Impaired spatio-temporal predictive motor timing associated with spinocerebellar ataxia type 6

Many daily life activities demand precise integration of spatial and temporal information of sensory inputs followed by appropriate motor actions. This type of integration is carried out in part by the cerebellum, which has been postulated to play a central role in learning and timing of movements. Cerebellar damage due to atrophy or lesions may compromise forward- model processing, in which both spatial and temporal cues are used to achieve prediction for future motor states. In the present study we sought to further investigate the cerebellar contribution to predictive and reactive motor timing, as well as to learning of sequential order and temporal intervals in these tasks. We tested patients with spinocerebellar ataxia type 6 (SCA6) and healthy controls for two related motor tasks; one requiring spatio-temporal prediction of dynamic visual stimuli and another one requiring reactive timing only. We found that healthy controls established spatio-temporal prediction in their responses with high temporal precision, which was absent in the cerebellar patients. SCA6 patients showed lower predictive motor timing, coinciding with a reduced number of correct responses during the 'anticipatory' period on the task. Moreover, on the task utilizing reactive motor timing functions, control participants showed both sequence order and temporal interval learning, whereas patients only showed sequence order learning. These results suggest that SCA6 affects predictive motor timing and temporal interval learning. Our results support and highlight cerebellar contribution to timing and argue for cerebellar engagement during spatio-temporal prediction of upcoming events

Thalamo-cortical circuits during sensory attenuation in emerging psychosis: a combined magnetoencephalography and dynamic causal modelling study

Evidence suggests that schizophrenia (ScZ) involves impairments in sensory attenuation. It is currently unclear, however, whether such deficits are present during early-stage psychosis as well as the underlying network and the potential as a biomarker. To address these questions, Magnetoencephalography (MEG) was used in combination with computational modeling to examine M100 responses that involved a "passive" condition during which tones were binaurally presented, while in an "active" condition participants were asked to generate a tone via a button press. MEG data were obtained from 109 clinical high-risk for psychosis (CHR-P) participants, 23 people with a first-episode psychosis (FEP), and 48 healthy controls (HC). M100 responses at sensor and source level in the left and right thalamus (THA), Heschl's gyrus (HES), superior temporal gyrus (STG) and right inferior parietal cortex (IPL) were examined and dynamic causal modeling (DCM) was performed. Furthermore, the relationship between sensory attenuation and persistence of attenuated psychotic symptoms (APS) and transition to psychosis was investigated in CHR-P participants. Sensory attenuation was impaired in left HES, left STG and left THA in FEP patients, while in the CHR-P group deficits were observed only in right HES. DCM results revealed that CHR-P participants showed reduced top-down modulation from the right IPL to the right HES. Importantly, deficits in sensory attenuation did not predict clinical outcomes in the CHR-P group. Our results show that early-stage psychosis involves impaired sensory attenuation in auditory and thalamic regions but may not predict clinical outcomes in CHR-P participants

NEUROTRANSMITTER AND BRAIN PARTS INVOLVED IN SCHIZOPHRENIA

Schizophrenia (SCZ) is a major debilitating, complex, and costly illness that strikes 1% of the world's population. It is characterized by three general types of symptoms: Atypical symptoms (aggressiveness, agitation, delusions, hallucinations), depressive symptoms (alogia, avolition, anhedonia, apathy), and cognitive symptoms (impaired attention, learning, memory). The etiology of SCZ has still not been fully understood. Alteration in various neurochemical systems such as dopamine, serotonin, norepinephrine, gamma-aminobutyric acid, and glutamate are involved in the pathophysiology of SCZ. The lack of understanding regarding the exact pathogenic process may be the likely a reason for the non-availability of effective treatment, which can prevent onset and progression of the SCZ. The tools of modern neuroscience, drawing from neuroanatomy, neurophysiology, brain imaging, and psychopharmacology, promise to provide a host of new insights into the etiology and treatment of SCZ. In this review, we will discuss the role of the various neurotransmitter concerned and brain parts exaggerated in the SCZ

Taking Sides with Pain – Lateralization aspects Related to Cerebral Processing of Dental Pain

The current fMRI study investigated cortical processing of electrically induced painful tooth stimulation of both maxillary canines and central incisors in 21 healthy, right-handed volunteers. A constant current, 150% above tooth specific pain perception thresholds was applied and corresponding online ratings of perceived pain intensity were recorded with a computerized visual analog scale during fMRI measurements. Lateralization of cortical activations was investigated by a region of interest analysis. A wide cortical network distributed over several areas, typically described as the pain or nociceptive matrix, was activated on a conservative significance level. Distinct lateralization patterns of analyzed structures allow functional classification of the dental pain processing system. Namely, certain parts are activated independent of the stimulation site, and hence are interpreted to reflect cognitive emotional aspects. Other parts represent somatotopic processing and therefore reflect discriminative perceptive analysis. Of particular interest is the observed amygdala activity depending on the stimulated tooth that might indicate a role in somatotopic encoding

Thalamo-cortical circuits during sensory attenuation in emerging psychosis: a combined magnetoencephalography and dynamic causal modelling study

Evidence suggests that schizophrenia (ScZ) involves impairments in sensory attenuation. It is currently unclear, however, whether such deficits are present during early-stage psychosis as well as the underlying network and the potential as a biomarker. To address these questions, Magnetoencephalography (MEG) was used in combination with computational modeling to examine M100 responses that involved a “passive” condition during which tones were binaurally presented, while in an “active” condition participants were asked to generate a tone via a button press. MEG data were obtained from 109 clinical high-risk for psychosis (CHR-P) participants, 23 people with a first-episode psychosis (FEP), and 48 healthy controls (HC). M100 responses at sensor and source level in the left and right thalamus (THA), Heschl’s gyrus (HES), superior temporal gyrus (STG) and right inferior parietal cortex (IPL) were examined and dynamic causal modeling (DCM) was performed. Furthermore, the relationship between sensory attenuation and persistence of attenuated psychotic symptoms (APS) and transition to psychosis was investigated in CHR-P participants. Sensory attenuation was impaired in left HES, left STG and left THA in FEP patients, while in the CHR-P group deficits were observed only in right HES. DCM results revealed that CHR-P participants showed reduced top-down modulation from the right IPL to the right HES. Importantly, deficits in sensory attenuation did not predict clinical outcomes in the CHR-P group. Our results show that early-stage psychosis involves impaired sensory attenuation in auditory and thalamic regions but may not predict clinical outcomes in CHR-P participants

Spatio-Temporal and Multisensory Integration: the relationship between sleep and the cerebellum

Does the cerebellum sleep? If so, does sleep contribute to cerebellar cognition? In this thesis, the sleep contribution to the consolidation process of spatial-temporal and multisensory integration was investigated in relation to the human cerebellum. Multiple experimental approaches were used to answer research questions addressed in the various chapters. Summarizing the evidence of the electrophysiology and neuroimaging studies, in Chapter1 we present intriguing evidence that the cerebellum is involved in sleep physiology, and that cerebellar-dependent memory formation can be consolidated during sleep. In Chapter 2, using functional neuroimaging in healthy participants during various forms of the Serial interception sequential learning (SISL) task, i.e., predictive timing, motor coordination, and motor imagination, we assessed the cerebellar involvement in spatio-temporal predictive timing; and possible cerebellar interactions with other regions, most notably the hippocampus. In Chapter 3, we add to the findings of Chapter 2 that indicate the cerebellum and hippocampus are involved in the task, by showing that more than simply activated, the cerebellum is a necessary and responsible region for the establishment of the spatio-temporal prediction. This follows from the deficits in behavioral properties of the predictive and reactive timing in the cerebellar ataxia type 6 patients, using the modified version of the SISL task. In Chapter 4, we assessed the subsequent post-interval behavioral performances on the learning of the fixed and random timing sequences in the SISL task, comparing a sleep group and wake group in healthy participants. Our findings show that sleep consolidates the process of cerebellar-dependent spatio-temporal integration. In Chapter 5, we investigated the establishment of visual-tactile integration during sleep through the examination of tactile motion stimulation during sleep and showed that, subsequent to sleep, directional visual motion discrimination i

The structural neurobiology of social anxiety disorder : a clinical neuroimaging study

Includes bibliographical referencesWhile a number of studies have explored the functional neuroanatomy of social anxiety disorder (SAD), comparatively few studies have investigated the structural underpinnings in SAD. 18 psychopharmacologically and psychotherapeutically naïve adult patients with a primary Axis I diagnosis of generalized social anxiety disorder and 18 demographically (age, gender and education) matched healthy controls underwent 3T structural magnetic resonance imaging. A manual tracing protocol was specifically developed to compute the volume of the most prominent subcortical gray matter structures implicated in SAD by previous functional research. Cortical thickness was estimated using an automated algorithm and whole brain analyses of white matter structure were performed using FSL's tract - based spatial statistics comparing fractional anisotropy (FA), mean diffusivity (MD) in individuals with SAD. Manual tracing demonstrated that compared to controls, SAD patients showed an enlarged right globus pallidus. Cortical thickness analyses demonstrated significant cortical thinning in the left isthmus of the cingulate gyrus, the left temporal pole, and the left superior temporal gyrus. Analyses of white matter tractographic data demonstrated reduced FA in in the genu, splenium and tapetum of the corpus callosum. Additionally reduced FA was noticed in the fornix and the right cingulum. Reduced FA was also noted in bilateral corticospinal tracts and the right corona radiata. The results demonstrate structural alterations in limbic circuitry as well as involvement of the basal glanglia and their cortical projections and input pathways

Neuropathology and cognitive dysfunction after early hypoglycaemia

Hypoglycaemia is the most common metabolic problem in neonatal medicine, occurring during the first days of life and usually resolving within the same time frame. However, some neonates and infants experience severe and recurrent episodes of hypoglycaemia, the most common aetiologies being congenital hyperinsulinism (CHI) and ketotic hypoglycaemia (KH). Children with CHI are at risk of lasting brain injury, while children with KH are considered to be protected from adverse sequelae owing to the presence of ketone bodies during hypoglycaemia. This thesis investigated the neuropsychological and neuroimaging profiles of these two patient groups in neurologically normal school-aged children. Thirty-one patients with CHI and twenty-one patients with KH participated in the study alongside a cohort of healthy controls. A comprehensive battery of neuropsychological tests revealed specific impairments in attention and motor skills in both patient groups, with additional impairments observed in children with CHI. Automated and manual measurements of subcortical volumes, as well as whole brain analyses (voxel based morphometry and tract based spatial statistics) were conducted. Compared to controls, patients with CHI have reduced volume of subcortical structures, as well as extensive white matter volume loss (accompanied by decreased intracranial volume) and reduced white matter integrity across the entire brain. Patients with KH did not significantly differ from controls on any brain measures, but the only significant difference between patient groups was in thalamic and intracranial volumes. Integrity of subcortical structures and white matter was found to be predictive of scores in memory, motor skills and attention. This study is the first to show the extent of brain abnormality as a result of CHI in neurologically normal children. Furthermore, the finding that both patient groups share a similar cognitive profile refutes the notion that children with KH are protected from adverse sequelae. The implications of these findings are discussed

Auditory sensory attenuation effect in emerging psychosis

Sensory consequences of one’s own voluntary action are perceived as less intense than externally initiated sensations. This process is referred to as sensory attenuation. This sensory attenuation has been identified in humans and animals across various modalities, including visual, auditory and somatosensory domains. The auditory sensory attenuation is explored by comparing the auditory N/M100 amplitude between self- and external-initiated conditions. The focus of auditory sensory attenuation is mainly on the primary auditory cortex and the superior temporal cortex, while emerging evidence indicates that the sensory attenuation is present in broader brain area. Moreover, the generation of sensory attenuation relies upon the precise coordination of the motor system with sensory areas. However, sensory attenuation across the whole brain and the underlying neural interaction between brain areas remain underexplored. Importantly, failure in sensory attenuation is considered to play a role in clinical psychotic symptoms, such as auditory hallucination and illusion. This has been confirmed in chronic schizophrenia (ScZ), possibly resulting from disrupted frontal-temporal coordination during generating sensory attenuation. However, it currently remains unclear whether deficits in sensory attenuation emerge before the prodromal phase of psychosis, as well as what aberrant neural mechanism underlie emerging psychosis. Given previous studies based on electroencephalogram(EEG) technology, the current thesis aimed to employ magnetoencephalography (MEG) to examine auditory M100 sensory attenuation. MEG-data were collected from 48 healthy controls (HC), 110 clinical high-risk psychosis (CHR), and 26 first-episode psychosis (FEP) participants during an auditory task in which pure tones were either elicited through a button press or passively presented. Auditory M100 event-related fields (ERFs) were recorded to assess auditory M100 sensory attenuation at the sensor- and source-level. The first aim was to map the sensory attenuation effect across the whole brain and further explore the association between motor-related activity and auditory sensory attenuation. Dynamic causal modelling (DCM) was also employed to determine the top-down and bottom-up modulation to determine the underpinning neural mechanism during sensory attenuation generation (Chapter 3). Subsequently, we focused on the auditory regions to address the sensory attenuation characteristics in emerging psychosis and its association with clinical features and cognitive functions. The goal was to address whether the sensory attenuation deficit could be regarded as a potential biomarker for early identification of psychosis (Chapter 4). Finally, DCM was employed to explore the alteration of neural interactions across the sensory attenuation network in emerging psychosis and investigate the aberrant neural mechanism of sensory attenuation (Chapter 5). The findings in Chapter 3 revealed that auditory M100 sensory attenuation was present in spatially distributed brain areas, involving various subcortical-cortical areas. In addition, the current results supported the modulation of motor-related activity with auditory sensory attenuation. The results from DCM further indicated the role of both top-down and bottom-up modulation of a thalamo-cortical network in generating auditory sensory attenuation. The results in Chapter 4 demonstrated impaired auditory M100 sensory attenuation in FEP and indicated that aberrant sensory attenuation emerged in the prodromal phase of psychosis. Moreover, the sensory attenuation effect in the auditory cortex was linearly associated with clinical symptom severity and cognitive performance. Finally, the DCM results in Chapter 5 suggested that the impaired sensory attenuation in FEP-participants originated from imprecise top-down control and subsequently enhanced bottom-up input (prediction error). The deficits in top-down control in CHR-individuals were not strong, while CHR participants were characterized by increased bottom-up inputs, which was intermediate between HC and FEP. Collectively, the results of this thesis suggested impaired auditory sensory attenuation in emerging psychosis, resulting from aberrant top-down and bottom-up interaction. This provides evidence that the auditory M100 sensory attenuation could be a potential candidate for the early detection of psychosis