Translational neurocardiology: preclinical models and cardioneural integrative aspects.

Neuronal elements distributed throughout the cardiac nervous system, from the level of the insular cortex to the intrinsic cardiac nervous system, are in constant communication with one another to ensure that cardiac output matches the dynamic process of regional blood flow demand. Neural elements in their various 'levels' become differentially recruited in the transduction of sensory inputs arising from the heart, major vessels, other visceral organs and somatic structures to optimize neuronal coordination of regional cardiac function. This White Paper will review the relevant aspects of the structural and functional organization for autonomic control of the heart in normal conditions, how these systems remodel/adapt during cardiac disease, and finally how such knowledge can be leveraged in the evolving realm of autonomic regulation therapy for cardiac therapeutics.

Hypofrontality in neuroleptic-naive patients and in patients with chronic schizophrenia. Assessment with xenon 133 single-photon emission computed tomography and the Tower of London.

The "hypofrontality hypothesis" has been supported by many neuroimaging studies, but not all, perhaps because of heterogeneity of samples. The present study examined three different samples that permitted assessment of a variety of confounders, such as effects of long-term treatment, chronicity of illness, and presenting phenomenology: (1) 13 neuroleptic-naive schizophrenic patients, (2) 23 nonnaive schizophrenic patients who had been relatively chronically ill but were medication free for at least 3 weeks, and (3) 15 healthy normal volunteers. Regional cerebral blood flow was measured using single-photon emission computed tomography with xenon 133 as the tracer. The control condition consisted of looking at undulating colored shapes on a video monitor, while the experimental task was the Tower of London. We observed the Tower of London to be a relatively specific stimulant of the left mesial frontal cortex (probably including parts of the cingulate gyrus) in healthy normal volunteers. Both the neuroleptic-naive and the nonnaive patients lacked this area of activation, as well as a related one in the right parietal cortex (representing the circuitry specifically activated by the Tower of London). Decreased activation occurred only in the patients with high scores for negative symptoms. These results suggest that hypofrontality is related to negative symptoms and is not a long-term effect of neuroleptic treatment or of chronicity of illness.

Auditory attentional deficits in patients with schizophrenia. A positron emission tomography study.

BACKGROUND: Patients with schizophrenia have frequently been found to perform poorly on tasks requiring selective attention, defined as the ability to focus attention on relevant information while simultaneously ignoring irrelevant stimuli. This study explores the brain mechanisms mediating attentional processing in patients with schizophrenia by measuring their regional cerebral blood flow (rCBF) with positron emission tomography using [15O] water as they performed tasks that differed systematically in attentional demand. METHODS: Ten schizophrenic patients (either neurolepticnaive or withdrawn from medication) (patient group) and 10 normal volunteers (control group) performed auditory target detection tasks. Different types of auditory stimuli (environmental sounds, meaningless speech sounds, and words) were presented either binaurally (ie, same sounds in both ears) or dichotically (simultaneous and different sounds in the 2 ears). In dichotic conditions, subjects were instructed to focus on either their left or right ear. RESULTS: Initial subtraction-based image analyses sought significant rCBF changes anywhere in the brain. Patients consistently had less significant activation than controls in right superotemporal gyrus (STG). Follow-up analyses used regions of interest traced on individual magnetic resonance images to precisely measure rCBF in STG. Unlike controls, patients had higher rCBF in the left STG during all activation conditions. CONCLUSIONS: The abnormal task-related rCBF asymmetry in STG of schizophrenic patients may indicate an isolated temporal lobe deficit, but it may also indicate abnormality in the thalamocortical circuitry mediating selective attention and/or in the brain systems that integrate auditory processing in the 2 hemispheres.

Cerebellar functional abnormalities in schizophrenia are suggested by classical eyeblink conditioning.

BACKGROUND: Previous research suggests that schizophrenia may result from disruptions in a cortico-cerebellar-thalamic-cortical circuit (CCTCC) producing a mental incoordination or "cognitive dysmetria." To further evaluate the cerebellar contribution to this disrupted circuitry, medication-free patients with schizophrenia completed classical eyeblink conditioning, a cerebellar-mediated learning task. METHODS: For classical eyeblink conditioning, 70 trials with a tone conditioned stimulus (CS) and air puff unconditioned stimulus (US) were presented to 15 patients with schizophrenia and 15 healthy control subjects. Acquisition rate for the conditioned response (CR) and response timing were compared between the two groups. RESULTS: Patients with schizophrenia displayed facilitated conditioning compared to control subjects based on a greater number of CRs during the session and a faster acquisition of the learned response. CONCLUSIONS: Facilitated conditioning suggests that an enhanced excitability in the cerebellum occurs as part of a disrupted CCTCC in schizophrenia. The enhanced cerebellar-mediated associative learning may be maladaptive in the context of normal cerebro-cerebellar interactions, leading to the characteristic motor and mental incoordination of the disorder. Classical eyeblink conditioning may provide a useful model system for studying cerebellar involvement in the pathogenesis and treatment of schizophrenia.

Lack of an association between delayed memory and hippocampal and temporal lobe size in patients with schizophrenia and healthy controls.

The purpose of the present study was to investigate putative neural substrates of long-term (delayed) memory in schizophrenia and young healthy controls. Ten "low" and 10 "high" memory patients were selected from a large sample of DSM-III-R diagnosed schizophrenia spectrum patients, based on composite verbal and nonverbal delayed recall memory scores. Ten "low" and 9 "high" memory individuals were also selected from a larger sample of young healthy controls. Magnetic resonance imaging scans were acquired on a 1.5-T GE Signa scanner using a SPGR sequence (repetition time = 24 msec, echo time = 5 msec). Hippocampal volumes were computed from manual tracings (intraclass correlation = .96), and temporal lobe and whole brain tissue volumes were obtained using a semiautomated technique. In both the patient sample and controls, there was no significant relationship between delayed memory ability and hippocampal, temporal lobe, or whole brain volume. The integration of results from this study, and from studies on normal aging and Alzheimer's disease, supports a model suggesting that hippocampal size may be an indicator of long-term memory ability, but only when hippocampal measures reflect aging and degenerative hippocampal atrophy. If the hippocampal measures reflect individual differences in hippocampal size prior to the onset of hippocampal atrophy, then hippocampal size does not appear to predict long-term memory ability.

Defining the phenotype of schizophrenia: cognitive dysmetria and its neural mechanisms.

All research on schizophrenia depends on selecting the correct phenotype to define the sample to be studied. Definition of the phenotype is complicated by the fact that there are no objective markers for the disorder. Further, the symptoms are diverse, leading some to propose that the disorder is heterogeneous and not a single disorder or syndrome. This article explores an alternative possibility. It proposes that schizophrenia may be a single disorder linked by a common pathophysiology (a neurodevelopmental mechanism), which leads to a misconnection syndrome of neural circuitry. Evidence for disruption in a specific circuit is explored: the cortical-thalamic-cerebellar-cortical circuit (CCTCC). It is suggested that a disruption in this circuit leads to an impairment in synchrony, or the smooth coordination of mental processes. When synchrony is impaired, the patient suffers from a cognitive dysmetria, and the impairment in this basic cognitive process defines the phenotype of schizophrenia and produces its diversity of symptoms.

Regional frontal abnormalities in schizophrenia: a quantitative gray matter volume and cortical surface size study.

BACKGROUND: Previous structural studies of the frontal lobe in schizophrenia have had somewhat inconsistent results, but most of them have measured the frontal lobe as a single brain structure. To investigate more specific abnormalities in frontal subregions, we measured gray matter volume and cortical surface size in 10 subregions in drug-naive patients during the early stages of the illness. METHODS: Magnetic resonance imaging was used to measure frontal subregions in 34 healthy male volunteers, and 26 male, drug-naive schizophrenia patients at early stages of the illness. Frontal subregions were manually traced using our locally developed parcellation method. RESULTS: Patients with schizophrenia had a significant deficit in cortical surface size in the right straight gyrus and left orbitofrontal cortex. No differences were found in gray matter volumes. CONCLUSIONS: Frontal structural abnormalities found in drug-naive schizophrenic patients appear to be subtle and circumscribed to ventral portions. Anomalies in the cortical surface size suggest neurodevelopmental abnormalities might occur during the early stages of the gyrogenesis. Further investigations are needed to explore the implications of paralimbic ventral frontal regions (i.e., straight gyrus and orbitofrontal cortex) in the pathophysiology of schizophrenia.

Comparison of the effects of risperidone and haloperidol on regional cerebral blood flow in schizophrenia.

BACKGROUND: Atypical antipsychotics, such as risperidone, have been shown to be more effective for the treatment of the symptoms of schizophrenia and have a greater beneficial effect on neurocognition compared to the conventional antipsychotics. The present study used [(15)O]H(2)O positron emission tomography imaging of regional cerebral blood flow to examine and compare the effects of haloperidol and risperidone on brain function. METHODS: Thirty-two subjects with schizophrenia participated in the study. Each subject was scanned in a medication-free state, and after being on a stable clinically assigned dose of either risperidone or haloperidol for 3 weeks. The off-medication scan was subtracted from the on-medication scan, using a within-subjects design. A randomization analysis was used to determine differences between the effects of haloperidol and risperidone on regional cerebral blood flow. RESULTS: Haloperidol was associated with a significantly greater increase in regional cerebral blood flow in the left putamen and posterior cingulate, and a significantly greater decrease in regional cerebral blood flow in frontal regions compared to risperidone. Risperidone was associated with a significantly greater decrease in regional cerebral blood flow in the cerebellum bilaterally compared to haloperidol. CONCLUSIONS: The results show that risperidone and haloperidol have significantly different effects on brain function, which may be related to their differences in efficacy and side effects. Further work is required to more precisely determine the mechanisms by which different antipsychotic medications exert their therapeutic effects on the clinical symptoms and cognition in schizophrenia. These findings emphasize the importance of controlling for both medication status and the individual antipsychotic in neuroimaging studies.

Tests for comparing images based on randomization and permutation methods.

Tests comparing image sets can play a critical role in PET research, providing a yes-no answer to the question "Are two image sets different?" The statistical goal is to determine how often observed differences would occur by chance alone. We examined randomization methods to provide several omnibus test for PET images and compared these tests with two currently used methods. In the first series of analyses, normally distributed image data were simulated fulfilling the requirements of standard statistical tests. These analyses generated power estimates and compared the various test statistics under optimal conditions. Varying whether the standard deviations were local or pooled estimates provided an assessment of a distinguishing feature between the SPM and Montreal methods. In a second series of analyses, we more closely simulated current PET acquisition and analysis techniques. Finally, PET images from normal subjects were used as an example of randomization. Randomization proved to be a highly flexible and powerful statistical procedure. Furthermore, the randomization test does not require extensive and unrealistic statistical assumptions made by standard procedures currently in use.

Effects of timing and duration of cognitive activation in [15O]water PET studies.

The multiple injection [15O]water method offers unique opportunities for studying cognitive processing by the human brain. The influence of the duration and temporal placement of an activation task, in relation to the arrival of the radiotracer in the brain, is a fundamental methodologic question for cognitive activation studies. A quantitative positron emission tomography (PET) study of five normal volunteers was performed in which the stimulation consisted of a visual activation task (alternating checkerboard pattern) superimposed on an auditory baseline task (syllable monitoring). Ten injection conditions, with varying duration and timing of the visual activation, were used. Regional CBF (rCBF) in visual cortex was measured quantitatively using the autoradiographic method. A 20-s stimulation, centered on the bolus arrival in the brain, produced significant changes in rCBF. Because varying the duration and timing of the activation task technically violates the temporal homogeneity assumption of the autoradiographic model, a mathematical simulation was formulated to evaluate the potential influence of these variations. Results of the simulation are consistent with the PET data and suggest that activation can be limited to a narrow temporal window centered on the radiotracer uptake. The ability to observe significant changes in rCBF with short stimulation intervals is of particular interest in the use of [15O]water PET for studies of cognitive processes with a short time course.

Sample size and statistical power in [15O]H2O studies of human cognition.

Determining the appropriate sample size is a crucial component of positron emission tomography (PET) studies. Power calculations, the traditional method for determining sample size, were developed for hypothesis-testing approaches to data analysis. This method for determining sample size is challenged by the complexities of PET data analysis: use of exploratory analysis strategies, search for multiple correlated nodes on interlinked networks, and analysis of large numbers of pixels that may have correlated values due to both anatomical and functional dependence. We examine the effects of variable sample size in a study of human memory, comparing large (n = 33), medium (n = 16,17), small (n = 11, 11, 11), and very small (n = 6,6,7,7,7) samples. Results from the large sample are assumed to be the "gold standard." The primary criterion for assessing sample size is replicability. This is evaluated using a hierarchically ordered group of parameters: pattern of peaks, location of peaks, number of peaks, size (volume) of peaks, and intensity of the associated t (or z) statistic. As sample size decreases, false negatives begin to appear, with some loss of pattern and peak detection; there is no corresponding increase in false positives. The results suggest that good replicability occurs with a sample size of 10-20 subjects in studies of human cognition that use paired subtraction comparisons of single experimental/baseline conditions with blood flow differences ranging from 4 to 13%.

Longitudinal study of cognitive function in first-episode and recent-onset schizophrenia.

OBJECTIVE: Whether cognitive function in schizophrenia deteriorates, improves, or remains stable is a crucial question. Few studies have examined the longitudinal stability of cognitive function and the relationship between cognitive performance and clinical symptoms over time in a cohort of well-treated patients with schizophrenia. METHOD: In the present study, 54 patients with first-episode and recent-onset schizophrenia completed a comprehensive cognitive test battery and were rated on symptom measures at index hospitalization and again after 5 years. RESULTS: Performance IQ and full-scale IQ significantly improved, whereas verbal IQ did not change. Group performance improved on some of the neuropsychological tests, including the Circle A letter-cancellation task, free recall of logical memory test score, and the Wisconsin Card Sorting Test. Mean finger-tapping performance worsened over time, whereas performance on other neuropsychological tests did not change. Negative, psychotic, and disorganized symptoms significantly improved over the time period. Changes in negative symptoms were correlated with performance changes in verbal IQ and full-scale IQ but not performance IQ. Improvement in verbal cognition was observed when negative symptoms improved. Psychotic and disorganized symptom dimensions were not correlated with any IQ measure. CONCLUSIONS: These results indicate that in a cohort of young patients receiving neuroleptic treatment early in their illness, cognitive performance does not deteriorate--and may improve. Only one of the three symptom dimensions--negative--was associated with change in cognitive performance. This study supports the view that negative symptoms are associated with a poor long-term cognitive outcome and may be closely related to the primary cognitive deficit in schizophrenia.

Interhemispheric transfer deficit and alexithymia.

The hypothesis that alexithymia reflects a functional disconnection between the two cerebral hemispheres was examined in 25 male combat veterans with posttraumatic stress disorder (PTSD). Multiple regression analysis revealed that the efficiency of interhemispheric communication, evaluated with a tactile finger localization task, was a significant predictor of the degree of alexithymia, as measured by the Toronto Alexithymia Scale, independent of PTSD severity and IQ. The PTSD subjects without alexithymia did not differ on the finger localization task from 10 male control subjects without alexithymia. These data suggest that at least some forms of alexithymia may be mediated by an interhemispheric communication deficit.

Intelligence and brain structure in normal individuals.

OBJECTIVE: This study was designed to evaluate the relation between intelligence and a variety of measures of brain structure. METHOD: Magnetic resonance imaging scans were used to measure the volume of the intracranial cavity, cerebral hemispheres, lateral ventricles, temporal lobes, hippocampus, caudate, and cerebellum, as well as the overall volume of gray matter, white matter, and CSF, in 67 healthy, normal volunteers. Intelligence was measured with the Wechsler Adult Intelligence Scale--Revised. RESULTS: Full-scale IQ was found to be significantly correlated with intracranial, cerebral, temporal lobe, hippocampal, and cerebellar volume but not with caudate and lateral ventricle volume. There were also significant correlations of full-scale, verbal, and performance IQ with overall gray matter volume but not with white matter or CSF volume. Gender differences were noted in the pattern and number of correlations between the volume of the brain and its subregions and full-scale, verbal, and performance IQ. CONCLUSIONS: The results suggest that the size of some cerebral structures may account for a significant, but modest, proportion of the variance in human intelligence.

Regional neural dysfunctions in chronic schizophrenia studied with positron emission tomography.

OBJECTIVE: Whether chronicity of illness produces progressive neural abnormality is an important question in current schizophrenia research. Positron emission tomography (PET) offers an opportunity to visualize and measure blood flow in vivo to address this issue. The authors previously compared healthy volunteers with neuroleptic-naive patients experiencing their first episode of schizophrenia and reported that abnormalities in blood flow, including lower flow in prefrontal regions and higher flow in the thalamus and cerebellum, are present at the early stage of schizophrenic illness. The goal of the present study was to measure blood flow with PET in patients with chronic schizophrenia. METHOD: PET was used to examine regional cerebral blood flow (rCBF) in 30 patients with chronic schizophrenia and 30 normal comparison subjects. To determine if the patterns of flow abnormality in the patients with chronic schizophrenia were similar to those of patients experiencing their first episode of schizophrenia, the same cognitive condition was examined as in the earlier study. The patients with chronic schizophrenia in the current study had been neuroleptic-free for at least 3 weeks. RESULTS: As in the authors' previous study, the chronically ill patients showed lower flow in prefrontal areas and higher flow in thalamic and cerebellar regions than normal comparison subjects, suggesting that a similar neural dysfunction occurs in both first-episode and chronic schizophrenia. CONCLUSIONS: rCBF abnormalities in patients with chronic schizophrenia are not due to chronicity of illness or the effects of medication. These results provide evidence that the primary neural abnormalities in schizophrenia may occur in cortical, cerebellar, and thalamic regions and that the dysfunction in these regions may explain the "loosening of associations" that Bleuler considered to be the fundamental cognitive phenotype of schizophrenia. These abnormalities can be reconceptualized as "cognitive dysmetria."

Remembering the past: two facets of episodic memory explored with positron emission tomography.

OBJECTIVE: This study used positron emission tomography to examine two kinds of personal memory that are used in psychiatric evaluation: focused episodic memory (recall of past experience, employed in "taking a history") and random episodic memory (uncensored thinking about experience, examined during analytic therapy using free association). For comparison, a third memory task was used to tap impersonal memory that represents general information about the world ("semantic memory"). METHOD: Thirteen subjects were studied using the [15O]H2O method to obtain quantitative measurements of cerebral blood flow. The three conditions were subtracted and their relative relationships examined. RESULTS: The random episodic condition produced activations in widely distributed association cortex (right and left frontal, parietal, angular/supramarginal, and posterior inferior temporal regions). Focused episodic memory engaged a network that included the medial inferior frontal regions, precuneus/retrosplenial cingulate, anterior cingulate, thalamus, and cerebellum. The use of medial frontal regions and the precuneus/retrosplenial cingulate was common to both focused and random episodic memory. The major difference between semantic and episodic memory was activation of Broca's area and the left frontal operculum by semantic memory. CONCLUSIONS: These results indicate that free-ranging mental activity (random episodic memory) produces large activations in association cortex and may reflect both active retrieval of past experiences and planning of future experiences. Focused episodic memory shares some components of this circuit (inferior frontal and precuneus), which may reflect the time-linked components of both aspects of episodic memory, and which permit human beings to experience personal identity, consciousness, and self-awareness.

Cerebral blood flow changes associated with attribution of emotional valence to pleasant, unpleasant, and neutral visual stimuli in a PET study of normal subjects.

OBJECTIVE: To assist in the development of a model for the psychopathology of emotions, the present study sought to identify the neural circuits associated with the evaluation of visual stimuli for emotional valence. METHOD: Seventeen healthy individuals were shown three sets of emotionally laden pictures carrying pleasant, unpleasant, and neutral content. While subjects evaluated the picture set for emotional valence, regional cerebral blood flow was measured with the use of [15O] water positron emission tomography. Subjective ratings of the emotional valence of the picture sets were recorded. Data were analyzed by comparing the images acquired during the neutral condition with the unpleasant and pleasant image sets and the unpleasant and pleasant conditions with each other. RESULTS: Processing of pleasant stimuli was associated with increased blood flow in the dorsal-lateral, orbital, and medial frontal cortex relative to the unpleasant condition and in the cingulate, precuneus, and visual cortex relative to the neutral condition. Evaluation of unpleasant stimuli activated the amygdala, visual cortex, and cerebellum relative to the pleasant condition and the nucleus accumbens, precuneus, and visual cortex relative to the neutral condition. CONCLUSIONS: Observing and assigning emotional value to unpleasant stimuli produced activations in subcortical limbic regions, whereas evaluation of pleasant stimuli produced activations in cortical limbic areas. These findings are consistent with the notion of a subcortical and archaic danger recognition system and a system detecting pleasantness in events and situations that is phylogenetically younger, involving primarily the prefrontal cortex.

Recalling word lists reveals "cognitive dysmetria" in schizophrenia: a positron emission tomography study.

OBJECTIVE: This study explored the neural circuitry used during recall of unstructured verbal material in schizophrenic patients and healthy volunteer subjects. METHOD: The subjects were 13 healthy volunteers and 14 schizophrenic patients. All patients were free of medication, and all subjects were right-handed. Two experimental cognitive conditions were used: recall of novel and practiced word lists (two 15-item lists from the Rey Auditory Verbal Learning Test). Both active recall tasks were compared with an eyes-closed resting baseline condition. A nonparametric randomization test was used to determine within- and between-group differences in regional cerebral blood flow. RESULTS: Performance on both the practiced and novel memory tasks was nonsignificantly different in the patients and control subjects. During the novel memory task, the patients showed decreased flow in the right anterior cingulate, right thalamus, and bilateral cerebellum (left greater than right) relative to the control subjects. When recalling the practiced word lists, the patients showed decreased flow in the left dorsolateral prefrontal cortex, bilateral medial frontal cortex, left supplementary motor area, left thalamus, left cerebellar regions, anterior vermis, and right cuneus. CONCLUSIONS: Patients with schizophrenia fail to activate cortical-cerebellar-thalamic-cortical circuitry during recall of both well-learned and novel word lists.

Effects of diagnosis, laterality, and gender on brain morphology in schizophrenia.

OBJECTIVE: Structural neuroimaging and neuropathological studies have demonstrated a variety of aspects of brain morphology that appear to distinguish schizophrenic patients from comparison subjects (diagnostic effects), a predominance of left-sided pathology (laterality effects), and a greater likelihood of brain abnormality among males (gender effects). However, findings have been inconsistent across studies, perhaps reflecting limited power due to small study group sizes. The goal of this study was to examine diagnostic, laterality, and gender effects of brain morphology as assessed by magnetic resonance imaging in a large, carefully evaluated group of schizophrenic and comparison subjects. METHOD: One hundred two patients with schizophrenia (DSM-III-R) (70 men and 32 women) and 87 normal comparison subjects, chosen to be equivalent to the patients in terms of familial socioeconomic background, underwent magnetic resonance imaging with a 1.5-tesla scanner. All regions of interest were outlined manually by an experienced technician on all slices in which they were visualized. Region of interest volumes were compared across groups, and age, sex, and stature were controlled. RESULTS: Schizophrenic patients were found to have larger lateral and third ventricles and smaller thalamic, hippocampal, and superior temporal volumes than comparison subjects. No significant differences were demonstrated for intracranial, cerebral, cerebellar, temporal lobe, caudate nuclei, or temporal horn volumes. There were no significant Laterality by Diagnosis effects and no significant Gender by Diagnosis effects for any of the regions of interest. CONCLUSIONS: Many, but not all, of the hypotheses informed by earlier studies regarding diagnostic effects were confirmed, while hypotheses regarding gender and laterality interactions with diagnosis were not supported.

The neuropsychology of the prefrontal cortex.

Single photon emission computed tomography with the xenon inhalation technique is used to compare activation of regional cerebral blood flow in frontal brain regions during the performance of four widely used neuropsychological tests: the Continuous Performance Test, the Wisconsin Card Sorting Test, the Tower of London, and Porteus Mazes. Healthy normal volunteers performing these tasks show significant increases in frontal regions during the Continuous Performance Test, the Wisconsin Card Sorting Test, and the Tower of London, but not the Porteus Mazes. Activation produced by the Continuous Performance Test and the Tower of London are mesial and bilateral and may reflect stimulation of midline attentional circuits. The Wisconsin Card Sorting Test produces a left dorsolateral area of prefrontal activation. These findings indicate that regional activation of the frontal lobes occurs in response to cognitive challenges produced through performance of standard neuropsychological tests.