Coleman Garrett

Motivation and its Relationship to Neurocognition, Social Cognition, and Functional Outcome in Schizophrenia

OBJECTIVE A burgeoning area of research has focused on motivational deficits in schizophrenia, producing hypotheses about the role that motivation plays in the well-known relationship between neurocognition and functional outcome. However, little work has examined the role of motivation in more complex models of outcome that include social cognition, despite our increased understanding of the critical role of social cognition in community functioning in schizophrenia, and despite new basic science findings on the association between social cognitive and reward processing in neural systems in humans. Using path analysis, we directly contrasted whether motivation 1) causally influences known social cognitive deficits in schizophrenia, leading to poor outcome or 2) mediates the relationship between social cognitive deficits and outcome in this illness. METHOD Ninety one patients with schizophrenia or schizoaffective disorder completed interview-based measures of motivation and functional outcome as well as standardized measures of neurocognition and social cognition in a cross-sectional design. RESULTS In line with recent research, motivation appears to mediate the relationship between neurocognition, social cognition and functional outcome. A model with motivation as a causal factor resulted in poor fit indicating that motivation does not appear to precede neurocognition. CONCLUSIONS Findings in the present study indicate that motivation plays a significant and mediating role between neurocognition, social cognition, and functional outcome. Potential psychosocial treatment implications are discussed, especially those that emphasize social cognitive and motivational enhancement.

Global and regional functional connectivity maps of neural oscillations in focal epilepsy

Intractable focal epilepsy is a devastating disorder with profound effects on cognition and quality of life. Epilepsy surgery can lead to seizure freedom in patients with focal epilepsy; however, sometimes it fails due to an incomplete delineation of the epileptogenic zone. Brain networks in epilepsy can be studied with resting-state functional connectivity analysis, yet previous investigations using functional magnetic resonance imaging or electrocorticography have produced inconsistent results. Magnetoencephalography allows non-invasive whole-brain recordings, and can be used to study both long-range network disturbances in focal epilepsy and regional connectivity at the epileptogenic zone. In magnetoencephalography recordings from presurgical epilepsy patients, we examined: (i) global functional connectivity maps in patients versus controls; and (ii) regional functional connectivity maps at the region of resection, compared to the homotopic non-epileptogenic region in the contralateral hemisphere. Sixty-one patients were studied, including 30 with mesial temporal lobe epilepsy and 31 with focal neocortical epilepsy. Compared with a group of 31 controls, patients with epilepsy had decreased resting-state functional connectivity in widespread regions, including perisylvian, posterior temporo-parietal, and orbitofrontal cortices (P < 0.01, t-test). Decreased mean global connectivity was related to longer duration of epilepsy and higher frequency of consciousness-impairing seizures (P < 0.01, linear regression). Furthermore, patients with increased regional connectivity within the resection site (n = 24) were more likely to achieve seizure postoperative seizure freedom (87.5% with Engel I outcome) than those with neutral (n = 15, 64.3% seizure free) or decreased (n = 23, 47.8% seizure free) regional connectivity (P < 0.02, chi-square). Widespread global decreases in functional connectivity are observed in patients with focal epilepsy, and may reflect deleterious long-term effects of recurrent seizures. Furthermore, enhanced regional functional connectivity at the area of resection may help predict seizure outcome and aid surgical planning.

Intensive cognitive training in schizophrenia enhances working memory and associated prefrontal cortical efficiency in a manner that drives long-term functional gains

We investigated whether intensive computerized cognitive training in schizophrenia could improve working memory performance and increase signal efficiency of associated middle frontal gyri (MFG) circuits in a functionally meaningful manner. Thirty schizophrenia participants and 13 healthy comparison participants underwent fMRI scanning during a letter N-back working memory task. Schizophrenia participants were then randomly assigned to either 80 h (16 weeks) of cognitive training or a computer games control condition. After this intervention, participants completed a second fMRI N-back scanning session. At baseline, during 2-back working memory trials, healthy participants showed the largest and most significant activation in bilateral MFG, which correlated with task performance. Schizophrenia participants showed impaired working memory, hypoactivation in left MFG, and no correlation between bilateral MFG signal and task performance. After training, schizophrenia participants improved their 2-back working memory performance and showed increased activation in left MFG. They also demonstrated a significant association between enhanced task performance and right MFG signal, similar to healthy participants. Both task performance and brain activity in right MFG after training predicted better generalized working memory at 6-month follow-up. Furthermore, task performance and brain activity within bilateral MFG predicted better occupational functioning at 6-month follow-up. No such findings were observed in the computer games control participants. Working memory impairments in schizophrenia and its underlying neural correlates in MFG can be improved by intensive computerized cognitive training; these improvements generalize beyond the trained task and are associated with enduring effects on cognition and functioning 6 months after the intervention.

Do People with Schizophrenia Have Difficulty Anticipating Pleasure, Engaging in Effortful Behavior, or Both?

Motivation deficits are common in schizophrenia, but little is known about underlying mechanisms, or the specific goals that people with schizophrenia set in daily life. Using neurobiological heuristics of pleasure anticipation and effort assessment, we examined the quality of activities and goals of 47 people with and 41 people without schizophrenia, utilizing ecological momentary assessment. Participants were provided cell phones and called 4 times a day for 7 days, and were asked about their current activities and anticipation of upcoming goals. Activities and goals were later coded by independent raters on pleasure and effort. In line with recent laboratory findings on effort computation deficits in schizophrenia, relative to healthy participants, people with schizophrenia reported engaging in less effortful activities and setting less effortful goals, which were related to patient functioning. In addition, patients showed some inaccuracy in estimating how difficult an effortful goal would be, which in turn was associated with lower neurocognition. In contrast to previous research, people with schizophrenia engaged in activities and set goals that were more pleasure-based, and anticipated goals as being more pleasurable than controls. Thus, this study provided evidence for difficulty with effortful behavior and not anticipation of pleasure. These findings may have psychosocial treatment implications, focusing on effort assessment or effort expenditure. For example, to help people with schizophrenia engage in more meaningful goal pursuits, treatment providers may leverage low-effort pleasurable goals by helping patients to break down larger, more complex goals into smaller, lower-effort steps that are associated with specific pleasurable rewards.

Combining computerized social cognitive training with neuroplasticity-based auditory training in schizophrenia.

OBJECTIVE Social cognitive deficits are an important treatment target in schizophrenia, but it is unclear to what degree they require specialized interventions and which specific components of behavioral interventions are effective. In this pilot study, we explored the effects of a novel computerized neuroplasticity-based auditory training delivered in conjunction with computerized social cognition training (SCT) in patients with schizophrenia. METHODS Nineteen clinically stable schizophrenia subjects performed 50 hours of computerized exercises that place implicit, increasing demands on auditory perception, plus 12 hours of computerized training in emotion identification, social perception, and theory of mind tasks. All subjects were assessed with MATRICS-recommended measures of neurocognition and social cognition, plus a measure of self-referential source memory before and after the computerized training. RESULTS Subjects showed significant improvements on multiple measures of neurocognition. Additionally, subjects showed significant gains on measures of social cognition, including the MSCEIT Perceiving Emotions, MSCEIT Managing Emotions, and self-referential source memory, plus a significant decrease in positive symptoms. CONCLUSIONS Computerized training of auditory processing/verbal learning in schizophrenia results in significant basic neurocognitive gains. Further, addition of computerized social cognition training results in significant gains in several social cognitive outcome measures. Computerized cognitive training that directly targets social cognitive processes can drive improvements in these crucial functions.

Action (verb) fluency in schizophrenia: Getting a grip on odd speech

BACKGROUND Formal thought disorder (TD) is a key symptom of schizophrenia with a significant impact on interpersonal relationships. Current cognitive models emphasize disordered language functioning and abnormalities accessing semantic representations. The cortical mechanisms for language and motor function are closely linked, hence action-related language may be impaired in TD, yet existing studies have focussed exclusively on object (noun) rather than action (verb) semantics. METHOD In order to examine this issue both action (verb) and traditional semantic (tools, fruits, musical instruments) and phonological (FAS) fluency tasks were completed by individuals with schizophrenia (N=53) and healthy controls (N=69). Fluency performance was measured as the total number of correct words generated in 60s. The Schizotypal Personality Questionnaire (SPQ) was used to index odd and disorganized speech, as well as positive and negative symptoms. RESULTS Fluency on all tasks was impaired in schizophrenia, compared to controls, with a similar effect size. Within the schizophrenia group Odd Speech was correlated with poor fluency for actions, tools and musical instruments but not fruit or phonological fluency. These action-related fluency deficits were also correlated with Constricted Affect and Social Anxiety but not with Unusual Perceptions/Odd Beliefs. CONCLUSION These results point to a unique connection and possible common aetiology between action fluency and odd speech in schizophrenia rather than a general impairment in language/executive functions common to fluency tasks. The findings provide the first evidence of a specific role of action-based language production deficits in TD together with a joint effect on social interaction skills.

Spatial plasticity of the auditory cortex in single‐sided deafness

To evaluate spatial plasticity of the auditory cortex in single‐sided deafness (SSD).

Distinct spatiotemporal patterns of neuronal functional connectivity in primary progressive aphasia variants

Primary progressive aphasia is a syndrome characterized by progressive loss of language abilities with three main phenotypic clinical presentations, including logopenic, non-fluent/agrammatic, and semantic variants. Previous imaging studies have shown unique anatomic impacts within language networks in each variant. However, direct measures of spontaneous neuronal activity and functional integrity of these impacted neural networks in primary progressive aphasia are lacking. The aim of this study was to characterize the spatial and temporal patterns of resting state neuronal synchronizations in primary progressive aphasia syndromes. We hypothesized that resting state brain oscillations will show unique deficits within language network in each variant of primary progressive aphasia. We examined 39 patients with primary progressive aphasia including logopenic variant (n = 14, age = 61 ± 9 years), non-fluent/agrammatic variant (n = 12, age = 71 ± 8 years) and semantic variant (n = 13, age = 65 ± 7 years) using magnetoencephalographic imaging, compared to a control group that was matched in age and gender to each primary progressive aphasia subgroup (n = 20, age = 65 ± 5 years). Each patient underwent a complete clinical evaluation including a comprehensive battery of language tests. We examined the whole-brain resting state functional connectivity as measured by imaginary coherence in each patient group compared to the control cohort, in three frequency oscillation bands-delta-theta (2-8 Hz); alpha (8-12 Hz); beta (12-30 Hz). Each variant showed a distinct spatiotemporal pattern of altered functional connectivity compared to age-matched controls. Specifically, we found significant hyposynchrony of alpha and beta frequency within the left posterior temporal and occipital cortices in patients with the logopenic variant, within the left inferior frontal cortex in patients with the non-fluent/agrammatic variant, and within the left temporo-parietal junction in patients with the semantic variant. Patients with logopenic variant primary progressive aphasia also showed significant hypersynchrony of delta-theta frequency within bilateral medial frontal and posterior parietal cortices. Furthermore, region of interest-based analyses comparing the spatiotemporal patterns of variant-specific regions of interest identified in comparison to age-matched controls showed significant differences between primary progressive aphasia variants themselves. We also found distinct patterns of regional spectral power changes in each primary progressive aphasia variant, compared to age-matched controls. Our results demonstrate neurophysiological signatures of network-specific neuronal dysfunction in primary progressive aphasia variants. The unique spatiotemporal patterns of neuronal synchrony signify diverse neurophysiological disruptions and pathological underpinnings of the language network in each variant.

Beta-band activity in medial prefrontal cortex predicts source memory encoding and retrieval accuracy

Reality monitoring is defined as the ability to distinguish internally self-generated information from externally-derived information. The medial prefrontal cortex (mPFC) is a key brain region subserving reality monitoring and has been shown to be activated specifically during the retrieval of self-generated information. However, it is unclear if mPFC is activated during the encoding of self-generated information into memory. If so, it is important to understand whether successful retrieval of self-generated information critically depends on enhanced neural activity within mPFC during initial encoding of this self-generated information. We used magnetoencephalographic imaging (MEGI) to determine the timing and location of cortical activity during a reality-monitoring task involving self generated contextual source memory encoding and retrieval. We found both during encoding and retrieval of self-generated information, when compared to externally-derived information, mPFC showed significant task induced oscillatory power modulation in the beta-band. During initial encoding of self-generated information, greater mPFC beta-band power reductions occurred within a time window of −700ms to −500ms prior to vocalization, activity in mPFC that was not observed during encoding of externally-derived information. This mPFC activity during encoding of self-generated information predicted subsequent retrieval accuracy of self-generated information. Beta-band activity in mPFC was also observed during the initial retrieval of self-generated information within a time window of 300 to 500ms following stimulus onset and correlated with accurate retrieval performance of self-generated information. Together, these results further highlight the importance of mPFC in mediating the initial generation and awareness of participants’ internal thoughts.

Association between increased serum D-serine and cognitive gains induced by intensive cognitive training in schizophrenia

Neuroscience-guided cognitive training induces significant improvement in cognition in schizophrenia subjects, but the biological mechanisms associated with these changes are unknown. In animals, intensive cognitive activity induces increased brain levels of the NMDA-receptor co-agonist d-serine, a molecular system that plays a role in learning-induced neuroplasticity and that may be hypoactive in schizophrenia. Here, we investigated whether training-induced gains in cognition were associated with increases in serum d-serine in outpatients with schizophrenia. Ninety patients with schizophrenia and 53 healthy controls were assessed on baseline serum d-serine, l-serine, and glycine. Schizophrenia subjects performed neurocognitive tests and were assigned to 50 h of either cognitive training of auditory processing systems (N = 47) or a computer games control condition (N = 43), followed by reassessment of cognition and serum amino acids. At study entry, the mean serum d-serine level was significantly lower in schizophrenia subjects vs. healthy subjects, while the glycine levels were significantly higher. There were no significant changes in these measures at a group level after the intervention. However, in the active training group, increased d-serine was significantly and positively correlated with improvements in global cognition and in Verbal Learning. No such associations were observed in the computer games control subjects, and no such associations were found for glycine. d-Serine may be involved in the neurophysiologic changes induced by cognitive training in schizophrenia. Pharmacologic strategies that target d-serine co-agonism of NMDA-receptor functioning may provide a mechanism for enhancing the behavioral effects of intensive cognitive training.