firing populations of neurons in the brain with electrodes placed on the scalp. This unit outlines the basics of setting up an EEG experiment with human participants, including equipment, and a step‐by‐step guide to applying and preparing an electrode cap. Also included are support protocols for two event‐related potential (ERP) paradigms, P50 suppression, and mismatch negativity (MMN), which are measures of early sensory processing. These paradigms can be used to assess the integrity of early sensory processing in normal individuals and clinical populations, such as individuals with schizophrenia. Curr. Protoc. Neurosci. 52:6.25.1‐6.25.24.

Evolutionarily conserved prefrontal-amygdalar dysfunction in early-life anxiety

Some individuals are endowed with a biology that renders them more reactive to novelty and potential threat. When extreme, this anxious temperament (AT) confers elevated risk for the development of anxiety, depression and substance abuse. These disorders are highly prevalent, debilitating and can be challenging to treat. The high-risk AT phenotype is expressed similarly in children and young monkeys and mechanistic work demonstrates that the central (Ce) nucleus of the amygdala is an important substrate. Although it is widely believed that the flow of information across the structural network connecting the Ce nucleus to other brain regions underlies primates’ capacity for flexibly regulating anxiety, the functional architecture of this network has remained poorly understood. Here we used functional magnetic resonance imaging (fMRI) in anesthetized young monkeys and quietly resting children with anxiety disorders to identify an evolutionarily conserved pattern of functional connectivity relevant to early-life anxiety. Across primate species and levels of awareness, reduced functional connectivity between the dorsolateral prefrontal cortex, a region thought to play a central role in the control of cognition and emotion, and the Ce nucleus was associated with increased anxiety assessed outside the scanner. Importantly, high-resolution 18-fluorodeoxyglucose positron emission tomography imaging provided evidence that elevated Ce nucleus metabolism statistically mediates the association between prefrontal-amygdalar connectivity and elevated anxiety. These results provide new clues about the brain network underlying extreme early-life anxiety and set the stage for mechanistic work aimed at developing improved interventions for pediatric anxiety.

Reduced gray matter volume in psychotic disorder patients with a history of childhood sexual abuse.

Childhood trauma is associated with smaller gray matter volume, similar to the pattern seen in psychotic disorders. We explored the relationship between childhood abuse, psychosis, and brain volume in a group of 60 individuals with a psychotic disorder and 26 healthy control subjects. We used voxel-based morphometry (VBM) to quantify gray and white matter volume and the Childhood Trauma Questionnaire (CTQ) to measure childhood abuse. Within the psychotic disorder group, total gray matter volume was inversely correlated with the severity of childhood sexual abuse (r=-.34, p=.008), but not the other types of abuse. When the 24 patients with sexual abuse were compared with demographically matched samples of 23 patients without sexual abuse and 26 control subjects, only patients with a history of sexual abuse had reduced total gray matter volume (t(48)=2.3, p=.03; Cohens d=.63). Voxel-based analysis revealed a cluster in the prefrontal cortex where volume was negatively correlated with sexual abuse severity. Voxel based comparison of the three matched groups revealed a similar pattern of results, with widespread reductions in psychosis patients with sexual abuse relative to controls that were not found in psychosis patients without sexual abuse. These findings indicate that some of the variance of gray matter volume in psychotic disorders can be explained by a history of sexual abuse.

Rapid Relief of Thalamic Pain Syndrome Induced by Vestibular Caloric Stimulation

Central post-stroke pain syndrome develops in a minority of patients following a stroke. The most usual causative lesion involves the lateral thalamus. The classic presentation is of severe, unrelenting pain that involves the entire contralateral half of the body. It is largely refractory to current treatments. We found that in two patients with this condition their pain was substantially improved by vestibular caloric stimulation, whereas placebo procedures had no effect. We proposed that this is because vestibular stimulation activates the posterior insula, which in turn inhibits the generation of pain in the anterior cingulate.

Behavioural evidence for vestibular stimulation as a treatment for central post-stroke pain

Background: Central post-stroke pain (CPSP) is often resistant to treatment. We have previously proposed that caloric vestibular stimulation might alleviate it. Methods: We conducted a single blind placebo controlled investigational study of caloric vestibular stimulation (CVS) in nine patients with CPSP. Participants rated their pain levels before and after the procedure on a 10 point scale. Results: We found a significant immediate treatment effect of the cold water caloric stimulation with an average pain reduction of 2.58 points (SEM 0.52) for the experimental condition compared with 0.54 points (SEM 0.49) for the placebo conditions. Conclusions: Participants who responded best to CVS had suffered strokes that spared and permitted activation of the dominant parieto-insular vestibular cortex (PIVC), which is known to be located in the non-dominant hemisphere. These findings tie in closely with the thermosensory disinhibition hypothesis for central pain, which leads us to propose that vestibular stimulation may alleviate CPSP from cross activation between the PIVC and the thermosensory cortex in the adjacent dorsal posterior insula. Alternatively, if one views vestibular function and thermoregulation as part of a larger interoceptive system that exists to maintain homeostasis, then it is possible they share a common integrative mechanism in the brainstem, which may act to reset the balance in central pain.

Eye-Movement Behavior Reveals Relational Memory Impairment in Schizophrenia

BACKGROUND Previous studies have demonstrated impaired relational memory in schizophrenia. We studied eye-movement behavior as an indirect measure of relational memory, together with forced-choice recognition as an explicit measure. METHODS Thirty-five patients with schizophrenia and 35 healthy participants were trained to associate a face with a background scene. During testing, scenes were presented as a cue and then overlaid with three previously studied faces. Participants were asked to recall the matching face, and both eye movements and forced-choice recognition were recorded. During Non-Match trials, no faces matched the scene. During Match trials, one of the faces had previously been paired with the scene. RESULTS On Non-Match trials, when no relational memory trace was present, both groups viewed the three faces equally. In contrast, on Match trials, control participants quickly (within 500 msec) and consistently (70%-75% of test trial viewing) showed preferential viewing of the matching face. Viewing of the matching face was significantly delayed and reduced in schizophrenia participants. Forced-choice recognition of the matching face was also impaired in the patient group. An analysis of all correct Match trials revealed that preferential viewing was significantly reduced and delayed in participants with schizophrenia. CONCLUSIONS This study provides novel evidence for a specific relational memory impairment in schizophrenia. Patients showed deficits in their forced-choice recognition responses, as well as abnormal eye-movement patterns during memory recall, even on trials when behavioral responses were accurate. We propose that eye movements provide a promising new avenue for studying relational memory in schizophrenia.

Childhood sexual abuse increases risk of auditory hallucinations in psychotic disorders

BACKGROUND/AIMS Previous studies point to an association between childhood sexual abuse (CSA) and auditory hallucinations (AH). However, methodological issues limit the strength of these results. Here we compared childhood abuse between psychotic disorder patients and healthy control subjects using a reliable measure of abuse, and assessed the relationship between CSA and AH. METHODS 114 psychotic disorder patients and 81 healthy control subjects were administered the Structured Clinical Interview of the DSM-IV (SCID) and the Childhood Trauma Questionnaire (CTQ). We compared the severity of abuse between groups, and tested the relationship between different types of childhood abuse and specific psychotic symptoms. RESULTS Psychotic patients reported more childhood abuse than controls (p<.001). Psychotic patients with a history of AH reported significantly more sexual, emotional, and physical abuse than patients without a history of AH (p<.05). Emotional and physical abuse, in the absence of sexual abuse, did not lead to a higher rate of AH. Finally, reports of childhood abuse did not increase the risk of any form of hallucination other than AH or of any form of delusion. CONCLUSIONS These results suggest that childhood abuse, especially childhood sexual abuse, shapes the phenotype of psychotic disorders by conferring a specific risk for AH.

Fear of the Unknown: Uncertain Anticipation Reveals Amygdala Alterations in Childhood Anxiety Disorders

Children with anxiety disorders (ADs) experience persistent fear and worries that are highly debilitating, conferring risk for lifelong psychopathology. Anticipatory anxiety is a core clinical feature of childhood ADs, often leading to avoidance of uncertain and novel situations. Extensive studies in non-human animals implicate amygdala dysfunction as a critical substrate for early life anxiety. To test specific amygdala-focused hypotheses in preadolescent children with ADs, we used fMRI to characterize amygdala activation during uncertain anticipation and in response to unexpected stimuli. Forty preadolescent (age 8–12 years) children, 20 unmedicated AD patients and 20 matched controls completed an anticipation task during an fMRI scan. In the task, symbolic cues preceded fear or neutral faces, such that ‘certain’ cues always predicted the presentation of fear or neutral faces, whereas ‘uncertain’ cues were equally likely to be followed by fear or neutral faces. Both AD children and controls showed robust amygdala response to faces. In response to the uncertain cues, AD children had increased amygdala activation relative to controls. Moreover, in the AD children, faces preceded by an ‘uncertain’ cue elicited increased amygdala activation, as compared with the same faces following a ‘certain’ cue. Children with ADs experience distress both in anticipation of and during novel and surprising events. Our findings suggest that increased amygdala activation may have an important role in the generation of uncertainty-related anxiety. These findings may guide the development of neuroscientifically informed treatments aimed at relieving the suffering and preventing the lifelong disability associated with pediatric ADs.

Reduced habituation in patients with schizophrenia

BACKGROUND Neural habituation, the decrease in brain response to repeated stimulation, is a basic form of learning. There is strong evidence for behavioral and physiological habituation deficits in schizophrenia, and one previous study found reduced neural habituation within the hippocampus. However, it is unknown whether neural habituation deficits are specific to faces and limited to the hippocampus. Here we studied habituation of several brain regions in schizophrenia, using both face and object stimuli. Post-scan memory measures were administered to test for a link between hippocampal habituation and memory performance. METHODS During an fMRI scan, 23 patients with schizophrenia and 21 control subjects viewed blocks of a repeated neutral face or neutral object, and blocks of different neutral faces and neutral objects. Habituation in the hippocampus, primary visual cortex and fusiform face area (FFA) was compared between groups. Memory for faces, words, and word pairs was assessed after the scan. RESULTS Patients showed reduced habituation to faces in the hippocampus and primary visual cortex, but not the FFA. Healthy control subjects exhibited a pattern of hippocampal discrimination that distinguished between repeated and different images for both faces and objects, and schizophrenia patients did not. Hippocampal discrimination was positively correlated with memory for word pairs. CONCLUSION Patients with schizophrenia showed reduced habituation of the hippocampus and visual cortex, and a lack of neural discrimination between old and new images in the hippocampus. Hippocampal discrimination correlated with memory performance, suggesting reduced habituation may contribute to the memory deficits commonly observed in schizophrenia.