Temporal processing dysfunction in schizophrenia

BackgroundStriatal hyperdopaminergia is implicated in the pathoetiology of schizophrenia, but how this relates to dopaminergic midbrain activity is unclear. Neuromelanin (NM)-sensitive magnetic resonance imaging provides a marker of long-term dopamine function. We examined whether midbrain NM-sensitive magnetic resonance imaging contrast-to-noise ratio (NM-CNR) was higher in people with schizophrenia than in healthy control (HC) participants and whether this correlated with dopamine synthesis capacity. MethodsOne hundred fifty-four participants (schizophrenia group: n = 74, HC group: n = 80) underwent NM-sensitive magnetic resonance imaging of the substantia nigra and ventral tegmental area (SN-VTA). A subset of the schizophrenia group (n = 38) also received [18F]-DOPA positron emission tomography to measure dopamine synthesis capacity (Kicer) in the SN-VTA and striatum. ResultsSN-VTA NM-CNR was significantly higher in patients with schizophrenia than in HC participants (effect size = 0.38, p = .019). This effect was greatest for voxels in the medial and ventral SN-VTA. In patients, SN-VTA Kicer positively correlated with SN-VTA NM-CNR (r = 0.44, p = .005) and striatal Kicer (r = 0.71, p < .001). Voxelwise analysis demonstrated that SN-VTA NM-CNR was positively associated with striatal Kicer (r = 0.53, p = .005) and that this relationship seemed strongest between the ventral SN-VTA and associative striatum in schizophrenia. ConclusionsOur results suggest that NM levels are higher in patients with schizophrenia than in HC individuals, particularly in midbrain regions that project to parts of the striatum that receive innervation from the limbic and association cortices. The direct relationship between measures of NM and dopamine synthesis suggests that these aspects of schizophrenia pathophysiology are linked. Our findings highlight specific mesostriatal circuits as the loci of dopamine dysfunction in schizophrenia and thus as potential therapeutic targets.

We investigated the associations of DRD3 rs6280, HTR1A rs6295, BDNF rs6265, SCL6A4 rs16965628, and 5HT2A rs7322347 with schizophrenia in a case–control study, and associations of these genetic variants with several clinical features. We also investigated markers of inflammatory response (C-reactive protein, IL-2, IL-6, IL-10), the activity of leukocytic elastase (LE) and α1-proteinase inhibitor (a1-PI), antibodies to S100B and myelin basic protein (MBP) in schizophrenia. Clinical symptoms were assessed on three scales: Positive and Negative Syndrome Scale, The Bush – Francis Catatonia Rating Scale and Frontal Assessment Battery. All SNPs were typed using predesigned TaqMan SNP genotyping assays. The biomarkers related to the immune system were routinely tested using ELISA kits. The association with schizophrenia was found for DRD3 rs6280 (p = 0.05) and HTR2A rs7322347 (p = 0.0013). We found differences between groups by parameters of LE and a1-PI and LE/a1-PI (p < 0.001). And IL-6 was evaluated in the schizophrenia group (p < 0.001). We showed that patients with the TT allele (BDNF rs6265) had more severe impairments in frontal lobe function. a1-PI can serve as a marker for assessing the severity of frontal lobe damage in patients with frontal dementia. We found some biological parameters reflecting the severity of frontal dysfunction in schizophrenia.

A preponderance of evidence suggests that the hippocampus is a key region of dysfunction in schizophrenia. Neuroimaging and other studies indicate a relationship between hippocampal dysfunction and the degree of psychosis. Clinical data indicate hyperactivity in the hippocampus that precedes the onset of psychosis, and is correlated with symptom severity. In this study, we sought to identify circuitry at the electron microscopic level that could contribute to region-specific imbalances in excitation and inhibition in the hippocampus in schizophrenia. We used postmortem tissue from the anterior hippocampus from patients with schizophrenia and matched controls. Using stereological techniques, we counted and measured synapses, postsynaptic densities (PSDs), and evaluated size, number and optical density of mitochondria and parvalbumin-containing interneurons in key nodes of the trisynaptic pathway. Compared to controls, the schizophrenia group had decreased numbers of inhibitory synapses in CA3 and increased numbers of excitatory synapses in CA1; together, this indicates deficits in inhibition and an increase in excitation. The thickness of the PSD was larger in excitatory synapses in CA1, suggesting greater synaptic strength. In the schizophrenia group, there were fewer mitochondria in the dentate gyrus and a decrease in the optical density, a measure of functional integrity, in CA1. The number and optical density of parvalbumin interneurons were lower in CA3. The results suggest region-specific increases in excitatory circuitry, decreases in inhibitory neurotransmission and fewer or damaged mitochondria. These results are consistent with the hyperactivity observed in the hippocampus in schizophrenia in previous studies.

Impaired Prefrontal-Basal Ganglia Functional Connectivity and Substantia Nigra Hyperactivity in Schizophrenia

Fronto-limbic interactions facilitate the generation of task-relevant responses while inhibiting interference from emotionally distracting information. Schizophrenia is associated with deficits in both executive attention and affective regulation. This study aims to elucidate the neural correlates of emotion-attention regulation and shifting in schizophrenia. We employed functional magnetic resonance imaging to probe the fronto-limbic regions in 16 adults with schizophrenia and 13 matched adults with no history of psychiatric illness. Subjects performed a forced-choice visual oddball task where they detected infrequent target circles embedded in a series of infrequent nontarget aversive and neutral pictures and frequent squares. In control participants, target events activated a dorsal frontoparietal network, whereas these regions were deactivated by aversive stimuli. Conversely, ventral frontolimbic brain regions were activated by aversive stimuli and deactivated by target events. In the patient group, regional hemodynamic timecourses revealed not only reduced activation to target and aversive events in dorsal executive and ventral limbic regions, respectively, but also reduced deactivation to target and aversive stimuli in ventral and dorsal regions, respectively, relative to the control group. Patients further showed reduced spatial extent of activation in the right inferior frontal gyrus during the target and aversive conditions. Activation of the anterior cingulate to aversive images was inversely related to severity of avolition and anhedonia symptoms in the schizophrenia group. These results suggest both frontal and limbic dysfunction in schizophrenia as well as aberrant reciprocal inhibitions between these regions during attention-emotion modulation in this disorder.

Quality versus quantity: Determining real-world social functioning deficits in schizophrenia

Duration perception is a complex phenomenon in linguistic studies. While it can be instrumentally measured in a straightforward fashion, its relationship to other acoustic measurements is still not well understood. Previous work has found that duration can influence the perception of other acoustic cues, such as pitch (Brigner, 1988). This implies that it is important to go beyond isolated analysis of individual acoustic cues, and consider the synergistic effects of multiple acoustic cues. This paper presents the results of an experiment designed to test the influence of changing pitch on duration in two tasks, one using linguistic stimuli and one using acoustic stimuli. I find an effect of pitch on duration perception in both tasks. However, the results are not identical. In the auditory task, there was a small effect where higher tones were heard as longer than low tones. However, in the linguistic task, higher tones were heard as shorter. This indicates that pitch can have both a direct and indirect effect on duration perception and that there are complex interactions that may have a significant impact on our language perception.

The symptomatic manifestations of Parkinson’s disease (PD) are mainly motor. The meaning and origin of these clinical motor symptoms are poorly understood at present. Adequate perception of the external world (time and space parameters) and of one’s body are required to achieve normal motor performance. Timing is a primary aspect of any movement since very few real life acts can be characterized by force attainment criteria independent of time. Deficits in timing are evident in most abnormalities reported in PD such as, increased reaction time and movement time, greater inter-onset latency in sequential movements and slowness in the performance of repetitive movements. There is some evidence indicative that the timing alteration of patients with PD may be not limited to the motor domain. Furthermore, motor disturbances may be either secondary to inadequate temporal perception (time discrimination and estimation) or to the dysfunction of the internal generator responsible to trigger the movement. Various aspects of timing were examined in 44 patients with PD. Compared to age-matched controls the patients had higher temporal discrimination thresholds (the minimal time interval required for a pair of stimuli to be felt separated in time) in the auditory, visual and somaesthetic sensory modalities. In time estimation and reproduction tasks, PD patients overestimated the duration of time intervals reproduced by internal counting compared to normals. The patients showed greater variability in the performance of repetitive alternating flexion-extension movements of the wrist at various frequencies. The results suggest that the timing deficits of patients with PD involve motor and perceptual tasks. The role of the internal time-keeper in these dysfunctions would be discussed.

Associations between reading performance and duration perception have been found both for domain-general and speech-specific duration perception. However, research seems limited to children and, critically, the predictive value of the two duration perception modalities has not been compared so far. In the present study we compared the weight of domain-general (comparison of time intervals defined by beeps) vs. speech-specific duration perception (pre-attentive EEG responses to consonants with different durations) as statistical predictors of reading in a sample of 46 neurotypical adults (18–43 years old) with 13 years of schooling on average. Reading included word and pseudoword decoding, as well as reading comprehension. We ran one regression model with domain-general and speech-specific duration perception as predictors for each of the three reading skills. Pseudoword decoding was the only reading skill that was significantly predicted by duration perception, and this happened for domain-general duration perception only. A complementary analysis adding 26 typically developing and 24 dyslexic adults to the main sample (n = 96 in total) showed the same pattern of results in dyslexics, but not in added controls. Our findings strengthen the idea that duration perception is important to phonological encoding and its use in grapheme-to-phoneme conversion, given that only pseudoword decoding was predicted by the interval comparison task. The irrelevance of speech-specific duration perception tones down the possibility that accurately perceiving the length of speech sounds is crucial to skilled reading.

Cross-modal manipulations of attention significantly affect the detectability of tactile stimuli, but the effects on a more complex perceptual task, the discrimination of surface texture, are unknown. This study sought to examine whether attention influences the ability to discriminate a change in texture during passive touch. Twelve subjects were trained to perform two discrimination tasks: discriminating an increase in the intensity of a visual stimulus, and discriminating a change in the texture of a surface that was displaced beneath the tip of one digit. The texture change consisted of an increase in the spatial period between rectangular arrays of raised dots on Nyloprint surfaces, and for each subject an increment close to his or her discrimination threshold was employed in the experiment. Each trial began with the presentation of two baseline stimuli: A standard voltage illuminated the visual stimulus (an array of yellow light-emitting diodes (LEDs), and a standard texture (3-mm spatial period) was displaced under the tip of digit 3. For visual trials, three different increments in luminous intensity were presented, at one of three different delays following the initial presentation of the baseline stimuli. For texture trials, a single increment in spatial period was presented at one of three delays after the onset of the baseline stimuli. In any one trial, only one modality changed in intensity. The subject's task was to signal, as quickly as possible, the occurrence of the change. Instructional cues (red and green LEDs) were used to direct the subjects' attention toward the modality that changed (valid cue), to divide the subjects' attention between the visual and tactile modalities (neutral cue) as either might change, or to direct the subjects' attention toward the modality that did not change (invalid cue). Two measures of performance were employed: accuracy (percentage correct) and reaction time (speed with which the subject responded). The results indicated that cue condition significantly influenced the ability of subjects to discriminate a change in texture: Both accuracy and speed were significantly improved when subjects' attention was selectively directed toward the textured surface, as compared to when it was misdirected toward the visual modality. Performance was intermediate when attention was divided between the two modalities. The results were compared with those obtained previously in a tactile detection task using a similar attentional manipulation.(ABSTRACT TRUNCATED AT 400 WORDS)

Time perception plays a fundamental role in human perceptual and motor activities, and can be influenced by various factors, such as selective attention and arousal. However, little is known about the influence of individual alerting efficiency on perceived duration. In this study, we explored this question by running two experiments. The Attentional Networks Test was used to evaluate individual differences in alerting efficiency in each experiment. Temporal bisection (Experiment 1) and time generalization task (Experiment 2) were used to explore the participants’ perception of duration. The results indicated that subjects in the high alerting efficiency group overestimated interval durations and estimated durations more accurately compared with subjects in the low alerting efficiency group. The two experiments showed that the sensitivity of time was not influenced by individual alerting efficiency. Based on previous studies and current findings, we infer that individual differences in alerting efficiency may influence time perception through modulating the latency of the attention-controlled switch and the speed of the peacemaker within the framework of the internal clock model.

In recent years, several studies have reported that the allocation of spatial attention fluctuates periodically. This periodic attention was revealed by measuring behavioral performance as a function of cue-to-target interval in the Posner cueing paradigm. Previous studies reported behavioral oscillations using target detection tasks. Whether the influence of periodic attention extends to cognitively demanding tasks remains unclear. To assess this, we examined the effects of periodic attention on the perception of duration. In the experiment, participants performed a temporal bisection task while a cue was presented with various cue-to-target intervals. Perceived duration fluctuated rhythmically as a function of cue-to-target interval at a group level but not at an individual level when the target was presented on the same side as the attentional cue. The results indicate that the perception of duration is influenced by periodic attention. In other words, periodic attention can influence the performance of cognitively demanding tasks such as the perception of duration.

Background: Functional near-infrared spectroscopy (fNIRS) has many advantages over other neuroimaging modalities for routine measurement of task-dependent cortical activation, but most fNIRS studies of schizophrenia have used letter fluency tasks (LFTs). Further, performances on category fluency tasks (CFTs) and LFTs may be distinct in Chinese patients due to the unique semantic features of Chinese written characters. To identify unique disease biomarkers measurable by fNIRS in Chinese schizophrenia patients, this study compared cortical oxygenated hemoglobin changes ([oxy-Hb]) during a Chinese LFT and CFT between patients and healthy controls.Methods: Inpatients of the Second Affiliated Hospital of Xinxiang Medical University were recruited from Match 2020 to July 2021. The Positive and Negative Symptom Scale (PANSS) was used to evaluate psychiatric symptoms. Dynamic changes in [oxy-Hb], an indicator of neural activity, were measured during CFT and LFT performance by 52-channel fNIRS.Results: Forty-seven schizophrenia inpatients and 29 healthy controls completed all tests. Schizophrenia patients showed significant cortical activation at 15 channels covering the left hemisphere and 17 channels over the right hemisphere during the CFT. During the LFT, activity was significantly increased at only six channels, all over the left hemisphere (FDR P < 0.05). In healthy controls, significant [oxy-Hb] increases were found at 24 channels over the left hemisphere and 19 channels over the right hemisphere during CFT. While during the LFT, the significant increases were found at 7 channels all over the left hemisphere (FDR P < 0.05). When years of education was included as a covariate, the schizophrenia group demonstrated no significant hypoactivation relative to healthy controls at any channel after FDR correction (FDR P < 0.05) during CFT while demonstrated significant hypoactivation at channel 11 during LFT (FDR P < 0.05). There were no significant associations between PANSS scores and [oxy-Hb] changes after FDR correction (FDR P < 0.05).Conclusions: Left lateralization during CFT was reduced among schizophrenia patients and may be related to the semantic deficit. The Chinese-CFT could be a more sensitive indicator of frontal-temporal dysfunction in schizophrenia.

No evidence for mirror system dysfunction in schizophrenia from a multimodal TMS/EEG study

Reliable duration perception of external events is necessary to coordinate perception with action, precisely discriminate speech, and for other daily functions. Visual duration perception can be heavily influenced by concurrent auditory signals; however, age-related effects on this process have received minimal attention. In the present study, we examined the effect of aging on duration perception by quantifying (1)duration discrimination thresholds, (2)auditory temporal dominance, and (3)visual duration expansion/compression percepts induced by an accompanying auditory stimulus of longer/shorter duration. Duration discrimination thresholds were significantly greater for visual than auditory tasks in both age groups, however there was no effect of age. While the auditory modality retained dominance in duration perception with age, older adults still performed worse than young adults when comparing durations of two target stimuli (e.g., visual) in the presence of distractors from the other modality (e.g., auditory). Finally, both age groups perceived similar visual duration compression, whereas older adults exhibited visual duration expansion over a wider range of auditory durations compared to their younger counterparts. Results are discussed in terms of multisensory integration and possible decision strategies that change with age.