Assessments of anterior cingulate cortex in experimental animals and humans have led to unifying theories of its structural organization and contributions to mammalian behaviour. The anterior cingulate cortex forms a large region around the rostrum of the corpus callosum that is termed the anterior executive region. This region has numerous projections into motor systems, however, since these projections originate from different parts of anterior cingulate cortex and because functional studies have shown that it does not have a uniform contribution to brain functions, the anterior executive region is further subdivided into ‘affect’ and ‘cognition’ components. The affect division includes areas 25, 33 and rostral area 24, and has extensive connections with the amygdala and periaqueductal grey, and parts of it project to autonomic brainstem motor nuclei. In addition to regulating autonomic and endocrine functions, it is involved in conditioned emotional learning, vocalizations associated with expressing internal states, assessments of motivational content and assigning emotional valence to internal and external stimuli, and maternal—infant interactions. The cognition division includes caudal areas 24' and 32', the cingulate motor areas in the cingulate sulcus and nociceptive cortex. The cingulate motor areas project to the spinal cord and red nucleus and have premotor functions, while the nociceptive area is engaged in both response selection and cognitively demanding information processing. The cingulate epilepsy syndrome provides important support of experimental animal and human functional imaging studies for the role of anterior cingulate cortex in movement, affect and social behaviours. Excessive cingulate activity in cases with seizures confirmed in anterior cingulate cortex with subdural electrode recordings, can impair consciousness, alter affective state and expression, and influence skeletomotor and autonomic activity. Interictally, patients with anterior cingulate cortex epilepsy often display psychopathic or sociopathic behaviours. In other clinical examples of elevated anterior cingulate cortex activity it may contribute to tics, obsessive—compulsive behaviours, and aberrent social behaviour. Conversely, reduced cingulate activity following infarcts or surgery can contribute to behavioural disorders including akinetic mutism, diminished self-awareness and depression, motor neglect and impaired motor initiation, reduced responses to pain, and aberrent social behaviour. The role of anterior cingulate cortex in pain responsiveness is suggested by cingulumotomy results and functional imaging studies during noxious somatic stimulation. The affect division of anterior cingulate cortex modulates autonomic activity and internal emotional responses, while the cognition division is engaged in response selection associated with skeletomotor activity and responses to noxious stimuli. Overall, anterior cingulate cortex appears to play a crucial role in initiation, motivation, and goal-directed behaviours. The anterior cingulate cortex is part of a larger matrix of structures that are engaged in similar functions. These structures form the rostral limbic system and include the amygdala, periaqueductal grey, ventral striatum, orbitofrontal and anterior insular cortices. The system formed by these interconnected areas assesses the motivational content of internal and external stimuli and regulates context-dependent behaviours.

Contributions of anterior cingulate cortex to behaviour.

Here we provide a review of the animal and human literature concerning the role of the amygdala in fear conditioning, considering its potential influence over autonomic and hormonal changes, motor behavior and attentional processes. A stimulus that predicts an aversive outcome will change neural transmission in the amygdala to produce the somatic, autonomic and endocrine signs of fear, as well as increased attention to that stimulus. It is now clear that the amygdala is also involved in learning about positively valenced stimuli as well as spatial and motor learning and this review strives to integrate this additional information. A review of available studies examining the human amygdala covers both lesion and electrical stimulation studies as well as the most recent functional neuroimaging studies. Where appropriate, we attempt to integrate basic information on normal amygdala function with our current understanding of psychiatric disorders, including pathological anxiety.

The amygdala: vigilance and emotion

The neurocognitive literature on test performance in schizophrenia is reviewed quantitatively. The authors report 22 mean effect sizes from 204 studies to index schizophrenia versus control differences in global and selective verbal memory, nonverbal memory, bilateral and unilateral motor performance, visual and auditory attention, general intelligence, spatial ability, executive function, language, and interhemispheric tactile-transfer test performance. Moderate to large raw effect sizes (d > .60) were obtained for all 22 neurocognitive test variables, and none of the associated confidence intervals included zero. The results indicate that schizophrenia is characterized by a broadly based cognitive impairment, with varying degrees of deficit in all ability domains measured by standard clinical tests.

Neurocognitive Deficit in Schizophrenia: A Quantitative Review of the Evidence

Stress affects cognition and increases noradrenaline and dopamine levels in the prefrontal cortex (PFC). Amy Arnsten discusses the intracellular signalling pathways that mediate the effects of these catecholamines on PFC function during acute and chronic stress, focusing on working memory. An interview with Amy Arnsten for Neuropod is available for
 download
 . The prefrontal cortex (PFC) — the most evolved brain region — subserves our highest-order cognitive abilities. However, it is also the brain region that is most sensitive to the detrimental effects of stress exposure. Even quite mild acute uncontrollable stress can cause a rapid and dramatic loss of prefrontal cognitive abilities, and more prolonged stress exposure causes architectural changes in prefrontal dendrites. Recent research has begun to reveal the intracellular signalling pathways that mediate the effects of stress on the PFC. This research has provided clues as to why genetic or environmental insults that disinhibit stress signalling pathways can lead to symptoms of profound prefrontal cortical dysfunction in mental illness.

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Stress signalling pathways that impair prefrontal cortex structure and function

A review of MRI findings in schizophrenia

• A hypothesis of psychosis localization in schizophrenia was derived from studying metabolic alterations in rat brain in response to phencyclidine hydrochloride administration. Since phencyclidine and its selective agonist dizocilpine maleate (MK801) induced overlapping and long-lasting metabolic alterations predominantly in limbic areas, the hypothesis developed that schizophrenic patients with psychosis would evidence functional abnormalities in limbic circuits compared with normal controls. Accordingly, 12 actively psychotic, drug-free patients with schizophrenia and matched normal controls underwent functional brain scans using positron emission tomography and fluorodeoxyglucose. Regions of interest were identified on five matched axial slices in each patient and control subject, and average metabolic rates were calculated. Patients with schizophrenia showed a significantly lower regional cere- bral metabolic rate of glucose in the hippocampus and the anterior cingulate cortex than did normal controls, but not in neocortical areas or in the extrapyramidal system. When the group of schizophrenic patients was divided into deficit and nondeficit types, a preliminary exploratory analysis suggested thalamic, frontal, and parietal cortical hypometabolism in the deficit subgroup, with normal metabolism in the nondeficit patient group in those areas; in contrast, hippocampal and anterior cingulate cortical metabolism was reduced in both deficit and nondeficit subtypes. These results suggest that the limbic system, especially the hippocampus, is functionally involved in schizophrenic psychosis and that different manifestations of schizophrenia may involve different neuronal circuits.

Limbic System Abnormalities Identified in Schizophrenia Using Positron Emission Tomography With Fluorodeoxyglucose and Neocortical Alterations With Deficit Syndrome

• We used magnetic resonance imaging to examine the morphologic characteristics of the amygdala/hippocampus, prefrontal cortex, and caudate nucleus in 29 healthy volunteers matched for age, gender, and head of household socioeconomic status and 44 patients with chronic schizophrenia. Total volumes of these structures were determined from 3-mm contiguous coronal sections. Schizophrenic patients, compared with healthy controls, had significantly smaller right and left amygdala/hippocampal complex volumes, smaller right and left prefrontal volumes, and larger left caudate volumes. A secondary analysis revealed reductions in the right and left amygdala and the left hippocampus. In addition, prefrontal white matter, but not gray matter, was reduced in the schizophrenic patients. Moreover, the right white matter volume in schizophrenic patients was significantly related to right amygdala/hippocampal volume ( r =.39), data that provide preliminary support for a hypothesis of abnormal limbic-cortical connection in schizophrenia. We studied the implications of these data for the pathophysiology of schizophrenia.

https://jamanetwork.com/journals/PSYCH/articlepdf/495963/archpsyc_49_12_003.pdf

Brain morphology and schizophrenia. A magnetic resonance imaging study of limbic, prefrontal cortex, and caudate structures.

Objective Clozapine is an atypical neuroleptic with superior efficacy in severely ill, treatment-resistant inpatients with schizophrenia. To determine if clozapine's differential efficacy generalizes to less ill, outpatients populations, the authors examined the effects of clozapine on positive and negative symptoms in outpatients with schizophrenia. Method Outpatients with schizophrenia who had histories of partial response to conventional neuroleptics and who had not responded to a prospective 6-week trial of fluphenazine participated in a 10-week, double-blind, parallel-groups comparison of clozapine and haloperidol. Thirteen men and six women were given clozapine, and 15 men and five women were given haloperidol. Clinical response rates were determined and effects on primary versus secondary negative symptoms were addressed. Doses of clozapine and haloperidol at the end of the 10-week trial were 410.5 mg/day (SD = 45.8) and 24.8 mg/day (SD = 5.5), respectively. Results Clozapine was superior to haloperidol for treating positive symptoms. In addition, eight of the patients given clozapine and only one of the patients given haloperidol fulfilled clinical responder criteria. Clozapine was also superior to haloperidol for treating negative symptoms, although these effects were relatively minor. Negative symptoms were significantly affected in the subgroup of patients with nondeficit schizophrenia but not in the subgroup with deficit schizophrenia. Overall, clozapine was well tolerated. Conclusions Clozapine has superior efficacy for treating positive symptoms in partially responsive outpatients with chronic schizophrenia, suggesting that it has utility for a broad spectrum of patients with schizophrenia beyond the most severely ill.

Effects of clozapine on positive and negative symptoms in outpatients with schizophrenia.

An association between inflammatory abnormalities and schizophrenia has been found repeatedly. The purposes of this special feature are to clarify the key findings on inflammation in schizophrenia, identify major gaps in the literature, and suggest priorities for research in this area. What is inflammation? Inflammation is one of the body’s first lines of defense in response to injury or infection, and increased inflammation is found in many diseases. Acute inflammation is a nonspecific response characterized by warmth, pain, and swelling. Leukocytes migrate to the area of injury and become activated, the blood supply to the area increases, and blood vessels become more permeable, allowing cells and molecules to leave blood vessels and enter the injured tissue. The inflammatory response also involves the complement system, a group of proteins that, when activated, combine to form a complex molecular structure that kills cells, usually bacteria and parasites. Cytokines are key molecules that regulate inflammation; they also have important roles in the immune system. They are produced by a wide variety of immune cells and cells outside of the immune system. The term cytokine derives from their ability to influence the movement of inflammatory cells, but they also have other functions. Chronic inflammation is usually a lower grade response, lacks the grossly visible signs of acute inflammation, and may be systemic rather than localized. Chronic inflammation plays a role in the pathophysiology of many chronic diseases, including cardiovascular and cerebrovascular disease, diabetes, Alzheimer’s disease, and some cancers. The characteristics of chronic inflammation differ somewhat in the brain from what occurs in other tissues. An important component of neuroinflammation is the microglial activation. The brain contains relatively few of the inflammatory cells that are found outside the brain. Microglia, which are related to the peripheral inflammatory cells, serve some of the protective functions such cells play in the rest of the body. Microglia are involved in other brain functions, including the pruning and maintenance of synapses, trafficking of neurotransmitters, and devouring—phagocytosis—of cell fragments and damaged cells. Activated microglia produce inflammatory cytokines and the phagocytose cells or proteins that provoke the inflammatory response. Microglial activation and subsequent proinflammatory cytokine production may disrupt the blood-brain barrier (BBB). An intact BBB usually tightly controls the entry of cytokines and leukocytes into brain tissue. Damage to the BBB impairs its ability to control which inflammatory cells and molecules enter the brain; other substances leak into brain tissue, and the brain is unable to function normally.

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Inflammation and Schizophrenia

Background: Previous studies have suggested that functional impairments of the frontal and parietal lobes are related to the deficit symptoms of schizophrenia. The purpose of the current study was to examine whether neuropsychological measures of frontal and parietal lobe function differentiated deficit from nondeficit patients. Neuropsychological measures of temporal lobe function were used as contrast measures. Methods: The performance of 18 deficit and 21 non-deficit schizophrenic patients was examined on neuropsychological measures of executive, visuospatial, and memory functions, selected on the basis of their association with lesions of either the frontal, parietal, or temporal lobes. The results from the schizophrenic subgroups were compared with the results on the same measures obtained from 30 normal controls. Results: Deficit patients performed more poorly than non-deficit patients on two frontal lobe measures, the Stroop Color-Word Interference and Trails Making B tests, and one parietal lobe measure, the Mooney Faces Closure Test. There were no differences in performance on the temporal lobe measures between the two groups. Both groups performed more poorly on the tests than the normal controls. Conclusion: The results suggest that deficit patients may have greater performance impairments on neuropsychological measures associated with frontal and parietal neuropsychological abnormalities.

Brian Kirkpatrick

Papers

Limbic System Abnormalities Identified in Schizophrenia Using Positron Emission Tomography With Fluorodeoxyglucose and Neocortical Alterations With Deficit Syndrome

Brain morphology and schizophrenia. A magnetic resonance imaging study of limbic, prefrontal cortex, and caudate structures.

Effects of clozapine on positive and negative symptoms in outpatients with schizophrenia.

Inflammation and Schizophrenia

Neuropsychological Impairments in Deficit vs Nondeficit Forms of Schizophrenia