Cortico-striato-thalamo-cortical Loop Research Articles

Gray matter structural alterations of cortico-striato-thalamo-cortical loop in familial Paroxysmal Kinesigenic Dyskinesia

BackgroundPrevious studies have indicated that patients with Paroxysmal Kinesigenic Dyskinesia (PKD) exhibit reduced gray matter volume in certain brain regions within the cortico-striato-thalamo-cortical (CSTC) loop. However, a comprehensive investigation specifically targeting the CSTC loop in PKD has never been conducted. ObjectivesTo provide evidence for the involvement of the CSTC loop in the pathogenesis of PKD from the perspective of structural alterations, this study carried out a surface-based morphometry (SBM), voxel-based morphometry (VBM), and structural covariance networks (SCN) combined analysis in familial PKD patients. MethodsA total of 8 familial PKD patients and 10 healthy family members were included in the study and underwent Brain MRI examinations. Based on 3D T1 MPRAGE data, neuroimaging metrics of cortical thickness from SBM, subcortical nuclei volume from VBM, and covariance coefficient from SCN were used to systematically investigate the brain structural alterations along the CSTC loop of PKD patients. ResultsA significant decrease in the average cortical thickness of the left S1 region in the PKD group was observed. The volumes of subcortical nuclei, including the thalamus, putamen, and globus pallidus were reduced, with a pronounced effect observed in the bilateral putamen. And the structural covariance connection between the left putamen and the left globus pallidus was significantly strengthened. ConclusionsThe study confirms the involvement of the CSTC loop in the pathogenesis of PKD from the perspective of structural alterations, and the findings may provide potential targets for objective diagnosis and therapeutic monitoring of PKD.

Altered Cortico-Striatal Functional Connectivity During Resting State in Obsessive-Compulsive Disorder.

Background: Neuroimaging studies show that obsessive–compulsive disorder (OCD) is characterized by an alteration of the cortico–striato–thalamo–cortical (CSTC) system in terms of an imbalance of activity between the direct and the indirect loop of the CSTC. As resting-state functional connectivity (FC) studies investigated only specific parts of the CSTC in patients with OCD up to now, the present study aimed at exploring FC in the CSTC as a whole. Methods: We investigated potential alterations in resting-state FC within the CSTC system in 44 OCD patients and 40 healthy controls by taking into consideration all relevant nodes of the direct and indirect CSTC loop. Results: Compared to healthy controls, OCD patients showed an increased FC between the left subthalamic nucleus (STN) and the left external globus pallidus (GPe), as well as an increased FC between the left GPe and the left internal globus pallidus (GPi). Conclusion: These findings may contribute to a better understanding of the OCD pathophysiology by providing further information on the connectivity alterations within specific regions of the CSTC system. In particular, increased FC between the STN and the left GPe may play a major role in OCD pathology. This assumption is consistent with the fact that these regions are also the main target sites of therapeutic deep brain stimulation in OCD.

Resting-state connectivity within and across neural circuits in anorexia nervosa.

IntroductionObsessional thoughts and ritualized eating behaviors are characteristic of Anorexia Nervosa (AN), leading to the common suggestion that the illness shares neurobiology with obsessive–compulsive disorder (OCD). Resting‐state functional connectivity MRI (rs‐fcMRI) is a measure of functional neural architecture. This longitudinal study examined functional connectivity in AN within the limbic cortico‐striato‐thalamo‐cortical (CSTC) loop, as well as in the salience network, the default mode network, and the executive control network (components of the triple network model of psychopathology).MethodsResting‐state functional connectivity MRI scans were collected in unmedicated female inpatients with AN (n = 25) and healthy controls (HC; n = 24). Individuals with AN were scanned before and after weight restoration and followed for one month after hospital discharge. HC were scanned twice over the same timeframe.ResultsUsing a seed‐based correlation approach, individuals with AN had increased connectivity within the limbic CSTC loop when underweight, only. There was no significant association between limbic CSTC connectivity and obsessive–compulsive symptoms or prognosis. Exploratory analyses of functional network connectivity within the triple network model showed reduced connectivity between the salience network and left executive control network among AN relative to HC. These abnormalities persisted following weight restoration.ConclusionsThe CSTC findings suggest that the neural underpinnings of obsessive–compulsive symptoms may differ from those of OCD. The inter‐network abnormalities warrant examination in relation to illness‐specific behaviors, namely abnormal eating behavior. This longitudinal study highlights the complexity of the neural underpinnings of AN.

Caudothalamic dysfunction in drug-free suicidally depressed patients: an MEG study.

Major depressive disorder (MDD), characterized by low mood or anhedonia, is commonly associated with a greater suicidal susceptibility. There are numerous suicide-related findings pertaining to the dorsolateral prefrontal cortex (DLPFC), caudate nucleus and thalamus, which form a cortico-striato-thalamo-cortical (CSTC) circuit responsible for executive function and working memory. An aberrant CSTC circuitry is hypothesized to be implicated in depressed patients with a high suicidal risk. 27 MDD patients were assessed with the Nurses Global Assessment of Suicide Risk (NGASR), following which 14 patients were classified into a high suicide risk group (NGASR ≥ 12) and 13 patients were assigned to a low suicide risk group (NGASR < 6). All 27 patients were enrolled with 25 healthy controls for resting-state magnetoencephalography (MEG). Cross-frequency coupling (CFC) measured the phase of alpha-band (8-13Hz) as it modulated to cortical gamma-band (30-48Hz). There was a significantly lower alpha-to-gamma phase-amplitude coupling (PAC) between the right caudate and left thalamus in high-risk suicide group compared to both the low-risk suicide group and healthy controls. The presence of a weaker coupling between the right caudate and left thalamus is indicative of a caudothalamic abnormality in suicidally depressed patients. This implies that a disruption of CSTC loop could result in executive dysfunction and working memory impairment, leading to an increased suicidal risk in MDD patients. In the future, this preliminary study has the possibility of being replicated on a larger scale, and hence validates caudothalamic dysfunction as a reliable neuroimaging biomarker for suicide in depression.

Cortico-Striato-Thalamo-Cortical Circuitry, Working Memory, and Obsessive-Compulsive Disorder.

Cortico-Striato-Thalamo-Cortical Circuitry, Working Memory, and Obsessive-Compulsive Disorder.

The new risk variant CACNA1C and brain circuits in schizophrenia

In recent genome-wide association studies of severe psychiatric disorders, several risk genes have been detected, but their neurobiological function is widely unknown. A polymorphism in the gene encoding the alpha-1C subunit of the L-type voltage-gated calcium channel (CACNA1C) has been associated with schizophrenia and bipolar disorder and may have impact on structure and function of the amygdala. Wolf et al. [1] investigated the influence of the SNP rs1006737 in CACNA1C on gray matter volumes of the amygdala in patients with schizophrenia, bipolar disorder and obsessive compulsive disorder (OCD). The risk genotype had significant effect on the relative amygdala volume in patients with schizophrenia, while this group and bipolar patients had a smaller left amygdala compared to controls. This supports the hypothesis of disturbed calcium metabolism as a neurobiological background of affective symptoms in schizophrenia. However, CACNA1C is also known to be involved in learning and memory. In a functional MRI study of two independent samples of healthy probands, Krug et al. [2] investigated the impact of rs1006737 on episodic memory encoding and retrieval in the right hippocampus. In both samples, they replicated that in the retrieval condition, carriers of the minor allele (A) had lower activations than G/G allele carriers, thus strengthening the hypothesis that this risk genotype is associated with dysfunction of hippocampus-related memory processes. Schizophrenia has been linked to disturbances in neuronal circuits such as the cortico–striato–thalamo–cortical loop. As a consequence, disinhibition of the thalamus plays a prominent role in the overflow of information to the prefrontal cortex and possibly is involved in the generation of positive symptoms. In a resting-state functional MRI study, Klingner et al. [3] found higher thalamocortical functional connectivity in chronic schizophrenia patients compared to healthy controls. Specifically, the connectivity to the right ventrolateral prefrontal and bilateral motor and sensory cortical areas was affected. Structural analysis revealed involvement of medial and anterior thalamic nuclei in correlation with the prefrontal and superior temporal cortex, contributing to alterations of the network in schizophrenia. However, treatment with antipsychotics may have an influence on macroconnectivity and myelination of fiber tracts. In a cell culture study of oligodendrocytes with or without the presence of the cuprizone, a white matter damaging agent, Xu et al. [4] reported that clozapine and quetiapine, but not haloperidol or olanzapine counteracted effects of cuprizone. These findings are relevant for the growing knowledge about the influence of antipsychotics on pathophysiological aspects such as myelination-related dysconnectivity in schizophrenia. In a clinical assessment of 56.861 schizophrenia patients, Grohmann et al. [5] compared the typical neuroleptic flupentixol to haloperidol and second-generation antipsychotics with respect to drug utilization and adverse drug reactions (ADR). Flupentixol ranked lowest among all ADR. Extrapyramidal symptoms were most frequently detected in flupentixol and risperidone and least in the olanzapine-/quetiapine-treated group. Altogether, the results justify the treatment approach with flupentixol in a subgroup of schizophrenia patients. Disturbances in semantic processing are proposed to be involved in the pathophysiology of formal thought disorder in schizophrenia. In a functional MRI study, Sass et al. [6] A. Schmitt (&) P. Falkai Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Nusbaumstr. 7, 80336 Munich, Germany e-mail: andrea.schmitt@med.uni-muenchen.de

Reduced functional connectivity within the limbic cortico‐striato‐thalamo‐cortical loop in unmedicated adults with obsessive‐compulsive disorder

Cortico-striato-thalamo-cortical (CSTC) loops project from the cortex to the striatum, then from the striatum to the thalamus via the globus pallidus, and finally from the thalamus back to the cortex again. These loops have been implicated in Obsessive-Compulsive Disorder (OCD) with particular focus on the limbic CSTC loop, which encompasses the orbitofrontal and anterior cingulate cortices, as well as the ventral striatum. Resting state functional-connectivity MRI (rs-fcMRI) studies, which examine temporal correlations in neural activity across brain regions at rest, have examined CSTC loop connectivity in patients with OCD and suggest hyperconnectivity within these loops in medicated adults with OCD. We used rs-fcMRI to examine functional connectivity within CSTC loops in unmedicated adults with OCD (n = 23) versus healthy controls (HCs) (n = 20). Contrary to prior rs-fcMRI studies in OCD patients on medications that report hyperconnectivity in the limbic CSTC loop, we found that compared with HCs, unmedicated OCD participants had reduced connectivity within the limbic CSTC loop. Exploratory analyses revealed that reduced connectivity within the limbic CSTC loop correlated with OCD symptom severity in the OCD group. Our finding of limbic loop hypoconnectivity in unmedicted OCD patients highlights the potential confounding effects of antidepressants on connectivity measures and the value of future examinations of the effects of pharmacological and/or behavioral treatments on limbic CSTC loop connectivity.

Altered 13C Glucose Metabolism in the Cortico—Striato—Thalamo—Cortical Loop in the MK-801 Rat Model of Schizophrenia

Using a modified MK-801 (dizocilpine) N-methyl-D-aspartic acid (NMDA) receptor hypofunction model for schizophrenia, we analyzed glycolysis, as well as glutamatergic, GABAergic, and monoaminergic neurotransmitter synthesis and degradation. Rats received an injection of MK-801 daily for 6 days and on day 6, they also received an injection of [1-(13)C]glucose. Extracts of frontal cortex (FCX), parietal and temporal cortex (PTCX), thalamus, striatum, nucleus accumbens (NAc), and hippocampus were analyzed using (13)C nuclear magnetic resonance spectroscopy, high-performance liquid chromatography, and gas chromatography-mass spectrometry. A pronounced reduction in glycolysis was found only in PTCX, in which (13)C labeling of glucose, lactate, and alanine was decreased. (13)C enrichment in lactate, however, was reduced in all areas investigated. The largest reductions in glutamate labeling were detected in FCX and PTCX, whereas in hippocampus, striatum, and Nac, (13)C labeling of glutamate was only slightly but significantly reduced. The thalamus was the only region with unaffected glutamate labeling. γ-Aminobutyric acid (GABA) labeling was reduced in all areas, but most significantly in FCX. Glutamine and aspartate labeling was unchanged. Mitochondrial metabolites were also affected. Fumarate labeling was reduced in FCX and thalamus, whereas malate labeling was reduced in FCX, PTCX, striatum, and NAc. Dopamine turnover was decreased in FCX and thalamus, whereas that of serotonin was unchanged in all regions. In conclusion, neurotransmitter metabolism in the cortico-striato-thalamo-cortical loop is severely impaired in the MK-801 (dizocilpine) NMDA receptor hypofunction animal model for schizophrenia.