Daphne J. Holt

Neurochemical architecture of the human striatum

The striatum of the human brain has a highly differentiated neurochemical architecture visible in stains for many of the neurotransmitter‐related molecules present in the striatum. The distributions for these chemical markers have never been analyzed comprehensively. We compared the distributions of multiple neurochemical markers in a serial‐section analysis of the caudate nucleus, the putamen, and the ventral striatum in normal human brains. The cholinergic system was identified with choline acetyltransferase (ChAT). The organization of the cholinergic fiber system was compared with that of striatal systems expressing immunoreactivity for calbindin D28k, met‐enkephalin, substance P, tyrosine hydroxylase, and parvalbumin.

Increased medial temporal lobe activation during the passive viewing of emotional and neutral facial expressions in schizophrenia

INTRODUCTION Patients with schizophrenia show deficits in facial affect and facial identity recognition and exhibit structural and neurophysiological abnormalities in brain regions known to mediate these processes. Functional neuroimaging studies of neural responses to emotional facial expressions in schizophrenia have reported both increases and decreases in medial temporal lobe (MTL) activity in schizophrenia. Some of this variability may be related to the tasks performed and the baseline conditions used. Here we tested whether MTL responses to human faces in schizophrenia are abnormal when unconstrained by a cognitive task and measured relative to a low-level baseline (fixation) condition. METHODS 15 patients with schizophrenia and 16 healthy control subjects underwent functional magnetic resonance imaging (fMRI) while passively viewing human faces displaying fearful, happy, and neutral emotional expressions. RESULTS Relative to control subjects, the patients demonstrated (1) significantly greater activation of the left hippocampus while viewing all three facial expressions and (2) increased right amygdala activation during the initial presentation of fearful and neutral facial expressions. CONCLUSIONS In schizophrenia, hippocampal and amygdala activity is elevated during the passive viewing of human faces.

Evidence for a deficit in cholinergic interneurons in the striatum in schizophrenia

Neurochemical and functional abnormalities of the striatum have been reported in schizophrenic brains, but the cellular substrates of these changes are not known. We hypothesized that schizophrenia may involve an abnormality in one of the key modulators of striatal output, the cholinergic interneuron. We measured the densities of cholinergic neurons in the striatum in schizophrenic and control brains in a blind analysis, using as a marker of this cell population immunoreactivity for choline acetyltransferase, the synthetic enzyme of acetylcholine. As an independent marker, we used immunoreactivity for calretinin, a protein which is co-localized with choline acetyltransferase in virtually all of the cholinergic interneurons of the striatum. A significant decrease in choline acetyltransferase-positive and calretinin-positive cell densities was found in the schizophrenic cases compared with controls in the striatum as a whole [for the choline acetyltransferase-positive cells: controls: 3.21 +/- 0.48 cells/mm2 (mean +/- S.D.), schizophrenics: 2.43 +/- 0.68 cells(mm2; P < 0.02]. The decrease was patchy in nature and most prominent in the ventral striatum (for the choline acetyltransferase-positive cells: controls: 3.47 +/- 0.59 cells/mm2, schizophrenics: 2.52 +/- 0.64 cells/ mm2; P < 0.005) which included the ventral caudate nucleus and nucleus accumbens region. Three of the schizophrenic cases with the lowest densities of cholinergic neurons had not been treated with neuroleptics for periods from more than a month to more than 20 years. A decrease in the number or function of the cholinergic interneurons of the striatum may disrupt activity in the ventral striatal-pallidal-thalamic-prefrontal cortex pathway and thereby contribute to abnormalities in function of the prefrontal cortex in schizophrenia.

Parcellating cortical functional networks in individuals

The capacity to identify the unique functional architecture of an individuals brain is a crucial step toward personalized medicine and understanding the neural basis of variation in human cognition and behavior. Here we developed a cortical parcellation approach to accurately map functional organization at the individual level using resting-state functional magnetic resonance imaging (fMRI). A population-based functional atlas and a map of inter-individual variability were employed to guide the iterative search for functional networks in individual subjects. Functional networks mapped by this approach were highly reproducible within subjects and effectively captured the variability across subjects, including individual differences in brain lateralization. The algorithm performed well across different subject populations and data types, including task fMRI data. The approach was then validated by invasive cortical stimulation mapping in surgical patients, suggesting potential for use in clinical applications.

Sustained activation of the hippocampus in response to fearful faces in schizophrenia

BACKGROUND In healthy individuals, the activity of the medial temporal lobe habituates rapidly with the repeated presentation of a stimulus. Using functional magnetic resonance imaging (fMRI), we tested the hypothesis that habituation of the medial temporal lobe is reduced in schizophrenia. METHODS During fMRI scanning, fearful and happy faces were presented repeatedly to healthy control subjects (n =16) and patients with schizophrenia (n =18). Habituation of medial temporal lobe structures was measured by comparing the hemodynamic response occurring during the early and late portions of the presentation of each face. RESULTS Control subjects demonstrated significant medial temporal lobe habituation to fearful but not to happy faces. In contrast, patients with schizophrenia did not demonstrate medial temporal lobe habituation in response to fearful or happy faces. In a direct, between-group comparison, right hippocampal habituation to fearful faces was significantly greater in control subjects than in the schizophrenia patients. Also, there were no significant differences between the patients and control subjects in the early medial temporal lobe response to fearful faces, suggesting that attenuated hippocampal habituation in schizophrenia is not associated with a reduction in initial activation. CONCLUSIONS These findings suggest that there is abnormal modulation of hippocampal responses to fearful faces in schizophrenia.

Lower-Level Stimulus Features Strongly Influence Responses in the Fusiform Face Area

An intriguing region of human visual cortex (the fusiform face area; FFA) responds selectively to faces as a general higher-order stimulus category. However, the potential role of lower-order stimulus properties in FFA remains incompletely understood. To clarify those lower-level influences, we measured FFA responses to independent variation in 4 lower-level stimulus dimensions using standardized face stimuli and functional Magnetic Resonance Imaging (fMRI). These dimensions were size, position, contrast, and rotation in depth (viewpoint). We found that FFA responses were strongly influenced by variations in each of these image dimensions; that is, FFA responses were not “invariant” to any of them. Moreover, all FFA response functions were highly correlated with V1 responses (r = 0.95–0.99). As in V1, FFA responses could be accurately modeled as a combination of responses to 1) local contrast plus 2) the cortical magnification factor. In some measurements (e.g., face size or a combinations of multiple cues), the lower-level variations dominated the range of FFA responses. Manipulation of lower-level stimulus parameters could even change the category preference of FFA from “face selective” to “object selective.” Altogether, these results emphasize that a significant portion of the FFA response reflects lower-level visual responses.

The COMT Val108/158Met Polymorphism and Medial Temporal Lobe Volumetry in Patients with Schizophrenia and Healthy Adults

Abnormalities of the medial temporal lobe have been consistently demonstrated in schizophrenia. A common functional polymorphism, Val108/158Met, in the putative schizophrenia susceptibility gene, catechol-O-methyltransferase (COMT), has been shown to influence medial temporal lobe function. However, the effects of this polymorphism on volumes of medial temporal lobe structures, particularly in patients with schizophrenia, are less clear. Here we measured the effects of COMT Val108/158Met genotype on the volume of two regions within the medial temporal lobe, the amygdala and hippocampus, in patients with schizophrenia and healthy control subjects. We obtained MRI and genotype data for 98 schizophrenic patients and 114 matched controls. An automated atlas-based segmentation algorithm was used to generate volumetric measures of the amygdala and hippocampus. Regression analyses included COMT met allele load as an additive effect, and also controlled for age, intracranial volume, gender and acquisition site. Across patients and controls, each copy of the COMT met allele was associated on average with a 2.6% increase in right amygdala volume, a 3.8% increase in left amygdala volume and a 2.2% increase in right hippocampus volume. There were no effects of COMT genotype on volumes of the whole brain and prefrontal regions. Thus, the COMT Val108/158Met polymorphism was shown to influence medial temporal lobe volumes in a linear-additive manner, mirroring its effect on dopamine catabolism. Taken together with previous work, our data support a model in which lower COMT activity, and a resulting elevation in extracellular dopamine levels, stimulates growth of medial temporal lobe structures.

Neurophysiological correlates of comprehending emotional meaning in context

Although the neurocognitive mechanisms of nonaffective language comprehension have been studied extensively, relatively less is known about how the emotional meaning of language is processed. In this study, electrophysiological responses to affectively positive, negative, and neutral words, presented within nonconstraining, neutral contexts, were evaluated under conditions of explicit evaluation of emotional content (Experiment 1) and passive reading (Experiment 2). In both experiments, a widely distributed Late Positivity was found to be larger to negative than to positive words (a “negativity bias”). In addition, in Experiment 2, a small, posterior N400 effect to negative and positive (relative to neutral) words was detected, with no differences found between N400 magnitudes to negative and positive words. Taken together, these results suggest that comprehending the emotional meaning of words following a neutral context requires an initial semantic analysis that is relatively more engaged for emotional than for nonemotional words, whereas a later, more extended, attention-modulated process distinguishes the specific emotional valence (positive vs. negative) of words. Thus, emotional processing networks within the brain appear to exert a continuous influence, evident at several stages, on the construction of the emotional meaning of language.

The misattribution of salience in delusional patients with schizophrenia

INTRODUCTION Delusions may arise from abnormalities in emotional perception. In this study, we tested the hypothesis that delusional schizophrenia patients are more likely than non-delusional schizophrenia patients and healthy participants to assign affective meanings to neutral stimuli. METHODS Unpleasant, pleasant, and neutral words were randomly presented to three subject groups--patients with schizophrenia with prominent delusions, patients with schizophrenia without delusions, and healthy participants. Participants performed three tasks: one in which they decided whether a letter string was a word or a non-word (lexical decision) and two affective classification tasks in which they judged whether words were 1) neutral or unpleasant, or 2) neutral or pleasant. RESULTS While there were no significant between-group differences in lexical decision performance, patients with delusions showed selective performance deficits in both affective classification tasks. First, delusional patients were significantly more likely than non-delusional patients and healthy participants to classify words as unpleasant. Second, delusional patients took significantly longer than both other groups to correctly classify neutral words in both affective classification tasks. CONCLUSIONS Taken together, these findings suggest that delusions are associated with the explicit misattribution of salience to neutral stimuli.

BDNF, relative preference, and reward circuitry responses to emotional communication†‡§

Brain derived neurotrophic factor (BDNF) regulates neural development and synaptic transmission. We have tested the hypothesis that functional variation in the BDNF gene (Val66Met polymorphism, rs6265) affects brain reward circuitry encoding human judgment and decision‐making regarding relative preference. We quantified relative preference among faces with emotional expressions (angry, fearful, sad, neutral, and happy) by a keypress procedure performed offline to measure effort traded for viewing time. Keypress‐based relative preferences across the ensemble of faces were mirrored significantly by fMRI signal in the orbitofrontal cortex, amygdala, and hippocampus when passively viewing these faces. For these three brain regions, there was also a statistically significant group difference by BDNF genotype in the fMRI responses to the emotional expressions. In comparison with Val/Met heterozygotes, Val/Val individuals preferentially sought exposure to positive emotions (e.g., happy faces) and had stronger regional fMRI activation to aversive stimuli (e.g., angry, fearful, and sad faces). BDNF genotype accounted for ∼30% of the variance in fMRI signal that mirrors keypress responses to these stimuli. This study demonstrates that functional allelic variation in BDNF modulates human brain circuits processing reward/aversion information and relative preference transactions.