Cognition in schizophrenia: core psychological and neural mechanisms

The challenge in understanding cognitive impairment in schizophrenia is that people with this illness have deficits in an array of domains. Here, we briefly review evidence regarding the pattern of deficits within three domains: context processing, working memory and episodic memory. We suggest that there may be a common mechanism driving deficits in these domains - an impairment in the ability to actively represent goal information in working memory to guide behavior, a function we refer to as proactive control. We suggest that such deficits in proactive control reflect impairments in dorsolateral prefrontal cortex, its interactions with other brain regions, such as parietal cortex, thalamus and striatum, and the influence of neurotransmitter systems, such as dopamine, GABA and glutamate.     

Role of prefrontal cortex and striatal output systems in short-term memory deficits associated with ageing, basal forebrain lesions, and cholinergic-rich grafts

The cholinergic hypothesis of geriatric memory dysfunction suggests (a) that basal forebrain lesions in animals should mimic cognitive and mnemonic impairments of human dementia and (b) that cholinergic grafts in the cortex and hippocampus may alleviate such impairments, whether induced by basal forebrain lesions or due to the intrinsic processes of ageing. Our own studies addressing these issues are reviewed. Although aged rats manifest impairments in short-term memory that are reversed by cholinergic grafts in the cortex and hippocampus, basal forebrain lesions have produced ambiguous results, which in part are attributable to nonspecific effects of the lesions. Acetylcholinesterase histochemistry and the topography of NBM-cortical connections indicate that basal forebrain lesions that include the NBM in general spare the cholinergic innervation of the prefrontal cortex, but can damage prefrontal cortical outflows via the globus pallidus. Two experiments are presented to indicate that the medial prefrontal cortex and its ventral striatal outputs provide a critical substrate for normal short-term memory performance in delayed matching and nonmatching tasks. These observations can resolve many of the discrepancies in previous lesion and graft studies.     

Cognition in schizophrenia: does working memory work?

Recent research suggests that disturbances in social and occupational functioning in individuals with schizophrenia may be more influenced by the severity of cognitive deficits than by the severity of symptoms such as hallucinations and delusions. In this article, I review evidence that one component of cognitive dysfunction in schizophrenia is a deficit in working memory, associated with disturbances in the dopamine system in dorsolateral prefrontal cortex. I suggest that although the cognitive deficits in schizophrenia include working memory dysfunction, because they arise from a disturbance in executive control processes (e.g., the representation and maintenance of context), they extend to a range of cognitive domains. Finally, I discuss the need for further research on the ways in which contextual processing deficits may influence other aspects of this illness, including emotional processing.     

Social cognition and its neural correlates in schizophrenia and autism

The study of social cognition in psychiatric disorders has become increasingly popular in recent years. This is due to the its proposed link to social functioning and the inability of general neurocognitive skills to explain the spectrum of impairments observed in patients. This article reviews research into two of the processes thought to underlie social cognition (emotion perception and theory of mind) in schizophrenia and autism. This is followed by a look at neuroimaging studies and their efforts to localize the neural correlates of emotion perception and theory of mind in the two disorders. We concluded that while a specific impairment in emotion perception and theory of mind skills cannot be generalized to all individuals with autism and schizophrenia, there are subpopulations that have lingering deficits of social cognition tasks. Neuroimaging work consistently points to the involvement of the fusiform gyrus and amygdala in emotion processing, while the medial prefrontal and frontal cortex are implicated in tasks invoking theory of mind. We propose that deficits of social cognition may benefit from cognitive remediation therapy and pharmacological cognitive enhancers.     

Alpha2A-adrenoceptor stimulation improves prefrontal cortical regulation of behavior through inhibition of cAMP signaling in aging animals

The working-memory functions of the prefrontal cortex (PFC) are improved by stimulation of postsynaptic, alpha2A-adrenoceptors, especially in aged animals with PFC cognitive deficits. Thus, the alpha2A-adrenoceptor agonist, guanfacine, greatly improves working-memory performance in monkeys and rats following systemic administration or intra-PFC infusion. Alpha2A-adrenoceptors are generally coupled to Gi, which can inhibit adenylyl cyclases and reduce the production of cAMP. However, no study has directly examined whether the working-memory enhancement observed with guanfacine or other alpha2A-adrenoceptor agonists results from cAMP inhibition. The current study confirmed this hypothesis in both rats and monkeys, showing that treatments that increase cAMP-mediated signaling block guanfacine's beneficial effects. In aged rats, guanfacine was infused directly into the prelimbic PFC and was challenged with co-infusions of the cAMP analog, Sp-cAMPS. In aging monkeys, systemically administered guanfacine was challenged with the phosphodiesterase 4 inhibitor, rolipram, using intramuscular doses known to have no effect on their own. In both studies, agents that mimicked the actions of cAMP (rats) or increased endogenous cAMP (monkeys) completely blocked the enhancing effects of guanfacine on working-memory performance. These results are consistent with alpha2A-adrenoceptor stimulation enhancing PFC working-memory function via inhibition of cAMP-mediated signaling.     

Role of the serotonin 5-HT(2A) receptor in learning

This study reviews the role of the serotonin 5-HT2A receptor in learning as measured by the acquisition of the rabbit's classically conditioning nictitating membrane response, a component of the eyeblink response. Agonists at the 5-HT2A receptor including LSD (d-lysergic acid diethylamide) enhanced associative learning at doses that produce cognitive effects in humans. Some antagonists such as BOL (d-bromolysergic acid diethylamide), LY53,857, and ketanserin acted as neutral antagonists in that they had no effect on learning, whereas others (MDL11,939, ritanserin, and mianserin) acted as inverse agonists in that they retarded learning through an action at the 5-HT2A receptor. These results were placed in the context of what is known concerning the anatomical distribution and electrophysiological effects of 5-HT2A receptor activation in frontal cortex and hippocampus, as well as the role of cortical 5-HT2A receptors in schizophrenia. It was concluded that the 5-HT2A receptor demonstrates constitutive activity, and that variations in this activity can produce profound alterations in cognitive states.     

Habituation and sensitization of acoustic startle: opposite influences of dopamine D1 and D2-family receptors

The startle response evoked by repeated presentation of a loud acoustic stimulus is regulated by the independent processes of sensitization and habituation. While schizophrenia is associated with information processing impairments, there is conflicting evidence regarding the existence of habituation deficits in schizophrenic patients. Recent clinical evidence, however, indicates that patients with schizophrenia display exaggerated startle sensitization and diminished habituation. Given the linkage between dopaminergic abnormalities and schizophrenia, the goal of the present investigation was to examine the effect of deleting D₁ and D₂-like dopamine receptors on sensitization and habituation of the acoustic startle reflex in mice. For these experiments, the acoustic startle reflex was assessed in dopamine D₁, D₂, and D₃ receptor wild-type (WT) and knockout (KO) mice on a C57BL/6J background, using a methodology that can measure both sensitization and habituation. Mice lacking the D₁ receptor gene displayed enhanced sensitization, along with a decrease in the amount of habituation that occurs in response to repetitive presentations of a startling stimulus. Conversely, the loss of the dopamine D₂ or D₃ receptor gene produced a sensitization deficit and a significant increase in habituation. The behavioral phenotype exhibited by D₁ receptor KO mice is clearly distinct from that of the D₂ and D₃ receptor KO mice. The findings in D₁ receptor KO mice are reminiscent of the abnormalities observed in schizophrenic patients tested in comparable startle paradigms, and indicate that D₁ agonists may possess therapeutic efficacy against the information processing deficits associated with schizophrenia.     

Working and long-term memory deficits in schizophrenia: is there a common prefrontal mechanism?

This study tested the hypothesis that dorsolateral prefrontal cortex deficits contribute to both working memory and long-term memory disturbances in schizophrenia. It also examined whether such deficits were more severe for verbal than nonverbal stimuli. Functional magnetic resonance imaging was used to assess cortical activation during performance of verbal and nonverbal versions of a working memory task and both encoding and recognition tasks in 38 individuals with schizophrenia and 48 healthy controls. Performance of both working memory and long-term memory tasks revealed disturbed dorsolateral prefrontal cortex activation in schizophrenia, although medial temporal deficits were also present. Some evidence was found for more severe cognitive and functional deficits with verbal than nonverbal stimuli, although these results were mixed.     

Developmental outcomes after early prefrontal cortex damage

The neuropsychological bases of cognitive, social, and moral development are minimally understood, with a seemingly wide chasm between developmental theories and brain maturation models. As one approach to bridging ideas in these areas, we review 10 cases of early prefrontal cortex damage from the clinical literature, highlighting overall clinical profiles and real life developmental outcomes. Based on these cases, there is preliminary evidence to support distinctive developmental differences after: (1) dorsolateral, (2) mesial, and (3) orbital-polar prefrontal lesions, for more profound impairments after bilateral damage, and possibly for recovery differences after very early vs. later childhood lesion onset. Further case and group studies are needed to confirm reliable effects of specific lesion locations, the influence of age of lesion onset, and related experiential and treatment variables in determining adult outcomes. Rather than a single underlying deficit associated with early prefrontal cortex damage, we interpret the findings to suggest that it is the altered integration and interplay of cognitive, emotional, self-regulatory, and executive/metacognitive deficits that contribute to diverse developmental frontal lobe syndromes. The findings support the fundamental importance of prefrontal cortex maturation in protracted cognitive, social-emotional, and moral development.     

Developmental depersonalization: the prefrontal cortex and self-functions in autism

The human self model suggests that the construct of self involves functions such as agency, body-centered spatial perspectivity, and long-term unity. Vogeley, Kurthen, Falkai, and Maieret (1999) suggest that agency is subserved by the prefrontal cortex and other association areas of the cortex, spatial perspectivity by the prefrontal cortex and the parietal lobes, and long-term unity by the prefrontal cortex and the temporal lobes and that all of these functions are impaired in schizophrenia. Exploring the connections between the prefrontal cortex and the construct of self, the present article extends the application of the self model to autism. It suggests that in contrast to schizophrenia, agency and spatial perspectivity are probably preserved in autism, but that, similarly to schizophrenia, long-term unity is probably impaired. This hypothesis is compatible with a model of neuropsychological dysfunction in autism in a neural network including parts of the prefrontal cortex, the temporal lobes, and the cerebellum.     

Conflict and Cognitive Control in the Brain

ABSTRACT— Recent research from cognitive psychology and cognitive neuroscience has suggested that the control mechanisms by which people are able to regulate task performance can be dissociated into evaluative and executive components. One process, implemented in the anterior cingulate cortex of the brain, monitors the amount of conflict that occurs during information processing; another process, implemented in the dorsolateral prefrontal cortex, is involved with maintaining the requirements of the task at hand and with biasing information processing in favor of appropriate responses. In the current article, we review this theory and some of the research that has supported it, including its implication for understanding cognitive disturbances in clinical disorders such as schizophrenia and obsessive-compulsive disorder. We conclude by addressing several interesting possibilities for future research.     

前额叶损害对个体一般智力、认知策略与自我监控能力影响的研究

本研究随机挑选了15名因外伤而造成的前额叶损害者和15名正常成人,采用韦氏成人智力量表和自编的图片分类作业,考查了他们在一般智力、认知策略与自我监控能力方面的差异,研究结果表明:(1)前额叶损害对个体的一般智力产生显著的影响,但是其智力仍然处于正常范围,可见智力的脑结构范围极为广泛,智力是一个具有多重性的系统。(2)前额叶损害者对无关刺激的抑制,对有效信息的提取与加工放大的心理活动受到极大影响,认知策略转换能力明显低于正常人,表现出了明显的认知不随意性,额叶可能更多的与个体的计划、认知策略选择、自我监控密切相关;(3)前额叶损害者对具体概念与抽象概念的自我监控能力表现出了不同的影响,对前者的损害显著大于后者,这表明个体依据具体概念进行的形象思维与凭借抽象概念进行的逻辑思维有不同的脑机制。     

Reduced susceptibility to confirmation bias in schizophrenia

Patients with schizophrenia (SZ) show cognitive impairments on a wide range of tasks, with clear deficiencies in tasks reliant on prefrontal cortex function and less consistently observed impairments in tasks recruiting the striatum. This study leverages tasks hypothesized to differentially recruit these neural structures to assess relative deficiencies of each. Forty-eight patients and 38 controls completed two reinforcement learning tasks hypothesized to interrogate prefrontal and striatal functions and their interaction. In each task, participants learned reward discriminations by trial and error and were tested on novel stimulus combinations to assess learned values. In the task putatively assessing fronto-striatal interaction, participants were (inaccurately) instructed that one of the stimuli was valuable. Consistent with prior reports and a model of confirmation bias, this manipulation resulted in overvaluation of the instructed stimulus after its true value had been experienced. Patients showed less susceptibility to this confirmation bias effect than did controls. In the choice bias task hypothesized to more purely assess striatal function, biases in endogenously and exogenously chosen actions were assessed. No group differences were observed. In the subset of participants who showed learning in both tasks, larger group differences were observed in the confirmation bias task than in the choice bias task. In the confirmation bias task, patients also showed impairment in the task conditions with no prior instruction. This deficit was most readily observed on the most deterministic discriminations. Taken together, these results suggest impairments in fronto-striatal interaction in SZ, rather than in striatal function per se.     

The Cognitive Demands of Gait Retraining in Runners: An EEG Study

Abstract

High impact forces during running have been associated with tibial stress injuries. Previous research has demonstrated increasing step rate will decrease impact forces during running. However, no research has determined the cognitive demand of gait retraining. The primary purpose was to determine the cognitive demand and effectiveness of field-based gait retraining. We hypothesized that in-field gait retraining would alter running mechanics without increasing cognitive workload as measured by EEG following learning. Runners with a history of tibial injury completed a gait retraining protocol which included a baseline run, retraining phase, practice phase, and re-assessment following retraining protocol. Results demonstrated an increase in the theta, beta, and gamma power within prefrontal cortex during new learning and corresponding return to baseline following skill acquisition and changes across alpha, beta, gamma, mu, and theta in the motor cortex (p < .05). In the midline superior parietal cortex, spectral power was greater for theta activity during new learning with a corresponding alpha suppression. Overall, the results demonstrated the use of EEG as an effective tool to measure cognitive demand for implicit motor learning and the effectiveness of in-field gait retraining.     

Molecular mechanisms of stress-induced prefrontal cortical impairment: implications for mental illness

The symptoms of mental illness often involve weakened regulation of thought, emotion, and behavior by the prefrontal cortex. Exposure to stress exacerbates symptoms of mental illness and causes marked prefrontal cortical dysfunction. Studies in animals have revealed the intracellular signaling pathways activated by stress exposure that induce profound prefrontal cortical impairment: Excessive dopamine stimulation of D1 receptors impairs prefrontal function via cAMP intracellular signaling, leading to disconnection of prefrontal networks, while excessive norepinephrine stimulation of alpha1 receptors impairs prefrontal function via phosphatidylinositol-protein kinase C intracellular signaling. Genetic studies indicate that the genes disrupted in serious mental illness (bipolar disorder and schizophrenia) often encode for the intracellular proteins that serve as brakes on the intracellular stress pathways. For example, disrupted in schizophrenia 1 (DISC1) normally regulates cAMP levels, while regulator of G protein signaling 4 (RGS4) and diacylglycerol kinase (DGKH)-the molecule most associated with bipolar disorder- normally serve to inhibit phosphatidylinositol-protein kinase C intracellular signaling. Patients with mutations resulting in loss of adequate function of these genes likely have weaker endogenous regulation of these stress pathways. This may account for the vulnerability to stress and the severe loss of PFC regulation of behavior, thought, and affect in these illnesses. This review highlights the signaling pathways onto which genetic vulnerability and stress converge to impair PFC function and induce debilitating symptoms such as thought disorder, disinhibition, and impaired working memory.     

Evidence for a detrimental relationship between hypertension history, prospective memory, and prefrontal cortex white matter in cognitively normal older adults

Hypertension affects many older adults and is associated with impaired neural and cognitive functioning. We investigated whether a history of hypertension was associated with impairments to prospective memory, which refers to the ability to remember to perform delayed intentions, such as remembering to take medication. Thirty-two cognitively normal older adult participants with or without a history of hypertension (self-reported) performed two laboratory prospective memory tasks, one that relied more strongly on executive control (nonfocal prospective memory) and one that relied more strongly on spontaneous memory retrieval processes (focal prospective memory). We observed hypertension-related impairments for nonfocal, but not focal, prospective memory. To complement our behavioral approach, we conducted a retrospective analysis of available structural magnetic resonance imaging data. Lower white matter volume estimates in the anterior prefrontal cortex were associated with lower nonfocal prospective memory and with a history of hypertension. A history of hypertension may be associated with worsened executive control and lower prefrontal white matter volume. The translational implication is that individuals who must remember to take antihypertensive medications and to monitor their blood pressure at home may be impaired in the executive control process that helps to support these prospective memory behaviors.     

Turning it Upside Down: Areas of Preserved Cognitive Function in Schizophrenia

Patients with schizophrenia demonstrate marked impairments on most clinical neuropsychological tests. These findings suggest that patients suffer from a generalized form of cognitive impairment, with little evidence of spared performance documented in several large meta-analytic reviews of the clinical literature. In contrast, we review evidence for relative sparing of aspects of attention, procedural memory, and emotional processing observed in studies that have employed experimental approaches adapted from the cognitive and affective neuroscience literature. These islands of preserved performance suggest that the cognitive deficits in schizophrenia are not as general as they appear to be when assayed with clinical neuropsychological methods. The apparent contradiction in findings across methods may offer important clues about the nature of cognitive impairment in schizophrenia. The documentation of preserved cognitive function in schizophrenia may serve to sharpen hypotheses about the biological mechanisms that are implicated in the illness.     

Neuroimaging of declarative memory in schizophrenia

The past three decades have seen tremendous growth in our understanding of the cerebral underpinnings of schizophrenia. including the neural correlates of the cognitive impairment seen in this syndrome. In this article we review the role that structural and functional neuroimaging has played in elucidating the cerebral basis for the declarative memory deficits associated with schizophrenia. Memory impairment in schizophrenia appears to involve abnormal connectivity between the prefrontal cortex and three regions important in normal learning and memory: the hippocampus, thalamus, and cerebellum.     

Remembering the time: a continuous clock

The neural mechanisms for time measurement are currently a subject of much debate. This article argues that our brains can measure time using the same dorsolateral prefrontal cells that are known to be involved in working memory. Evidence for this is: (1) the dorsolateral prefrontal cortex is integral to both cognitive timing and working memory; (2) both behavioural processes are modulated by dopamine and disrupted by manipulation of dopaminergic projections to the dorsolateral prefrontal cortex; (3) the neurons in question ramp their activity in a temporally predictable way during both types of processing; and (4) this ramping activity is modulated by dopamine. The dual involvement of these prefrontal neurons in working memory and cognitive timing supports a view of the prefrontal cortex as a multipurpose processor recruited by a wide variety of tasks.     

Functional Neuroimaging Correlates of Functional Amnesia

Especially in the field of memory encoding and retrieval, the results of functional neuroimaging have provided new insights in anatomico-functional interactions. In particular this holds true for the role of the prefrontal cortex in mnestic information processing, for the contribution and participation of the two hemispheres in various processes of information transmission, and for views on disturbed information processing after organically obvious and so-called psychogenic forms of memory impairments. This report particularly stresses the insights obtained by functional neuroimaging for probably environmentally triggered deficiencies in memory processing and discusses possible subtle neuroanatomical correlates of functional amnesias. It is especially emphasised that stress conditions and depressive states may modify the release of steroids (glucocorticoids) and transmitter agonists at the brain level with the consequence of selective memory disturbances which may manifest as a ‘mnestic block syndrome’.