Veena Kumari

Nicotine use in schizophrenia : The self medication hypotheses

The behavioural and cognitive effects of nicotine in schizophrenia have received much interest in recent years. The rate of smoking in patients with schizophrenia is estimated to be two- to four-fold the rate seen in the general population. Furthermore such patients favour stronger cigarettes and may also extract more nicotine from their cigarettes than other smokers. The question has been raised whether the widespread smoking behaviour seen in this patient group is in fact a manifestation of a common underlying physiology, and that these patients smoke in an attempt to self-medicate. We present an overview of the explanations for elevated rates of smoking in schizophrenia, with particular emphasis on the theories relating this behaviour to sensory gating and cognitive deficits in this disorder that have been viewed as major support for the self-medication hypotheses.

The relationship between brain structure and neurocognition in schizophrenia: a selective review

Both Kraepelin [1919. Dementia Praecox and Paraphrenia, Livingston, Edinburgh.] and Bleuler [1911. Dementia Praecox or the Group of Schizophrenias. Reprinted 1950 (trans. and ed. J. Zinkin). New York: International Univ. Press.] proposed that cognitive disturbances in schizophrenia are manifestations of brain abnormality. With the advent of magnetic resonance imaging (MRI) methodology, a number of studies have attempted to determine the relationship between brain structure and neurocognition in schizophrenia. We performed a review (1991-to date) of such studies with the aim of identifying the most consistent and compelling findings. The review revealed that whole brain volume tends to correlate with the measures of general intelligence as well as with a range of specific cognitive functions in normal controls and female schizophrenia patients, but this relationship is disrupted in male patients. The enlargement of the third ventricle, relative to the whole brain volume, is associated with deficient abstraction/flexibility, language, and attention/concentration in patients, whereas disproportionally larger lateral ventricles are associated with poorer psychomotor speed and attention/concentration in women, but not in men, with schizophrenia. Archicortical, but not paleocortical, prefrontal cortex tends to associate with the measures of executive function in both sexes regardless of diagnosis. Temporal lobe, hippocampus and parahippocampal gyrus correlate with cognitive abilities such as performance speed and accuracy, memory and executive function, verbal endowment and abstraction/categorization, respectively. Some of these medial temporal lobe/neurocognition relationships appear to be specific to schizophrenia (i.e. not seen in controls). Striatal size is positively associated with goal-directed behavior, but not perseveration, in schizophrenia. Larger cerebellum is associated with higher IQ in normal controls and affected women, but this association is disrupted in affected men. Increased white matter of the vermis is associated with poorer language and immediate verbal memory in schizophrenia. Finally, the methodological limitations of the reviewed studies are discussed and suggestions for future research are offered.

Longitudinal study of symptoms and cognitive function in chronic schizophrenia.

There is conflicting evidence of a relationship between changes in symptoms and cognitive functioning in schizophrenia. This study investigated longitudinal changes in psychopathology and cognitive functioning in chronic schizophrenia utilising three different dimensional models of symptomatology. Sixty-two patients diagnosed with DSM-IV schizophrenia or schizoaffective disorder were examined on two occasions over a period of 6 months for symptom improvement, measured by Positive and Negative Syndrome Scale (PANSS) [Kay et al., Schizophr. Bull. 13 (1987) 261]. Participants also completed a comprehensive battery of neuropsychological tasks designed to assess attention, verbal and non-verbal memory, psychomotor processing and executive/frontal functioning on both occasions. Twenty-five control subjects were assessed for comparison purposes. Severity of negative symptoms predicted poor neuropsychological performance on IQ, verbal fluency and memory measures at occasion one. However, using regression analyses, significant improvements in symptom ratings over time using two-, three- or five-dimensional models did not predict improvements in any aspect of cognitive functioning measured, except motor speed. The results do not suggest a causal relationship between the course of symptoms and neuropsychological functioning in chronic schizophrenia.

Cognitive generation of affect in bipolar depression: an fMRI study

Individuals with bipolar disorder manifest the full spectrum of emotions ranging from depression to mania. In attempting to understand the functional substrates of mood we attempted to identify brain regions associated with the cognitive generation of affect in bipolar depressed patients. We therefore examined ten depressed female subjects with bipolar affective disorder, and ten age‐matched and sex‐matched healthy comparison subjects using functional magnetic resonance imaging (fMRI) while viewing alternating blocks of captioned pictures designed to evoke negative, positive or no affective change. The activation paradigm involved the presentation of the same visual materials over three experiments alternating (experiment 1) negative and reference; (experiment 2) positive and reference and (experiment 3) positive and negative captioned pictures. The stimuli produced activation in both patients and comparison subjects in brain regions previously implicated in the generation and modulation of affect, in particular the prefrontal and anterior cingulate cortices. The activation in patients, when compared with healthy subjects, involved additional subcortical regions, in particular the amygdala, thalamus, hypothalamus and medial globus pallidus. Patients and comparison subjects displayed differential sensitivity to affective change with negative (experiment 1) and positive (experiment 2) affect induction producing converse patterns of activation. We conclude that bipolar depressed patients perhaps recruit additional subcortical limbic systems for emotional evaluation and this may reflect state‐related or trait‐related dysfunction. The differential patterns of activation inform us about bipolar depression and have potential diagnostic and therapeutic significance.

The relationship of structural alterations to cognitive deficits in schizophrenia: a voxel-based morphometry study.

BACKGROUND Region of interest studies have identified a number of structure-cognition associations in schizophrenia and revealed alterations in structure-cognition relationship in this population. METHODS We examined the relationship of structural brain alterations, identified using voxel-based morphometry, to cognitive deficits in 45 schizophrenia patients relative to 43 healthy control subjects and tested the hypothesis that structure-cognition relationship is altered in schizophrenia. RESULTS Patients had smaller total brain, gray matter, and white matter volumes. Regional alterations were left-hemisphere specific, including: gray matter reduction of inferior frontal, lingual, and anterior superior temporal gyri; white matter reduction of posterior and occipital lobes; and gray matter increase of the putamen and the precuneus. Smaller whole brain and gray matter volumes were associated with lower premorbid intelligence quotient (IQ) and poorer performance on IQ-dependent cognitive measures in patients and to a similar extent in control subjects. Larger precuneus was associated with better immediate verbal memory in patients, whereas verbal and nonverbal memory were positively associated with inferior frontal gyrus volume in control subjects. Smaller occipital white matter volume was associated with slower information processing speed in patients but not in control subjects. CONCLUSIONS Regional volume alterations are associated with specific cognitive deficits in schizophrenia. Some structure-cognition relationships differentiate this population from healthy control subjects.

Neural correlates of tactile prepulse inhibition: a functional MRI study in normal and schizophrenic subjects

Prepulse inhibition (PPI) of the startle reflex refers to the ability of a weak prestimulus, the prepulse, to inhibit the response to a closely following strong sensory stimulus, the pulse. PPI is found to be deficient in a number of psychiatric and neurological disorders associated with abnormalities at some level in the limbic and cortico-pallido-striato-thalamic circuitry. We applied whole-brain functional magnetic resonance imaging to elucidate the neural correlates of PPI using airpuff stimuli as both the prepulse and the pulse in groups of (i) healthy subjects and (ii) schizophrenic patients. Cerebral activation during prepulse-plus-pulse stimuli with stimulus-onset asynchronies of 120 ms was contrasted with activation during pulse-alone stimuli. In healthy subjects, PPI was associated with increased activation bilaterally in the striatum extending to hippocampus and thalamus, right inferior frontal gyrus and bilateral inferior parietal lobe/supramarginal gyrus, and with decreased activation in the right cerebellum and left medial occipital lobe. All activated regions showed significantly greater response in healthy subjects than schizophrenic patients, who also showed a trend for lower PPI. The findings demonstrate involvement of the striatum, hippocampus, thalamus, and frontal and parietal cortical regions in PPI. Dysfunctions in any of these regions may underlie observations of reduced PPI in schizophrenia.

Personality Predicts Brain Responses to Cognitive Demands

Eysenck (1981) proposed that the personality dimension of introversion- extraversion (E) reflects individual differences in a cortical arousal system modulated by reticulothalamic- cortical pathways: it is chronically more active in introverts relative to extraverts and influences cognitive performance in interaction with task parameters. A circuit with connections to this system, including the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate (AC) cortex, has been identified in studies applying functional magnetic resonance imaging (fMRI) to a broad range of cognitive tasks. We examined the influence of E, assessed with the Eysenck Personality Questionnaire-Revised (Eysenck and Eysenck, 1991), in fMRI activity during an “n-back” task involving four memory loads (0-, 1-, 2-, and 3-back) and a rest condition in healthy men. To confirm the specificity of E effects, we also examined the effects of neuroticism and psychoticism (P) scores. We observed that, as predicted by Eysencks model, the higher the E score, the greater the change in fMRI signal from rest to the 3-back condition in the DLPFC and AC. In addition, E scores were negatively associated with resting fMRI signals in the thalamus and Brocas area extending to Wernickes area, supporting the hypothesized (negative) relationship between E and resting arousal. P scores negatively correlated with resting fMRI signal in the globus pallidus-putamen, extending previous findings of a negative relationship of schizotypy to striatal activity seen with older neuroimaging modalities to fMRI. These observations suggest that individual differences affect brain responses during cognitive activity and at rest and provide evidence for the hypothesized neurobiological basis of personality.

Volumetric structural brain abnormalities in men with schizophrenia or antisocial personality disorder

Brain abnormalities are found in association with antisocial personality disorder and schizophrenia, the two mental disorders most implicated in violent behaviour. Structural magnetic resonance imaging was used to investigate the whole brain, cerebellum, temporal lobe, lateral ventricles, caudate nucleus, putamen, thalamus, hippocampus, amygdala and the prefrontal, pre-motor, sensorimotor, occipito-parietal regions in 13 men with antisocial personality disorder, 13 men with schizophrenia and a history of violence, 15 men with schizophrenia without violent history and 15 healthy non-violent men. Compared to controls, the antisocial personality disorder group displayed reductions in whole brain volume and temporal lobe as well as increases in putamen volume. Both schizophrenia groups regardless of violence history exhibited increased lateral ventricle volume, while the schizophrenia group with violent history showed further abnormalities including reduced whole brain and hippocampal volumes and increased putamen size. The findings suggest that individuals with antisocial personality disorder as well as those with schizophrenia and a history of violence have common neural abnormalities, but also show neuro-anatomical differences. The processes by which they came to apparently common ground may, however, differ. The finding of temporal lobe reductions prevalent among those with antisocial personality disorder and hippocampal reduction in the violent men with schizophrenia contributes support for the importance of this region in mediating violent behaviour.

Identical, but not the same: Intra-site and inter-site reproducibility of fractional anisotropy measures on two 3.0 T scanners

Diffusion Tensor Imaging (DTI) is being increasingly used to assess white matter integrity and it is therefore paramount to address the test–retest reliability of DTI measures. In this study we assessed inter- and intra-site reproducibility of two nominally identical 3 T scanners at different sites in nine healthy controls using a DTI protocol representative of typical current “best practice” including cardiac gating, a multichannel head coil, parallel imaging and optimized diffusion gradient parameters. We calculated coefficients of variation (CV) and intraclass correlation coefficients (ICC) of fractional anisotropy (FA) measures for the whole brain, for three regions of interest (ROI) and for three tracts derived from these ROI by probabilistic tracking. We assessed the impact of affine, nonlinear and template based methods for spatially aligning FA maps on the reproducibility. The intra-site CV for FA ranged from 0.8% to 3.0% with ICC from 0.90 to 0.99, while the inter-site CV ranged from 1.0% to 4.1% with ICC of 0.82 to 0.99. Nonlinear image coregistration improved reproducibility compared to affine coregistration. Normalization to template space reduced the between-subject variation, resulting in lower ICC values and indicating a possibly reduced sensitivity. CV from probabilistic tractography were about 50% higher than for the corresponding seed ROI. Reproducibility maps of the whole scan volume showed a low variation of less than 5% in the major white matter tracts but higher variations of 10–15% in gray matter regions. One of the two scanners showed better intra-site reproducibility, while the intra-site CV for both scanners was significantly better than inter-site CV. However, when using nonlinear coregistration of FA maps, the average inter-site CV was below 2%. There was a consistent inter-site bias, FA values on site 2 were 1.0–1.5% lower than on site 1. Correction for this bias with a global scaling factor reduced the inter-site CV to the range of intra-site CV. Our results are encouraging for multi-centre DTI studies in larger populations, but also illustrate the importance of the image processing pipeline for reproducibility.

Effects of typical and atypical antipsychotics on prepulse inhibition in schizophrenia: a critical evaluation of current evidence and directions for future research

Prepulse inhibition (PPI) of the startle response refers to an attenuation in response to a strong stimulus (pulse) if this is preceded shortly by a weak non-startling stimulus (prepulse). PPI provides a simple operational measure of sensorimotor gating, serving to prevent the interruption of ongoing perceptual and early sensory analysis. In accord with postulated deficits in early stages of information processing, there is ample evidence that PPI is disrupted in individuals with schizophrenia. PPI in animals is thought to represent a well-validated model for evaluating potential new treatments for schizophrenia. Currently, available data on the differential effects of typical and atypical antipsychotics suggest that atypical antipsychotics, in particular clozapine and risperidone, may be more effective than typical antipsychotics in improving PPI deficits in schizophrenia. However, studies have so far used small samples and/or between-subjects designs, and not examined the effects of other concomitant medications that may also influence PPI. The directions are identified for further applications of this model using within-subjects longitudinal designs and reasonable sample sizes to establish superiority of particular atypical antipsychotics over typical antipsychotics in improving PPI in schizophrenic populations.