Normal Comparison Participants Research Articles

Evidence of Slow Neural Processing, Developmental Differences and Sensitivity to Cannabis Effects in a Sample at Clinical High Risk for Psychosis From the NAPLS Consortium Assessed With the Human Startle Paradigm.

Biomarkers are important in the study of the prodromal period of psychosis because they can help to identify individuals at greatest risk for future psychotic illness and provide insights into disease mechanism underlying neurodevelopmental abnormalities. The biomarker abnormalities can then be targeted with treatment, with an aim toward prevention or mitigation of disease. The human startle paradigm has been used in translational studies of psychopathology including psychotic illness to assess preattentive information processing for over 50 years. In one of the largest studies to date in clinical high risk (CHR) for psychosis participants, we aimed to evaluate startle indices as biomarkers of risk along with the role of age, sex, treatment, and substance use in this population of high risk individuals.MethodsStartle response reactivity, latency, and prepulse inhibition (PPI) were assessed in 543 CHR and 218 Normal Comparison (NC) participants between the ages of 12 and 35.ResultsAt 1 year follow-up, 58 CHR participants had converted to psychosis. CHR and NC groups did not differ across any of the startle measures but those CHR participants who later converted to psychosis had significantly slower startle latency than did those who did not convert to psychosis, and this effect was driven by female CHR participants. PPI was significantly associated with age in the CHR, but not the NC, participants with the greatest positive age correlations present in those CHR participants who later converted to psychosis, consistent with a prior report. Finally, there was a significant group by cannabis use interaction due to greater PPI in cannabis users and opposite PPI group effects in users (CHR>NC) and non-users (NC>CHR).DiscussionThis is the first study to demonstrate a relationship of startle response latency to psychotic conversion in a CHR population. PPI is an important biomarker that may be sensitive to the neurodevelopmental abnormalities thought to be present in psychosis prone individuals and the effects of cannabis. The significant correlations with age in this sample as well as the finding of greater PPI in CHR cannabis users replicate findings from another large sample of CHR participants.

Ventromedial Prefrontal Cortex Is Necessary for Normal Associative Inference and Memory Integration

The ability to flexibly combine existing knowledge in response to novel circumstances is highly adaptive. However, the neural correlates of flexible associative inference are not well characterized. Laboratory tests of associative inference have measured memory for overlapping pairs of studied items (e.g., AB, BC) and for nonstudied pairs with common associates (i.e., AC). Findings from functional neuroimaging and neuropsychology suggest the ventromedial prefrontal cortex (vmPFC) may be necessary for associative inference. Here, we used a neuropsychological approach to test the necessity of vmPFC for successful memory-guided associative inference in humans using an overlapping pairs associative memory task. We predicted that individuals with focal vmPFC damage (n = 5; 3F, 2M) would show impaired inferential memory but intact non-inferential memory. Performance was compared with normal comparison participants (n = 10; 6F, 4M). Participants studied pairs of visually presented objects including overlapping pairs (AB, BC) and nonoverlapping pairs (XY). Participants later completed a three-alternative forced-choice recognition task for studied pairs (AB, BC, XY) and inference pairs (AC). As predicted, the vmPFC group had intact memory for studied pairs but significantly impaired memory for inferential pairs. These results are consistent with the perspective that the vmPFC is necessary for memory-guided associative inference, indicating that the vmPFC is critical for adaptive abilities that require application of existing knowledge to novel circumstances. Additionally, vmPFC damage was associated with unexpectedly reduced memory for AB pairs post-inference, which could potentially reflect retroactive interference. Together, these results reinforce an emerging understanding of a role for the vmPFC in brain networks supporting associative memory processes.SIGNIFICANCE STATEMENT We live in a constantly changing environment, so the ability to adapt our knowledge to support understanding of new circumstances is essential. One important adaptive ability is associative inference which allows us to extract shared features from distinct experiences and relate them. For example, if we see a woman holding a baby, and later see a man holding the same baby, then we might infer that the two adults are a couple. Despite the importance of associative inference, the brain systems necessary for this ability are not known. Here, we report that damage to human ventromedial prefrontal cortex (vmPFC) disproportionately impairs associative inference. Our findings show the necessity of the vmPFC for normal associative inference and memory integration.

Putting race in context: social class modulates processing of race in the ventromedial prefrontal cortex and amygdala.

A growing body of literature demonstrates that racial group membership can influence neural responses, e.g. when individuals perceive or interact with persons of another race. However, little attention has been paid to social class, a factor that interacts with racial inequalities in American society. We extend previous literature on race-related neural activity by focusing on how the human brain responds to racial out-groups cast in positively valued social class positions vs less valued ones. We predicted that the ventromedial prefrontal cortex (vmPFC) and the amygdala would have functionally dissociable roles, with the vmPFC playing a more significant role within socially valued in-groups (i.e. the middle-class) and the amygdala having a more crucial role for socially ambivalent and threatening categories (i.e. upper and lower class). We tested these predictions with two complementary studies: (i) a neuropsychological experiment with patients with the vmPFC or amygdala lesions, contrasted with brain damaged and normal comparison participants, and (ii) a functional magnetic resonance imaging experiment with 15 healthy adults. Our findings suggest that two distinct mechanisms underlie class-based racial evaluations, one engaging the vmPFC for positively identified in-group class and another recruiting the amygdala for the class groups that are marginalized or perceived as potential threats.

What relates newspaper, definite, and clothing? An article describing deficits in convergent problem solving and creativity following hippocampal damage.

Creativity relies on a diverse set of cognitive processes associated with distinct neural correlates, and one important aspect of creativity, divergent thinking, has been associated with the hippocampus. However, hippocampal contributions to another important aspect of creativity, convergent problem solving, have not been investigated. We tested the necessity of hippocampus for convergent problem solving using a neuropsychological method. Participants with amnesia due to hippocampal damage (N = 5) and healthy normal comparison participants (N = 5) were tested using a task that promoted solutions based on existing knowledge (Bowden and Jung-Beeman, 2003). During each trial, participants were given a list of three words (e.g., fly, man, place) and asked to respond with a word that could be combined with each of the three words (e.g., fire). The amnesic group produced significantly fewer correct responses than the healthy comparison group. These findings indicate that the hippocampus is necessary for normal convergent problem solving and that changes in the status of the hippocampus should affect convergent problem solving in the context of creative problem-solving across short intervals. This proposed contribution of the hippocampus to convergent problem solving is consistent with an expanded perspective on hippocampal function that acknowledges its role in cognitive processes beyond declarative memory. © 2016 Wiley Periodicals, Inc.

Investigating the Neural Correlates of Schemas: Ventromedial Prefrontal Cortex Is Necessary for Normal Schematic Influence on Memory.

In the human brain, new memories are strongly influenced by existing knowledge of relevant context (sometimes called "schemas"). Schemas can benefit memory by expediting learning and increasing capacity in familiar contexts, but these benefits may simultaneously reduce episode-specific memory. Here we show that damage to the human ventromedial prefrontal cortex (vmPFC) reduced the influence of existing knowledge on new memories. Our findings suggest that the vmPFC plays a key role in schematic memory processes by integrating previous experiences and contextual information to influence memory. These findings provide novel insight into the brain regions necessary for normal schematic memory and enhance our understanding of the brain networks supporting memory processes.

Impaired naming of famous musical melodies is associated with left temporal polar damage.

Previous research has shown that damage to the left temporal pole (LTP) is associated with impaired retrieval of words for unique entities, including names of famous people and landmarks. However, it is not known whether retrieving names for famous melodies is associated with the LTP. The aim of this study was to investigate the hypothesis that damage to the LTP would be associated with impaired naming of famous musical melodies. A Melody Naming Test was administered to patients with LTP damage, brain damaged comparison (BDC) patients, and normal comparison participants (NC). The test included various well-known melodies (e.g., "Pop Goes the Weasel"). After hearing each melody, participants were asked to rate their familiarity with the melody and identify it by name. LTP patients named significantly fewer melodies than BDC and NC participants. Recognition of melodies did not differ significantly between groups. The findings suggest that LTP supports retrieval of names for famous melodies. More broadly, these results extend support for the theoretical notion that LTP is important for retrieving proper names for unique concepts, irrespectively of stimulus modality or category.

Illness insight and neurophysiological error-processing deficits in schizophrenia

Impaired illness insight in schizophrenia is associated with non-adherence and worse outcomes. Schizophrenia patients also exhibit error-monitoring deficits, which have been proposed to cause poor insight. To test this hypothesis, we examined whether schizophrenia patients' deficits in neurophysiological error-monitoring indices, the error-related negativity (ERN) and error positivity (Pe) event-related potential (ERP) amplitudes, are associated with impaired insight. ERPs were recorded in 18 schizophrenia patients and 18 normal comparison participants during a Stroop task. Patients' subnormal ERN and Pe amplitudes did not correlate with insight, suggesting that impaired insight in schizophrenia stems from neurocognitive mechanisms other than deficient error monitoring.

An investigation of semantic similarity judgments about action and non-action verbs in Parkinson's disease: implications for the Embodied Cognition Framework.

The Embodied Cognition Framework maintains that understanding actions requires motor simulations subserved in part by premotor and primary motor regions. This hypothesis predicts that disturbances to these regions should impair comprehension of action verbs but not non-action verbs. We evaluated the performances of 10 patients with Parkinson's disease (PD) and 10 normal comparison (NC) participants on a semantic similarity judgment task (SSJT) that included four classes of action verbs and two classes of non-action verbs. The patients were tested both ON and OFF medication. The most salient results involved the accuracies and reaction times (RTs) for the action verbs taken as a whole and the non-action verbs taken as a whole. With respect to accuracies, the patients did not perform significantly worse than the NC participants for either the action verbs or the non-action verbs, regardless of whether they were ON or OFF their medication. And with respect to RTs, although the patients' responses were significantly slower than those of the NC participants for the action verbs, comparable processing delays were also observed for the non-action verbs; moreover, there was again no notable influence of medication. The major dissociation was therefore not between action and non-action verbs, but rather between accuracies (relatively intact) and RTs (relatively delayed). Overall, the data suggest that semantic similarity judgments for both action and non-action verbs are correct but slow in individuals with PD. These results provide new insights about language processing in PD, and they raise important questions about the explanatory scope of the Embodied Cognition Framework.

Differential amygdala response to lower face in patients with autistic spectrum disorders: An fMRI study

Much functional neuroimaging evidence indicates that autistic spectrum disorders (ASD) demonstrate marked brain abnormalities in face processing. Most of these findings were obtained from studies using tasks related to whole faces. However, individuals with ASD tend to rely more on individual parts of the face for identification than on the overall configuration. Therefore, this neuroimaging evidence might reflect differential visual attention systems in face recognition. It was hypothesized that differential brain function is shown between ASD and control participants with face recognition tasks presenting parts of faces separately. Nine adults with high-functioning ASD and 24 age-matched normal comparison participants were studied using a 3T-MR scanner. We investigated brain activation when processing whole faces and parts of faces displaying positive or negative expressions. The control group showed bilateral amygdalae activation to the whole face, but not to parts of the face. The ASD group showed bilateral amygdalae activation to the lower face (mainly mouth region), but not to the whole face and upper face (mainly eye region). These findings suggest that differential amygdala function for face processing exists in ASD. This aberrant amygdala function might cause abnormalities in gaze processing or recognition of emotional expressions, shown clinically in ASD.

Detection of imminent collisions by drivers with Alzheimer's disease and Parkinson's disease: A preliminary study

The aim of this study was to assess whether patients with neurodegenerative disease, namely Alzheimer's disease (AD) and Parkinson's disease (PD), differed from age-matched, neurologically normal comparison participants in their ability to detect impending collisions. Six AD patients and 8 PD patients, together comprising the neurodegenerative disease group, and 18 comparison participants completed a collision detection simulation task where they must judge whether approaching objects would collide with them or pass by them. The neurodegenerative disease group was less sensitive in detecting collisions than the comparison group, and sensitivity worsened with increasing number of objects in the display and increasing time to contact of those objects. Poor performance on tests of cognition and visual attention were associated with poor collision detection sensitivity. The results of this study indicate that neurodegenerative disease impairs the ability to accurately detect impending collisions and that these decrements are likely the combined result of visual and cognitive disturbances related to disease status.

The relationship between preattentive sensory processing deficits and age in schizophrenia patients

Auditory mismatch negativity (MMN) and P3a index preattentive detection of rare stimuli. Their amplitudes normally decrease with age. Previous studies have reported generally smaller than normal MMN and P3a in schizophrenia patients. We aimed to further characterize the course of these deficits over schizophrenia patients' lifespan. In 253 schizophrenia patients and 147 normal comparison participants (NCPs) encompassing a wide age range (18-65), event-related potentials were recorded while participants watched a silent video and were presented binaurally with 1-kHz tones 500ms apart, including standards (P=.90, 50-ms duration) and deviants (P=0.10, 100-ms). Over the entire age range, MMN and P3a were smaller in schizophrenia patients than NCPs. MMN amplitude declined with age in both groups, though slightly less steeply in schizophrenia patients than NCPs. P3a amplitude declined with age in NCPs but not in schizophrenia patients. In our cohort of schizophrenia patients, MMN and P3a deficits were already present at the youngest ages. MMN declined further with age, whereas P3a amplitude remained stable. This knowledge about how MMN and P3a amplitudes vary with age in schizophrenia patients compared to NCPs can help improve the utility of these indices as clinical endophenotypes or biomarkers.

Verbal learning and memory in patients with dementia with Lewy bodies or Parkinson's disease with dementia

This study compared verbal learning and memory in patients with autopsy-confirmed dementia with Lewy bodies (DLB) and patients with Parkinson's disease with dementia (PDD). A total of 24 DLB patients, 24 PDD patients, and 24 normal comparison participants were administered the California Verbal Learning Test. The three groups were matched on demographic variables, and the two patient groups were matched on the Mattis Dementia Rating Scale. The results indicated that DLB patients recalled less information than PDD patients on all but one recall measure and displayed a more rapid rate of forgetting. In contrast, the PDD patients committed a greater percentage of perseveration errors than the DLB patients. The two groups did not differ in the percentage of recall intrusion errors or any measures of recognition. A discriminant function analysis (DFA) using short-delay cued recall, percentage of perseveration errors, and List B recall differentiated the DLB and PDD groups with 81.3% accuracy. The application of the DFA algorithm to another sample of 42 PDD patients resulted in a 78.6% correct classification rate. The results suggest that, despite equivalent levels of general cognitive impairment, patients with DLB or PDD exhibit a different pattern of verbal learning and memory deficits.

Selective Alterations in Postsynaptic Markers of Chandelier Cell Inputs to Cortical Pyramidal Neurons in Subjects with Schizophrenia

Markers of GABA neurotransmission between chandelier neurons and their synaptic targets, the axon initial segment (AIS) of pyramidal neurons, are altered in the dorsolateral prefrontal cortex (dlPFC) of subjects with schizophrenia. For example, immunoreactivity for the GABA membrane transporter (GAT1) is decreased in presynaptic chandelier neuron axon terminals, whereas immunoreactivity for the GABAA receptor α2 subunit is increased in postsynaptic AIS. To understand the nature and functional significance of these alterations, we determined the density, laminar distribution and length of AIS immunoreactive for ankryin-G and βIV spectrin, two proteins involved in the regulation of synapse structure and ion channel clustering at AIS, in dlPFC area 46 from 14 matched triads of subjects with schizophrenia or major depressive disorder (MDD) and normal comparison subjects. The density of ankyrin-G-immunoreactive (IR) AIS in the superficial, but not in the deep, cortical layers was significantly decreased by 15-19% in the subjects with schizophrenia relative to the other subject groups. In contrast, no group differences were present in the density of βIV spectrin-IR AIS. The length of labeled AIS did not differ across subject groups for either ankyrin-G or βIV spectrin. The density of ankyrin-G-IR AIS was not altered in the dlPFC of macaque monkeys chronically exposed to antipsychotic medications. Given the important role of ankyrin-G in the recruitment and stabilization of sodium channels and other integral membrane proteins to AIS, our findings suggest that these processes are selectively altered in superficial layer pyramidal neurons in subjects with schizophrenia.

Hippocampal damage abolishes the cortisol response to psychosocial stress in humans

The hippocampus (HC) is necessary for learning and memory, but it also plays a role in other behaviors such as those related to stress and anxiety. In support of the latter idea, we show here that bilateral HC damage abolishes the cortisol response to psychosocial stress. We collected salivary cortisol, heart rate, and affective responses to the Trier Social Stress Test (TSST) from 7 participants with bilateral HC lesions, 12 participants with damage outside the HC, and 28 healthy normal comparison participants matched to the HC participants on age and sex. HC participants showed elevated pre-stress cortisol, but no cortisol response to the TSST. Heart rate and affective responses in the HC group were similar to those of the comparison groups. Participants with brain damage outside the HC showed stress responses that were comparable to those of the healthy comparison group. These findings support the idea that the functions of the human HC extend beyond learning and memory, and suggest that the HC is necessary for producing the cortisol response to psychosocial stress.

Increased feelings with increased body signals

Since the beginning of psychology as a scientific endeavour, the question of whether the body plays a role in how a person experiences emotion has been the centre of emotion research. Patients with structural gastrointestinal disorders, such as Crohn's disease, provide an intriguing opportunity to study the influence of body signals on emotions and feelings. In the present study, emotionally salient films were presented to participants with Crohn's disease in either the active state (Crohn's-active, CA) or silent state (Crohn's-silent, CS), and to normal comparison (NC) participants. We hypothesized that CA participants would have increased feelings, compared with CS and NC participants, when viewing emotional films designed to elicit happiness, disgust, sadness and fear. Gastric myoelectrical activity (electrogastrogram, or EGG) was measured during the films, and after each film was presented, participants rated emotion intensity (arousal) and pleasantness (valence). All groups labelled the emotions similarly. In support of the hypothesis, CA participants showed an increase in subjective arousal for negative emotions compared with CS and NC participants. The CA participants also showed increased EGG during emotional film viewing, as well as a strong positive correlation of EGG with arousal ratings. Together, these findings can be taken as evidence that aberrant feedback from the gastrointestinal system up-regulates the intensity of feelings of negative emotions.

Sensorimotor Gating Deficits in Adults with Autism

Prepulse inhibition (PPI) is an operational measure of sensorimotor gating and is impaired in a family of neuropsychiatric disorders characterized by abnormalities of inhibitory function. Adults with autistic disorder (AD) exhibit clinical features of inhibitory deficits, such as restrictive and repetitive behaviors, that may be explained by deficits in sensorimotor gating. Acoustic startle reactivity, habituation, and PPI (30-, 60-, 120-msec interstimulus intervals) were assessed in 14 adult men diagnosed with AD and 16 typically developing normal comparison (NC) participants. All participants were administered measures of intelligence and frontal-executive functioning. Adults with AD exhibited significantly less PPI in the 60-msec condition than NC participants, which was correlated with increased ratings of restricted and repetitive behaviors. The groups did not differ on measures of startle amplitude or overall habituation. There was, however, a significant group-by-block habituation effect. Furthermore, PPI was not related to intelligence but was moderately associated with performance on a measure of frontal-executive functioning. Adults with AD have sensorimotor gating deficits similar to other neurodevelopmental disorders, implicating a failure of normal inhibitory regulation of sensory, motor, and attentional mechanisms. Thus, PPI deficits may be indirectly linked to one of the hallmark features of AD.

The Functional Neuroanatomy of Spatial Attention in Autism Spectrum Disorder

This study investigated the functional neuroanatomical correlates of spatial attention impairments in autism spectrum disorders (ASD) using an event-related functional magnetic resonance imaging (FMRI) design. Eight ASD participants and 8 normal comparison (NC) participants were tested with a task that required stimulus discrimination following a spatial cue that preceded target presentation by 100 msec (short interstimulus interval [ISI]) or 800 msec (long ISI). The ASD group showed significant behavioral spatial attention impairment in the short ISI condition. The FMRI results showed a reduction in activity within frontal, parietal, and occipital regions in ASD relative to the NC group, most notably within the inferior parietal lobule. ASD behavioral performance improved in the long ISI condition but was still impaired relative to the NC group. ASD FMRI activity in the long ISI condition suggested that the rudimentary framework of normal attention networks were engaged in ASD including bilateral activation within the frontal, parietal, and occipital lobes. Notable activation increases were observed in the superior parietal lobule and extrastriate cortex. No reliable activation was observed in the posterior cerebellar vermis in ASD participants during either long or short ISI conditions. In addition, no frontal activation during short ISI and severely reduced frontal activation during long ISI was observed in the ASD group. Taken together, these findings suggest a dysfunctional cerebello-frontal spatial attention system in ASD. The pattern of findings suggests that ASD is associated with a profound deficit in automatic spatial attention abilities and abnormal voluntary spatial attention abilities. This article also describes a method for reducing the contribution of physical eye movements to the blood-oxygenation level dependent activity in studies of ASD.

Verbal memory in first-episode schizophrenia: Heterogeneity in performance?

It is unclear if the commonly observed "subcortical" verbal memory profile in schizophrenic patients is present at the onset of the disease. Therefore, the performance of 43 first-episode patients with schizophrenia or schizophreniform disorder on the Dutch version of the California Verbal Learning Test (VLGT) was compared to that of 43 normal comparison participants. We hypothesized that the first-episode patients would exhibit a "subcortical" memory profile, that is, they would show a primary retrieval deficit. This hypothesis was not confirmed: the patients displayed a profile suggestive of a prominent storage deficit, that is, a "cortical" memory profile. Subsequently, patients' VLGT performance was cluster analyzed to determine whether subgroups could be identified exhibiting a cortical, subcortical, and normal profile, respectively. Two subgroups (N=22; N=13) exhibited memory impairments, while one subgroup (N=8) was unimpaired. The memory profiles of the two impaired subgroups differed both qualitatively and quantitatively, but did not conform neatly to a cortical and a subcortical profile. Demographic and verbal fluency data provided limited validation of the subgroup classification. Our results may suggest that combining the verbal memory performance of first-episode patients obscures meaningful heterogeneity. Alternatively, the cluster solution could merely reflect a continuum of severity.

Use of the mini-mental state exam in middle-aged and older outpatients with schizophrenia: cognitive impairment and its associations.

The authors examined cognitive impairment with a commonly used cognitive screening tool (the Mini-Mental State Exam [MMSE]) and its relationship to psychopathology, functional status, and other clinically relevant participant characteristics in 161 middle-aged and older outpatients with schizophrenia and 86 normal-comparison participants (NCs). Participants completed the MMSE and standardized rating scales of psychopathology and motor symptoms. Other aspects of daily functioning were also evaluated. Patients had worse mean MMSE scores than NCs; 23% of the patients, but no NCs, had MMSE totals </=24 (a commonly used cutoff score to define impairment). Examination of the individual cognitive domains assessed by the MMSE showed that schizophrenia patients had the greatest impairment on tasks of word recall and attention. Among the patients, impaired MMSE performance was associated with lower education, living in a structured setting, being unmarried, and more severe negative symptoms. The MMSE was useful in detecting functionally relevant cognitive deficits among middle-aged and older schizophrenia patients who scored in the impaired range; however, those patients in the unimpaired range may still have subtle cognitive deficits that were not detected with the MMSE.

Use of the Mini-Mental State Exam in Middle-Aged and Older Outpatients With Schizophrenia: Cognitive Impairment and Its Associations

Objective: The authors examined cognitive impairment with a commonly used cognitive screening tool (the Mini-Mental State Exam [MMSE]) and its relationship to psychopathology, functional status, and other clinically relevant participant characteristics in 161 middle-aged and older outpatients with schizophrenia and 86 normalcomparison participants (NCs).Methods: Participants completed the MMSE and standardized rating scales of psychopathology andmotor symptoms. Other aspects of daily functioning were also evaluated. Results: Patients had worse mean MMSE scores than NCs; 23% of the patients, but no NCs, had MMSE totals 24 (a commonly used cutoff score to define impairment). Examination of the individual cognitive domains assessed by the MMSE showed that schizophrenia patients had the greatest impairment on tasks of word recall and attention. Among the patients, impaired MMSE performance was associated with lower education, living in a structured setting, being unmarried, and more severe negative symptoms. Conclusion: The MMSE was useful in detecting functionally relevant cognitive deficits amongmiddle-aged and older schizophrenia patients who scored in the impaired range; however, those patients in the unimpaired range may still have subtle cognitive deficits that were not detected with the MMSE. (Am J Geriatr Psychiatry 2004; 12:412–419)