Background: The default mode network (DMN) is a set of brain regions typically activated at rest and suppressed during extrinsic cognition. Schizophrenia has been associated with deficient DMN suppression, though the extent to which DMN dysfunction predates psychosis onset is unclear. This study examined DMN suppression during working memory (WM) performance in youth at clinical high-risk (CHR) for psychosis, early schizophrenia (ESZ) patients, and healthy controls (HC). We hypothesized that the DMN would show load-dependent suppression during WM retrieval in HC but not in ESZ, with CHR participants showing an intermediate pattern.
Methods: fMRI data were collected from CHR (n = 32), ESZ (n = 22), and HC (n = 54) participants, ages 12–30. DMN regions were defined via seed-based connectivity analysis of resting-state fMRI data from an independent HC sample. Load-dependent deactivations of these DMN regions in response to WM probes were interrogated.
Results: Healthy controls showed linear load-dependent increases in DMN deactivation. Significant Group-by-Load interactions were observed in DMN regions including medial prefrontal and lateral posterior parietal cortices. Group-by-Load effects in posterior DMN nodes resulted from less suppression at higher WM loads in ESZ relative to HC, with CHR differing from neither group. In medial prefrontal cortex, suppression of activity at higher WM loads was significantly diminished in both CHR and ESZ groups, relative to HC. In addition, investigation of dorsolateral prefrontal cortex (DLPFC) activations revealed that ESZ activated right DLPFC significantly more than HC, with CHR differing from neither group.
Conclusion: While HC showed WM load-dependent modulation of DMN suppression, CHR individuals had deficient higher-load DMN suppression that was similar to, but less pronounced than, the distributed suppression deficits evident in ESZ patients. These results suggest that DMN dysregulation associated with schizophrenia predates psychosis onset.
schizophrenia prodrome; ultra-high-risk youth; dorsolateral prefrontal cortex; fMRI task-induced deactivation; adolescent mental health
Emotion processing deficits are prominent in schizophrenia and exist prior to the onset of overt psychosis. However, developmental trajectories of neural circuitry subserving emotion regulation and the role that they may play in illness onset have not yet been examined in patients at risk for psychosis. The present study employed a cross-sectional analysis to examine age-related functional activation in amygdala and prefrontal cortex, as well as functional connectivity between these regions, in adolescents at clinical high risk (CHR) for psychosis relative to typically developing adolescents. Participants (n=34) performed an emotion processing fMRI task, including emotion labeling, emotion matching, and non-emotional control conditions. Regression analyses were used to predict activation in the amygdala and ventrolateral prefrontal cortex (vlPFC) based on age, group, sex, and the interaction of age by group. CHR adolescents exhibited altered age-related variation in amygdala and vlPFC activation, relative to controls. Controls displayed decreased amygdala and increased vlPFC activation with age, while patients exhibited the opposite pattern (increased amygdala and decreased vlPFC activation), suggesting a failure of prefrontal cortex to regulate amygdala reactivity. Moreover, a psychophysiological interaction analysis revealed decreased amygdala-prefrontal functional connectivity among CHR adolescents, consistent with disrupted brain connectivity as a vulnerability factor in schizophrenia. These results suggest that the at-risk syndrome is marked by abnormal development and functional connectivity of neural systems subserving emotion regulation. Longitudinal data are needed to confirm aberrant developmental trajectories intra-individually and to examine whether these abnormalities are predictive of conversion to psychosis, and of later deficits in socioemotional functioning.
psychosis; brain development; emotion; amygdala; prefrontal cortex; fMRI
Characterizing neuropsychological (NP) functioning of individuals at clinical high risk (CHR) for psychosis may be useful for prediction of psychosis and understanding functional outcome. The degree to which NP impairments are associated with general cognitive ability and/or later emergence of full psychosis in CHR samples requires study with well-matched controls.
We assessed NP functioning across eight cognitive domains in a sample of 73 CHR youth, 13 of whom developed psychotic-level symptoms after baseline assessment, and 34 healthy comparison (HC) subjects. Groups were matched on age, sex, ethnicity, handedness, subject and parent grade attainment, and median family income, and were comparable on WRAT-3 Reading, an estimate of premorbid IQ. Profile analysis was used to examine group differences and the role of IQ in profile shape.
The CHR sample demonstrated a significant difference in overall magnitude of NP impairment but only a small and nearly significant difference in profile shape, primarily due to a large impairment in olfactory identification. Individuals who subsequently developed psychotic-level symptoms demonstrated large impairments in verbal IQ, verbal memory and olfactory identification comparable in magnitude to first episode samples.
CHR status may be associated with moderate generalized cognitive impairments marked by some degree of selective impairment in olfaction and verbal memory. Impairments were greatest in those who later developed psychotic symptoms. Future study of olfaction in CHR samples may enhance early detection and specification of neurodevelopmental mechanisms of risk.
Schizophrenia; Prodrome; Cognition; Ultra High Risk; Neurocognitive Functioning; IQ
Functional disability is a key component of many psychiatric illnesses, particularly schizophrenia. Impairments in social and role functioning are linked to cognitive deficits, a core feature of psychosis. Retrospective analyses demonstrate that substantial functional decline precedes the onset of psychosis. Recent investigations reveal that individuals at clinical-high-risk (CHR) for psychosis show impairments in social relationships, work/school functioning and daily living skills. CHR youth also demonstrate a pattern of impairment across a range of cognitive domains, including social cognition, which is qualitatively similar to that of individuals with schizophrenia. While many studies have sought to elucidate predictors of clinical deterioration, specifically the development of schizophrenia, in such CHR samples, few have investigated factors relevant to psychosocial outcome. This review integrates recent findings regarding cognitive and social-cognitive predictors of outcome in CHR individuals, and proposes potential directions for future research that will contribute to targeted interventions and improved outcome for at-risk youth.
Schizophrenia; Prodrome; Ultra-high-risk; Social cognition; Clinical high-risk; Psychosocial functioning; Functional outcome; Neurocognition
Early detection and prospective evaluation of clinical high-risk
(CHR) individuals who may develop schizophrenia or other psychotic disorders
is critical for predicting psychosis onset and for testing preventive
To elucidate the neuropsychology of the CHR syndrome, to determine
the association of neuropsychological function with conversion to psychosis
and family history (FH) of psychosis, and to examine whether baseline
neuropsychological functioning predicts subsequent psychosis.
Design, Setting, and Participants
Longitudinal study with 2 1/2 years follow-up of 304 prospectively
identified CHR individuals meeting Structured Interview for Prodromal
Syndromes (SIPS) criteria, 52 non-CHR persons with a FH of psychosis in
first- or second-degree relatives (“family HR”/FHR), and 193
normal controls with neither a FH of psychosis nor a CHR syndrome, all of
whom had baseline neuropsychological evaluations, recruited across eight
centers as part of the North American Prodrome Longitudinal Study
A neurocognitive composite score, eight individual neuropsychological
measures, an IQ estimate, and HR status.
Global (“composite”) neuropsychological functioning
was comparably impaired in CHR and FHR groups compared to controls, but
profiles differed significantly between groups. Neuropsychological
functioning in the CHR group was significantly lower in persons who
progressed to psychosis than in those who did not, and worst in the subgroup
with a FH of psychosis. Tests of processing speed and verbal learning and
memory were most sensitive in discriminating CHR from controls, although
reductions were less severe than in established schizophrenia.
Neuropsychological functioning did not contribute uniquely to the prediction
of psychosis beyond clinical criteria, but worse verbal memory predicted
more rapid conversion.
These findings document that CHR individuals have significant
neuropsychological difficulties, particularly those who later develop
psychosis. This dysfunction is generally of moderate severity but less than
in first episode schizophrenia, suggesting that a further decline may occur
after baseline CHR assessment.
Given the fundamental role of thought disorder in schizophrenia, subtle communication disturbance may be a valuable predictor of subsequent development of psychosis. Here we examined the contribution of thought and communication disturbance to the prediction of outcome in adolescents identified as putatively prodromal for psychosis.
Transcribed speech samples were elicited from 105 adolescents (54 identified as being at clinical high risk for a first episode of psychosis (CHR) and 51 demographically comparable comparison subjects) and coded for formal thought disorder (FTD) and linguistic cohesion. We then examined the association of baseline FTD/cohesion with conversion to psychosis and social and role outcome at follow-up, approximately one year later.
At baseline, CHR patients who subsequently converted to psychosis (CHR+) showed an elevated rate of illogical thinking and poverty of content (POC) in their speech, relative to both typically developing controls and non-converters (CHR−). CHR+ youth also used significantly less referential cohesion at baseline, indicating that they provide fewer references to people, objects, or events mentioned in preceding utterances. Multiple regression models indicated that, among measures of FTD/cohesion, illogical thinking was uniquely predictive of subsequent conversion to psychosis, whereas POC and referential cohesion were significant predictors of social and role functioning, respectively.
Despite the absence of fully psychotic symptoms, putatively prodromal individuals evidence signs of communication disturbance that are qualitatively similar to those seen in schizophrenia, and are predictive of both conversion to psychosis and psychosocial outcome. These findings suggest that FTD measures have prognostic significance for at-risk youth.
thought disorder; psychosis prodrome; schizophrenia; language; psychosocial outcome
Individuals with schizophrenia demonstrate stable deficits in affect recognition. Similar deficits in affect recognition have been observed in those who are at clinical high risk (CHR) of developing psychosis. The current project aimed to longitudinally examine affect processing in CHR individuals, to determine if affect processing predicted later conversion to psychosis and if affect processing deficits were unique to those who met established criteria for prodromal syndromes. The sample consisted of 172 CHR and 100 help-seeking individuals (HS) who were followed for up to 24 months. All CHR individuals met the Criteria of Prodromal States (COPS) based on the Structured Interview for Prodromal Symptoms (SIPS). The SIPS was used to determine conversion to psychosis. Affect recognition was assessed using two facial affect recognition tasks and a measure of affective prosody. In comparison to previously published data from non-psychiatric controls, both CHR and HS groups demonstrated deficits on affect recognition. By 2 years 25 CHR participants converted to psychosis. Interestingly, there were no differences between converters and non-converters on any affect recognition tasks. This is one of the first studies to longitudinally examine affect processing and its relationship to later conversion to psychosis in individuals at-risk for psychosis. While poorer affect recognition may be associated with vulnerability for psychosis, the current results suggest that it may not be a marker of developing a psychotic illness.
psychosis prodrome; social cognition; affect recognition; facial affect; affective prosody
Poor social functioning is a hallmark of schizophrenia. The purpose of this study was to examine social functioning in individuals at clinical high risk for psychosis. Social functioning was assessed in a sample of 86 clinical high risk (CHR) individuals and compared to that of 50 first-episode of psychosis (FE) subjects, 53 multi-episode schizophrenia subjects (ME) and 55 non-psychiatric controls (NPC). Subjects were assessed on the Social Functioning Scale (SFS), the Role Functioning subscale of the Quality of Life Scale (QLS-role), and the premorbid functioning scale. On the SFS, the CHR group did not differ significantly from the FE and ME groups and all were impaired relative to the NPCs. On QLS-role, the CHR group performed significantly better than the ME patients and significantly worse than NPCs. CHR subjects did not differ from patients in terms of premorbid functioning. This study demonstrates that even at the pre-psychotic phase of the illness, these young people are demonstrating significant deficits in social functioning, supporting that social deficits are present long before the onset of psychotic symptoms.
clinical high risk; prodrome; early psychosis; schizophrenia; social functioning; role functioning
Patients with schizophrenia have a decreased ability to interpret the intentions of other individuals, called Theory of Mind (ToM). As capacity for ToM normally advances with brain maturation, research on ToM in individuals at heightened clinical risk for psychosis may reveal developmental differences independent of disease based differences.
We examined ToM in at clinical high risk and schizophrenia patients as well as healthy controls: 1) 63 clinical high risk (CHR) patients and 24 normal youths ascertained by a CHR program; and 2) in 13 schizophrenia cases and 14 normal adults recruited through a schizophrenia program. ToM measures included first- and second-order false belief cartoon tasks (FBT) and two “higher order” tasks (“Strange Stories Task” (SST) and the “Reading the Mind in the Eyes” task). In the first study, CHR patients and normal youths were also assessed for cognition, “prodromal” symptoms and social function.
Errors on first- and second-order false belief tasks were made primarily by patients. CHR patients and their young comparison group had equivalent performance on higher order ToM, which was not significantly different from the worse ToM performance of schizophrenia patients and the higher performance of normal adult controls. In the combined dataset from both studies, all levels of ToM were associated with IQ, controlling for age and sex. ToM bore no relation to explicit memory, prodromal symptoms, social function, or later transition to psychosis.
Higher order ToM capacity was equally undeveloped in high risk cases and younger controls, suggesting performance on these tasks is not fully achieved until adulthood. This study also replicates the association of IQ with ToM performance described in previous studies of schizophrenia.
psychosis; theory of mind; IQ; risk; prodrome
Psychosis has been associated with aberrant brain activity concurrent with both the anticipation and integration of monetary outcomes. The extent to which abnormal reward-related neural signals can be observed in chronic, medicated patients with schizophrenia (SZ), however, is not clear.
In an fMRI study involving 17 chronic outpatients with SZ and 17 matched controls, we used a monetary incentive delay (MID) task, in which different-colored shapes predicted gains, losses, or neutral outcomes. Subjects needed to respond to a target within a time window in order to receive the indicated gain, or avoid the indicated loss. Group differences in BOLD responses to cues and outcomes were assessed through voxel-wise whole-brain analyses and regions-of-interest analyses in the neostriatum and prefrontal cortex (PFC).
Significant group by outcome valence interactions were observed in medial and lateral PFC, lateral temporal cortex, and the amygdalae, such that controls, but not patients, showed greater activation for gains, relative to losses. In the striatum, neural activity was modulated by outcome magnitude in both groups. Additionally, we found that ratings of negative symptoms in patients correlated with sensitivity to obtained losses in medial PFC, obtained gains in lateral PFC, and anticipated gains in left ventral striatum. Sensitivity to obtained gains in lateral PFC also correlated with positive symptom scores in patients.
Our findings of systematic relationships between clinical symptoms and neural responses to stimuli associated with rewards and punishments offer promise that reward-related neural responses may provide sensitive probes of the effectiveness of treatments for negative symptoms.
schizophrenia; dopamine; reinforcement; basal ganglia; ventromedial prefrontal cortex
Language processing in context requires more than merely comprehending words and sentences. Important subprocesses are inferences for bridging successive utterances, the use of background knowledge and discourse context, and pragmatic interpretations. The functional neuroanatomy of these text comprehension processes has only recently been investigated. Although there is evidence for right-hemisphere contributions, reviews have implicated the left lateral prefrontal cortex, left temporal regions beyond Wernicke’s area, and the left dorso-medial prefrontal cortex (dmPFC) for text comprehension. To objectively confirm this extended language network and to evaluate the respective contribution of right hemisphere regions, meta-analyses of 23 neuroimaging studies are reported here. The analyses used replicator dynamics based on activation likelihood estimates. Independent of the baseline, the anterior temporal lobes (aTL) were active bilaterally. In addition, processing of coherent compared with incoherent text engaged the dmPFC and the posterior cingulate cortex. Right hemisphere activations were seen most notably in the analysis of contrasts testing specific subprocesses, such as metaphor comprehension. These results suggest task dependent contributions for the lateral PFC and the right hemisphere. Most importantly, they confirm the role of the aTL and the fronto-medial cortex for language processing in context.
text comprehension; theory-of-mind; pragmatics; language interpretation; anterior temporal lobe; fronto-medial cortex; right hemisphere; metaanalysis; neuroimaging
Individuals with autism and schizophrenia exhibit atypical language and social symptoms. The extent to which these symptoms are evident during development and in current functioning is unclear.
Three groups of patients aged 11–20 diagnosed as clinical-high-risk for psychosis (CHR; n = 15), first episode psychosis (FEP; n = 16), and autism spectrum disorders (ASD; n = 20), plus typically developing individuals (TYP; n = 20) were compared on common autism parent-report questionnaires assessing social and language development and current functioning including the Social Communication Questionnaire, the Children’s Communication Checklist, and the Social Reciprocity Scale.
All clinical groups demonstrated atypical social and language development, with social impairment highest in ASD. Twenty percent of participants with CHR and FEP met diagnostic criteria for ASD as assessed by parent-report. ASD exhibited greater current syntactic, and pragmatic language symptoms including delayed echolalia, pedantic speech, and deficits in appreciating irony and sarcasm. All clinical groups exhibited current deficits in social functioning. CHR and FE had similar and intermediate levels of functioning relative to ASD and TYP, with CHR generally scoring closer to TYP, providing construct validity for the CHR diagnostic label.
The results of this study suggest that ASDs, CHR, and FEP share common features of atypical neurodevelopment of language and social function. Evidence of impaired social reciprocity across both disorders and distinct language symptoms in ASDs provides important information for differential diagnosis and psychosis prevention, as well as leads for future investigations of comparative genetics and pathophysiology.
language; social; neurodevelopment; schizophrenia; autism; thought disorder
Structural and functional abnormalities have been found in language-related brain regions in patients with schizophrenia. We previously reported findings pointing to differences in word processing between people with schizophrenia and individuals who are at high-risk for schizophrenia using a voxel-based (whole brain) fMRI approach. We now extend this finding to specifically examine functional activity in three language related cortical regions using a larger cohort of individuals.
A visual lexical discrimination task was performed by 36 controls, 21 subjects at high genetic-risk for schizophrenia, and 20 patients with schizophrenia during blood oxygenation level dependent (BOLD) fMRI scanning. Activation in bilateral inferior frontal gyri (Brodmann's area 44-45), bilateral inferior parietal lobe (Brodmann's area 39-40), and bilateral superior temporal gyri (Brodmann's area 22) was investigated. For all subjects, two-tailed Pearson correlations were calculated between the computed laterality index and a series of cognitive test scores determining language functioning.
Regional activation in Brodmann's area 44-45 was left lateralized in normal controls, while high-risk subjects and patients with schizophrenia or schizoaffective disorder showed more bilateral activation. No significant differences among the three diagnostic groups in the other two regions of interest (Brodmann's area 22 or areas 39-40) were found. Furthermore, the apparent reasons for loss of leftward language lateralization differed between groups. In high-risk subjects, the loss of lateralization was based on reduced left hemisphere activation, while in the patient group, it was due to increased right side activation. Language ability related cognitive scores were positively correlations with the laterality indices obtained from Brodmann's areas 44-45 in the high-risk group, and with the laterality indices from Brodmann's areas 22 and 44-45 in the patient group.
This study reinforces previous language related imaging studies in high-risk subjects and patients with schizophrenia suggesting that reduced functional lateralization in language related frontal cortex may be a vulnerability marker for schizophrenia. Future studies will determine whether it is predictive of who develops illness.
fMRI; schizophrenia; High risk, genetic; Language lateralization; ROI based study
After decades of research, schizophrenia and related psychotic disorders are still among the most debilitating disorders in medicine. The chronic illness course in most individuals, greater treatment responsiveness during the first episode, progressive grey matter decline during early disease stages, and retrospective accounts of “prodromal” or early illness signs and symptoms formed the basis for research on the psychosis risk syndrome,, known variably as “clinical high risk”(CHR), or “ultra-high risk“ (UHR), or “prodromal”. The pioneering era of research on the psychosis risk syndrome focused on the development and validation of specific assessment tools and the delineation of high risk criteria. This was followed by the examination of conversion rates in psychosis risk cohorts followed naturalistically, identification of predictors of conversion to psychosis, and investigation of interventions able to abort or delay the development of full psychosis. Despite initially encouraging results concerning the predictive validity of the psychosis risk syndrome criteria, recent findings of declining conversion rates demonstrate the need for further investigations. Results from intervention studies, mostly involving second-generation antipsychotics and cognitive behavioral therapy, are encouraging, but are currently still insufficient to make treatment recommendations for this early, relatively non-specific illness phase. The next phase of research on the psychosis risk syndrome just now beginning, has moved to larger, “multi-site” projects to increase generalizability and to ensure that sufficiently large samples at true risk for psychosis are included. Emphasis in these emerging studies is on: 1) identification of biomarkers for conversion to psychosis; 2) examination of non-antipsychotic, neuroprotective and low-risk pharmacologic and non-pharmacologic interventions; 3) testing of potentially phase-specific interventions; 4) examination of the relationship between treatment response during yhre of psychosis risk syundrome and prognosis for the course of illness; 5) follow-up of patients who developed schizophrenia despite early interventions and comparison of illness trajectories with patients who did not receive early interventions; 6) characterization of individuals with outcomes other than schizophrenia spectrum disorders, including bipolar disorder and remission from the psychosis risk syndrome, including false positive cases; 7) assessment of meaningful social and role functioning outcomes. While the research conducted to date has already yielded crucial information, the translation of the concept of a clinically identifiable psychosis risk syndrome into clinical practice does not seem justified at this point.
Schizophrenia; Psychosis; Risk Syndrome; Prodrome; Early Recognition; Early Intervention; Biomarker; DSM-V
Response monitoring abnormalities have been reported in chronic schizophrenia patients, but it is unknown whether they predate the onset of psychosis, are present in early stages of illness, or are late-developing abnormalities associated with illness progression. Response-synchronized event-related potentials (ERP) recorded during a picture-word matching task yielded error-related negativity (ERN), correct-response negativity (CRN), and error positivity (Pe) from 84 schizophrenia patients (SZ), 48 clinical high risk patients (CHR), and their age-matched healthy controls (HC; n = 110 and 88, respectively). A sub-sample of 35 early illness schizophrenia patients (ESZ) was compared to 93 age-matched HC and the CHR patients (after statistically removing the effects of normal aging). Relative to HC, 1) SZ, ESZ, and CHR had smaller ERNs, and 2) SZ and ESZ had larger CRNs and smaller Pes. Within the SZ, longer illness duration was associated with larger CRNs but was unrelated to ERN or Pe. CHR and ESZ did not differ on ERN or CRN, although Pe was smaller in ESZ than CHR. These results indicate that while ERN, CRN, and Pe abnormalities are present early in the illness, only the ERN abnormality is evident prior to psychosis onset, and only the CRN abnormality appears to worsen progressively over the illness course. Brain regions subserving response monitoring may be compromised early in the illness and possibly during its clinical prodrome.
schizophrenia; prodrome; at-risk; error-related negativity; performance monitoring
Individuals at ultra-high risk (UHR) for psychosis have self-disturbances and deficits in social cognition and functioning. Midline default network areas, including the medial prefrontal cortex and posterior cingulate cortex, are implicated in self-referential and social cognitive tasks. Thus, the neural substrates within the default mode network (DMN) have the potential to mediate self-referential and social cognitive information processing in UHR subjects.
This study utilized functional magnetic resonance imaging (fMRI) to investigate resting-state DMN and task-related network (TRN) functional connectivity in 19 UHR subjects and 20 matched healthy controls. The bilateral posterior cingulate cortex was selected as a seed region, and the intrinsic organization for all subjects was reconstructed on the basis of fMRI time series correlation.
Default mode areas included the posterior/anterior cingulate cortices, the medial prefrontal cortex, the lateral parietal cortex, and the inferior temporal region. Task-related network areas included the dorsolateral prefrontal cortex, supplementary motor area, the inferior parietal lobule, and middle temporal cortex. Compared to healthy controls, UHR subjects exhibit hyperconnectivity within the default network regions and reduced anti-correlations (or negative correlations nearer to zero) between the posterior cingulate cortex and task-related areas.
These findings suggest that abnormal resting-state network activity may be related with the clinical features of UHR subjects. Neurodevelopmental and anatomical alterations of cortical midline structure might underlie altered intrinsic networks in UHR subjects.
Schizophrenia and related psychoses are associated with brain structural abnormalities. Recent findings in ‘at risk’ populations have identified progressive changes in various brain regions preceding illness onset, while changes especially in prefrontal and superior temporal regions have been demonstrated in first-episode schizophrenia patients. However, the timing of the cortical changes and their regional extent, relative to the emergence of psychosis, has not been clarified. We followed individuals at high-risk for psychosis to determine whether structural changes in the cerebral cortex occur with the onset of psychosis. We hypothesized that progressive volume loss occurs in prefrontal regions during the transition to psychosis.
35 individuals at ultra-high risk (UHR) for developing psychosis, of whom 12 experienced psychotic onset by 1-year follow-up (‘converters’), participated in a longitudinal structural MRI study. Baseline and follow-up T1-weighted MR images were acquired and longitudinal brain surface contractions were assessed using Cortical Pattern Matching.
Significantly greater brain contraction was found in the right prefrontal region in the ‘converters’ compared with UHR cases who did not develop psychosis (‘non-converters’).
These findings show cortical volume loss is associated with the onset of psychosis, indicating ongoing pathological processes during the transition stage to illness. The prefrontal volume loss is in line with structural and functional abnormalities in schizophrenia, suggesting a critical role for this change in the development of psychosis.
schizophrenia; MRI; brain mapping; longitudinal; prodrome; ultra-high risk
Cognitive deficits across a wide range of domains have been consistently observed in schizophrenia and are linked to poor functional outcome (Green, 1996; Carter, 2006). Language abnormalities are among the most salient and include disorganized speech as well as deficits in comprehension. In this review, we aim to evaluate impairments of language processing in schizophrenia in relation to a domain-general control deficit. We first provide an overview of language comprehension in the healthy human brain, stressing the role of cognitive control processes, especially during discourse comprehension. We then discuss cognitive control deficits in schizophrenia, before turning to evidence suggesting that schizophrenia patients are particularly impaired at processing meaningful discourse as a result of deficits in control functions. We conclude that domain-general control mechanisms are impaired in schizophrenia and that during language comprehension this is most likely to result in difficulties during the processing of discourse-level context, which involves integrating and maintaining multiple levels of meaning. Finally, we predict that language comprehension in schizophrenia patients will be most impaired during discourse processing. We further suggest that discourse comprehension problems in schizophrenia might be mitigated when conflicting information is absent and strong relations amongst individual words are present in the discourse context.
“There is no “centre of Speech” in the brain any more than there is a faculty of Speech in the mind.
The entire brain, more or less, is at work in a man who uses language”William JamesFrom The Principles of Psychology, 1890“The mind in dementia praecox is like an orchestra without a conductor”Kraepelin, 1919
Understanding language relies on concurrent activation of multiple areas within a distributed neural network. Hemodynamic measures (fMRI and PET) indicate their location and electromagnetic measures (MEG and EEG) reveal the timing of brain activity during language processing. Their combination can show the spatiotemporal characteristics (where and when) of the underlying neural network. Activity to written and spoken words starts in sensory-specific areas and progresses anteriorly via respective ventral (“what”) processing streams towards the simultaneously active supramodal regions. The process of understanding a word in its current context peaks about 400 ms after word onset. It is carried out mainly through interactions of the temporal and inferior prefrontal areas on the left during word reading, and bilateral temporo-prefrontal areas during speech processing. Neurophysiological evidence suggests that lexical access, semantic associations, and contextual integration may be simultaneous as the brain uses available information in a concurrent manner, with the final goal of rapidly comprehending verbal input. Because the same areas may participate in multiple stages of semantic or syntactic processing, it is crucial to consider both spatial and temporal aspects of their interactions to appreciate how the brain understands words.
language; functional neuroimaging; N400; fMRI; ERP; MEG
To determine common and distinctive brain activation patterns associated with encoding and recognition of face-name associations and identify the neural structures with BOLD amplitude differences specific to binding and memory consolidation processes.
Five healthy adult participants viewed face-name pairs during the encoding phase and completed the multiple choice recognition memory task after a brief delay. BOLD response amplitudes in specific regions of interest and whole brain activation maps were analyzed.
Common activations were observed in encoding and recognition memory tasks in several ROI encompassing the medial temporal and occipital regions. Higher amplitudes occurred in right fusiform gyrus and right hippocampus during encoding. In contrast, higher BOLD response amplitudes were detected in the lingual gyrus bilaterally during recognition memory. Encoding activated distributed prefrontal and temporal cortical regions bilaterally that spanned attentional, executive, language, and memory systems. Recognition memory recruited convergence zones in the left prefrontal cortex and the parietal-occipital-temporal region bilaterally where multimodal visual association, language, memory and decision-making systems interact.
The higher right fusiform gyrus and right hippocampus activation during encoding suggests a potentially specific binding pathway. The increased lingual gyrus BOLD response during recognition memory may indicate a neural substrate for memory consolidation and long-term knowledge. Average activation maps revealed task-specific differences in areas of the prefrontal, temporal, and occipital-parietal-temporal cortices. Findings suggest that lesions in fairly widespread cerebral regions may potentially disrupt specific binding or memory consolidation processes.
fMRI; encoding; memory retrieval; face name processing
Pre-psychotic and early psychotic characteristics are investigated in the high-risk (HR) populations for psychosis. There are two different approaches based either on hereditary factors (genetic high risk, G-HR) or on the clinically manifested symptoms (clinical high risk, C-HR). Common features are an increased risk for development of psychosis and similar cognitive as well as structural and functional brain abnormalities.
We reviewed the existing literature on longitudinal structural, and on functional imaging studies, which included G-HR and/or C-HR individuals for psychosis, healthy controls (HC) and/or first episode of psychosis (FEP) or schizophrenia patients (SCZ).
With respect to structural brain abnormalities, vulnerability to psychosis was associated with deficits in frontal, temporal, and cingulate regions in HR, with additional insular and caudate deficits in C-HR population. Furthermore, C-HR had progressive prefrontal deficits related to the transition to psychosis.
With respect to functional brain abnormalities, vulnerability to psychosis was associated with prefrontal, cingulate and middle temporal abnormalities in HR, with additional parietal, superior temporal, and insular abnormalities in C-HR population. Transition-to-psychosis related differences emphasized prefrontal, hippocampal and striatal components, more often detectable in C-HR population.
Multimodal studies directly associated psychotic symptoms displayed in altered prefrontal and hippocampal activations with striatal dopamine and thalamic glutamate functions.
There is an evidence for similar structural and functional brain abnormalities within the whole HR population, with more pronounced deficits in the C-HR population. The most consistent evidence for abnormality in the prefrontal cortex reported in structural, functional and multimodal studies of HR population may underlie the complexity of higher cognitive functions that are impaired during HR mental state for psychosis.
Clinical high-risk for psychosis; Genetic high-risk for psychosis; At-risk mental state; functional MRI.
Various investigators suggest that some discourse-level comprehension difficulties in adults with right hemisphere brain damage (RHD) have a lexical-semantic basis. As words are processed, the intact right hemisphere arouses and sustains activation of a wide-ranging network of secondary or peripheral meanings and features—a phenomenon dubbed “coarse coding”. Coarse coding impairment has been postulated to underpin some prototypical RHD comprehension deficits, such as difficulties with nonliteral language interpretation, discourse integration, some kinds of inference generation, and recovery when a reinterpretation is needed. To date, however, no studies have addressed the hypothesised link between coarse coding deficit and discourse comprehension in RHD.
The current investigation examined whether coarse coding was related to performance on two measures of narrative comprehension in adults with RHD.
Methods & Procedures
Participants were 32 adults with unilateral RHD from cerebrovascular accident, and 38 adults without brain damage. Coarse coding was operationalised as poor activation of peripheral/weakly related semantic features of words. For the coarse coding assessment, participants listened to spoken sentences that ended in a concrete noun. Each sentence was followed by a spoken target phoneme string. Targets were subordinate semantic features of the sentence-final nouns that were incompatible with their dominant mental representations (e.g., “rotten” for apple). Targets were presented at two post-noun intervals. A lexical decision task was used to gauge both early activation and maintenance of activation of these weakly related semantic features. One of the narrative tasks assessed comprehension of implied main ideas and details, while the other indexed high-level inferencing and integration. Both comprehension tasks were presented auditorily. For all tasks, accuracy of performance was the dependent measure. Correlations were computed within the RHD group between both the early and late coarse coding measures and the two discourse measures. Additionally, ANCOVA and independent t-tests were used to compare both early and sustained coarse coding in subgroups of good and poor RHD comprehenders.
Outcomes & Results
The group with RHD was less accurate than the control group on all measures. The finding of coarse coding impairment (difficulty activating/sustaining activation of a word’s peripheral features) may appear to contradict prior evidence of RHD suppression deficit (prolonged activation for context-inappropriate meanings of words). However, the sentence contexts in this study were unbiased and thus did not provide an appropriate test of suppression function. Correlations between coarse coding and the discourse measures were small and nonsignificant. There were no differences in coarse coding between RHD comprehension subgroups on the high-level inferencing task. There was also no distinction in early coarse coding for subgroups based on comprehension of implied main ideas and details. But for these same subgroups, there was a difference in sustained coarse coding. Poorer RHD comprehenders of implied information from discourse were also poorer at maintaining activation for semantically distant features of concrete nouns.
This study provides evidence of a variant of the postulated link between coarse coding and discourse comprehension in RHD. Specifically, adults with RHD who were particularly poor at sustaining activation for peripheral semantic features of nouns were also relatively poor comprehenders of implied information from narratives.
Hallucinations and delusions - two diagnostic features of psychosis shared across the spectrum of heterogeneous schizophrenia constructs - can be described in terms of the pathophysiology of sensory information processing: hallucination is the impaired ability to classify representations as internally or externally generated, while delusion is the immutable linking of representations with each other in the absence of external dependency. The key anatomical systems in higher-order information processing are the cortex, thalamus, basal ganglia, and medial temporal lobe, each of which is modulated by neurotransmitter projection systems. Preliminary evidence, concentrating to date on the dorsolateral prefontal cortex, thalamus, and hippocampal region of the medial temporal lobe, points to neural circuitry dysfunction within and between each system in psychosis. This may account for specific symptoms and associated cognitive deficits such as memory impairment, attention deficit, and language disturbance.
schizophrenia; neural model; cortex; thalamus; basal ganglia; medial temporal lobe
Ts65Dn is a mouse model of Down syndrome; a syndrome that results from Chromosome (Chr) 21 trisomy and is associated with congenital defects, cognitive impairment, and ultimately Alzheimer’s Disease. Ts65Dn mice have segmental trisomy for distal mouse Chr 16, a region sharing conserved synteny with human Chr 21. As a result, this strain harbors three copies of over half of the human Chr 21 orthologs. The trisomic segment of Chr 16 is present as a translocation chromosome (Mmu 1716), with breakpoints that have not been defined previously. To molecularly characterize the Chr 16 and Chr 17 breakpoints on the translocation chromosome in Ts65Dn mice, we used a selective enrichment and high-throughput, paired end sequencing approach. Analysis of paired end reads flanking the Chr 16, Chr 17 junction on Mmu1716 and de-novo assembly of the reads directly spanning the junction provided the precise locations of the Chr 16 and Chr 17 breakpoints at 84,351,351 bp and 9,426,822 bp, respectively. These data provide the basis for low cost, highly efficient genotyping of Ts65Dn mice. More importantly, these data provide, for the first time, complete characterization of gene dosage in Ts65Dn mice.
Adults with traumatic brain injury (TBI) can demonstrate marked difficulty producing discourse during story retell and story generation tasks. Changes in discourse production have been detailed in terms of fewer content units and infrequent use of story grammar elements essential for organization. One implication is that poor use of story grammar elements during discourse production may signal reduced ability to utilize these elements in other communication realms (e.g., reading comprehension). The neural architecture that supports discourse organization, primarily the medial prefrontal cortex, is particularly susceptible to damage secondary to acquired brain injury. In this event related functional magnetic resonance imaging (fMRI) study, we describe cortical activation patterns of unimpaired readers as they are presented with discourse that is varied in terms of structural organization. The results suggest reading discourse with less structure is associated with increased cortical activity (e.g., higher processing demands) as compared to reading discourse with more traditional structural cues (e.g., story grammar). We discuss cortical areas implicated and potential implications for supporting discourse communication in persons following TBI.