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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 th...
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Background:
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Objectives:
Brain volume reduction occurs with age, especially in Parkinson plus syndrome or psychiatric disorders. We s...
Reactive inhibitory control is crucial for survival. Traditionally, this control in mammals was attributed solely to the hyperdirect pathway, with cortical control signals flowing unidirectionally from the subthalamic nucleus (STN) to basal ganglia output regions. Yet recent findings have put this model into question, suggesting that the STN is ass...
Citations
... Both cases highlight the neurophysiological underpinnings of OCD, namely the research implicating dysfunction in the cortico-striatal-thalamo-cortical (CSTC) loop [15]. In fact, dysfunction in the CSTC loop has been noted in pediatric populations even during the subclinical phase [5]. ...
... Although Nauczyciel et al. employed different treatment parameters than those used in our study, such as rTMS, double-cone coil, pulse numbers, and stimulation intensity, and no additional targets other than ROFC, we postulate that our TBS-20 Hz protocol alleviates the OCD symptoms in a similar manner, which is by decreasing the metabolic activity of ROFC. The functional hyperactivity of the CTSC loop, which includes OFC, the anterior cingulate cortex (ACC), the basal ganglia, and the thalamus, is widely accepted as the key neurobiological model of OCD [28]. As suggested in a meta-analysis by Gargano et al., TMS targeting OFC may modulate hyperactivity in the CTSC region, counteracting the dysregulation of the related neural circuits and ultimately alleviating OCD symptoms [29]. ...
Background: Despite the availability of pharmacotherapy and psychotherapy for treating obsessive–compulsive disorder (OCD), alternative approaches need to be explored due to the high likelihood of treatment resistance. Neuronavigated 20 Hz theta burst stimulation (TBS-20 Hz), targeting the bilateral dorsolateral prefrontal cortex (DLPFC) augmented with the right orbitofrontal cortex (ROFC), was tested for treating OCD comorbid with depression and anxiety disorders. Methods: A retrospective chart review was performed on fourteen patients treated for moderate-to-severe OCD in a private outpatient clinic. Twelve patients had comorbid major depressive disorder (MDD), and thirteen patients had either generalized anxiety disorder (GAD) or panic disorder (PD). Patients completed the Y-BOCS-SR, BDI-II, and BAI rating scales weekly, which were used to measure the changes in OCD, depression, and anxiety symptoms, respectively. Results: Neuronavigated TBS-20 Hz was sequentially applied to the right DLPFC (RDLPFC), left DLPFC (LDLPFC), and ROFC. A total of 64% (9/14) of patients achieved remission from OCD (Y-BOCS-SR ≤ 14) in an average of 6.1 weeks of treatment (SD = 4.0). A total of 58% (7/12) of patients remitted from MDD (BDI < 13) in an average of 4.1 weeks (SD = 2.8), and 62% (8/13) of patients remitted from GAD/PD (BAI < 8) in an average of 4.3 weeks (SD = 2.5). Conclusions: The neuronavigated TBS-20 Hz sequential stimulation of RDLPFC and LDLPFC, followed by ROFC, significantly reduced OCD, MDD, and GAD/PD symptoms. Randomized sham controls are warranted to validate these results.
... Obsessive-compulsive disorder (OCD) is a psychiatric condition affecting about two percent of the population, marked by chronic and persistent urges or thoughts leading to compulsive behaviors. The pathophysiology of OCD is poorly understood, but it is believed to involve the cortico-striatal-thalamic loop circuits, mainly [58]. The DBS device probably inhibits or functionally overrides this pathological network hyperactivity [59]. ...
In recent decades, deep brain stimulation (DBS) has been extensively studied due to its reversibility and significantly fewer side effects. DBS is mainly a symptomatic therapy, but the stimulation of subcortical areas by DBS is believed to affect the cytoarchitecture of the brain, leading to adaptability and neurogenesis. The neurological disorders most commonly studied with DBS were Parkinson’s disease, essential tremor, obsessive-compulsive disorder, and major depressive disorder. The most precise approach to evaluating the location of the leads still relies on the stimulus-induced side effects reported by the patients. Moreover, the adequate voltage and DBS current field could correlate with the patient’s symptoms. Implantable pulse generators are the main parts of the DBS, and their main characteristics, such as rechargeable capability, magnetic resonance imaging (MRI) safety, and device size, should always be discussed with patients. The safety of MRI will depend on several parameters: the part of the body where the device is implanted, the part of the body scanned, and the MRI-tesla magnetic field. It is worth mentioning that drug-resistant individuals may have different pathophysiological explanations for their resistance to medications, which could affect the efficacy of DBS therapy. Therefore, this could explain the significant difference in the outcomes of studies with DBS in individuals with drug-resistant neurological conditions.
... Our preclinical research on melatonin, a naturally occurring molecule for OCD, reveals promising novel activity on cellular and molecular pathways implicated in the pathogenesis of OCD. Neuroinflammation, neurotransmitter imbalance [83], and frontostriatal circuitry imbalance [84] are all associated with disruptions in the CSTC pathway leading to perseverance behaviour in rodents induced by 8-OH-DPAT, as evidenced by several behavioural parameters [1]. Glutamate, GABA, serotonin, and dopamine play a significant role in movement and behaviour. ...
Obsessive-compulsive disorder (OCD) is a neuropsychiatric condition characterized by intrusive, repetitive thoughts and behaviors. Our study uses a validated 8-OH-DPAT-induced experimental model of OCD in rodents. We focus on the modulatory effects of Insulin-like growth factor-1 (IGF-1) and glucagon-like peptide-1 (GLP-1), which are linked to neurodevelopment and survival. Current research investigates melatonin, a molecule with neuroprotective properties and multiple functions. Melatonin has beneficial effects on various illnesses, including Alzheimer's, Parkinson's, and depression, indicating its potential efficacy in treating OCD. In the present study, we employed two doses of melatonin, 5 mg/kg and 10 mg/kg, demonstrating a dose-dependent effect on 8-OH-DPAT-induced rat changes. In addition, the melatonin antagonist luzindole 5 mg/kg was utilized to compare and validate the efficacy of melatonin. In-silico studies also contribute to understanding the activation of IGF-1/GLP-1 pathways by melatonin. Current research indicates restoring neurochemical measurements on various biological samples (brain homogenates, CSF, and blood plasma) and morphological and histological analyses. In addition, the current research seeks to increase understanding of OCD and investigate potential new treatment strategies. Therefore, it is evident from the aforementioned research that the protective effect of melatonin can serve as a strong basis for developing a new OCD treatment by upregulating IGF-1 and GLP-1 levels. The primary focus of current study revolves around the examination of melatonin as an activator of IGF-1/GLP-1, with the aim of potentially mitigating behavioral, neurochemical, and histopathological abnormalities in an experimental model of obsessive–compulsive disorder caused by 8-OH-DPAT in adult Wistar rats.
... Furthermore, the significance of the glutamatergic system in OCD has been firmly linked to the disruption of the cortico-striato-thalamo-cortical (CSTC) circuit, which governs numerous behavioral and cognitive activities in the cortex (Gao et al. 2019;Calzà et al. 2019;Pauls et al. 2014). Several findings indicate that OCD-like behaviors such as anxiety, fear preservation, compulsion, and repeated behavior may be influenced by neuronal development system maintenance, survival, regulation, synaptic connection, and aberrant release of serotonin, dopamine, and glutamate from neurons. ...
The smoothened sonic hedgehog (Smo-Shh) pathway is one mechanism that influences neurogenesis, including brain cell differentiation and development during childhood. Shh signaling dysregulation leads to decreased target gene transcription, which contributes to increased neuronal excitation, apoptosis, and neurodegeneration, eventually leading to neurological deficits. Neuropsychiatric disorders such as OCD and related neurological dysfunctions are characterized by neurotransmitter imbalance, neuroinflammation, oxidative stress, and impaired neurogenesis, disturbing the cortico-striato-thalamo-cortical (CSTC) link neuronal network. Despite the availability of several treatments, such as selective serotonin reuptake inhibitors, some individuals may not benefit much from them. Several trials on the use of antipsychotics in the treatment of OCD have also produced inadequate findings. This evidence-based review focuses on a potential pharmacological approach to alleviating OCD and associated neuronal deficits by preventing neurochemical alterations, in which sonic hedgehog activators are neuroprotective, lowering neuronal damage while increasing neuronal maintenance and survival. As a result, stimulating SMO-Shh via its potential activators may have neuroprotective effects on neurological impairment associated with OCD. This review investigates the link between SMO-Shh signaling and the neurochemical abnormalities associated with the progression of OCD and associated neurological dysfunctions.
Graphical Abstract
Role of Smo-Shh signaling in serotonergic neurogenesis and in maintaining their neuronal identity. The Shh ligand activates two main transcriptional factors known as Foxa2 and Nkx2.2, which again activates another transcriptional factor, GATA (GATA2 and GATA3), in post mitotic precursor cells of serotonergic neurons—following increased expression of Pet-1 and Lmx1b after GATA regulates the expression of many serotonergic enzymes such as TPH2, SERT, VMAT, slc6a4, Htr1a, Htr1b (Serotonin receptor enzymes), and MAO that regulate and control the release of serotonin and maintain their neuronal identity after their maturation. Abbreviation: Foxa2: Forkhead box; GATA: Globin transcription factor; Lmx1b: LIM homeobox transcription factor 1 beta; TPH2: Tryptophan hydroxylase 2; Htr1a: Serotonin receptor 1a; Htr1b: Serotonin receptor 1b; SERT: Serotonin transporter; VMAT: Vesicular monoamine transporter; MAO: Monoamine oxidase
... Consistent with previous results [38,39], higher lpFCs in the left thalamus and right thalamus/caudate were observed in the current study. As a motor and sensory pathway and an important part of the cortical-striatalthalamic-cortical (CSTC) circuit, the thalamus/caudate plays a crucial role in the regulation of behavior and cognition [40,41]. Long-range FC is punished for connectivity because of its higher metabolic cost [14,15]. ...
Background
Brain functional abnormalities at rest have been observed in obsessive–compulsive disorder (OCD). However, whether and how anatomical distance influences functional connectivity (FC) at rest is ambiguous in OCD.
Methods
Using resting-state functional magnetic resonance imaging data, we calculated the FC of each voxel in the whole-brain and divided FC into short- and long-range FCs in 40 medicine-free patients with OCD and 40 healthy controls (HCs). A support vector machine (SVM) was used to determine whether the altered short- and long-range FCs could be utilized to distinguish OCD from HCs.
Results
Patients had lower short-range positive FC (spFC) and long-range positive FC (lpFC) in the left precentral/postcentral gyrus (t = -5.57 and -5.43; P < 0.05, GRF corrected) and higher lpFC in the right thalamus/caudate, left thalamus, left inferior parietal lobule (IPL) and left cerebellum CrusI/VI (t = 4.59, 4.61, 4.41, and 5.93; P < 0.05, GRF corrected). Furthermore, lower spFC in the left precentral/postcentral gyrus might be used to distinguish OCD from HCs with an accuracy of 80.77%, a specificity of 81.58%, and a sensitivity of 80.00%.
Conclusion
These findings highlight that anatomical distance has an effect on the whole-brain FC patterns at rest in OCD. Meanwhile, lower spFC in the left precentral/postcentral gyrus might be applied in distinguishing OCD from HCs.
... (3) Modulating region-specific glutamatergic neurotransmission Shmelkov et al. have discovered the protein amounts of glutamate receptor subunits NAMDAR2A, NAMDAR2B, Glutamate Receptor-1, and Glutamate Receptor-2 involved in excitatory neurotransmission were decreased by 20-60% in SliTrk5 deficiency mice, greatly modulating the glutamatergic neurotransmission of specific region [16].The sequence variation of SliTrk5 was also considered may be associated with the structural neuroimaging phenotype of obsessive-compulsive disorder [76]. Probably because of these defects, the corticostriatal neurotransmission of SliTrk5 deficiency mice was impaired, agreeing with the observation of altered corticostriatal transmission in OCD patients [77,78]. Current studies have highlighted the important role of excitatory synapses in the striatum and cortical striatum nerve conduction in the pathogenesis of OCD-like behavior (Table 1) [79]. ...
SLIT and NTRK-like protein-5 (SliTrk5) is one of the six members of SliTrk protein family, which is widely expressed in the central nervous system (CNS), regulating and participating in many essential steps of central nervous system development, including axon and dendritic growth, neuron differentiation, and synaptogenesis. SliTrk5, as a neuron transmembrane protein, contains two important conservative domains consisting of leucine repeats (LRRs) located at the amino terminal in the extracellular region and tyrosine residues (Tyr) located at the carboxyl terminal in the intracellular domains. These special structures make SliTrk5 play an important role in the pathological process of the CNS. A large number of studies have shown that SliTrk5 may be involved in the pathogenesis of CNS diseases, such as obsessive-compulsive-disorder (OCD), attention deficit/hyperactivity disorder (ADHD), glioma, autism spectrum disorders (ASDs), and Parkinson’s disease (PD). Targeting SliTrk5 is expected to become a new target for the treatment of CNS diseases, promoting the functional recovery of CNS. The purpose of this article is to review the current research progression of the role of SliTrk5 in CNS and its potential mechanisms in CNS diseases.
... Recently, a growing body of evidence consistently showed that OCD might derive from distortions within large-scale brain networks rather than abnormal individual subnetworks in specific ROIs by seed-based approaches [6]- [9]. After all, the selected ROIs were usually based on a priori anatomical considerations with the hypothesis of local abnormalities [10], [11] or task-based symptom provocation paradigm [12], [13] in previous studies. Few studies have looked at the topological organization of the whole-brain in OCD patients in different resting states. ...
... After eliminating the influence of various artifacts, the 30s artifact-free EEG data (15000 sample points) were selected from each participant and divided into five segments. Each segment of the EEGs was decomposed into the conventional EEG frequency bands, including theta (4-7 Hz), alpha (8)(9)(10)(11)(12), beta (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), and gamma (31-48 Hz) bands for calculating PLVs. To further improve the reliability of the current results, we took the average PLVs of the five segments in each frequency band and applied them in the subsequent analysis of brain functional networks. ...
Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disorder characterized by intrusive thoughts (obsessions) and repetitive behaviors (compulsions), and few studies have assessed the whole-brain functional connectivity architecture of OCD with electroencephalogram (EEG) during different resting states. Graph theory and network-based statistics (NBS) were employed to examine the neural synchronization and the whole-brain functional connectivity (FC) based on the phase-locking value (
PLV
) of OCD patients and healthy controls (HCs) during eyes-closed (EC) and eyes-open (EO) states. Compared with HCs, OCD patients exhibited not only decreased global synchronization in terms of phase synchrony but also aberrant global topological properties (decreased average shortest path lengths and normalized shortest path lengths together with increased global efficiencies and normalized clustering coefficients) together with inhibited intra-hemispheric and interhemispheric FCs during rest, which suggested an imbalance between functional integration and segregation of brain networks for OCD patients. Meanwhile, OCD patients had increased global efficiencies and normalized clustering coefficients, but decreased average clustering coefficients and normalized shortest path lengths together with significantly decreased FCs in the alpha band from EC to EO states, which suggested a dynamic switch between highly integrated (EC state) and highly specialized (EO state) modes of information processing. Moreover, the decreased FCs of OCD patients showed obvious hemispheric asymmetry within or between groups during EC and EO states, which might serve as a potential biomarker to classify OCD patients from HCs.
... 15,16 Thus, it has been hypothesized that functional imbalance between the direct and indirect pathways within a certain CBGTC circuit, including the vlPFC, produces a lack of cognitive control in OCD. 15,17,18 This idea has been supported by neuroimaging findings that reduced vlPFC-caudal and striato-external pallidal connectivities, parts of the indirect pathway, are associated with impaired set shifting and habit-learning bias in OCD. 10,11 Despite substantial efforts to reveal the circuitry mechanism of OCD, our understanding covers a fragment (i.e. ...
... 24 Thus, most studies of CBGTC circuitry in OCD have investigated individual connections confined to a small number of seed regions of interest to preclude the need for mass univariate tests. 11,18,[25][26][27][28] As a connectome approach enables us to reveal a complex brain system, graph-based methods of network science have been introduced. The network-based statistic (NBS) method has substantially greater power to detect subnetworks (i.e. ...
Maladaptive habitual behaviours of obsessive-compulsive disorder are characterized by cognitive inflexibility, which hypothetically arises from dysfunctions of a certain cortico-basal ganglia-thalamo-cortical circuit including the ventrolateral prefrontal region. Inside this neurocircuit, an imbalance between distinct striatal projections to basal ganglia output nuclei, either directly or indirectly via the external globus pallidus, is suggested to be relevant for impaired arbitration between facilitation and inhibition of cortically initiated activity. However, current evidence of individually altered cortico-striatal or thalamo-cortical connectivities is insufficient to understand how cortical dysconnections are linked to the imbalanced basal ganglia system in patients.
In this study, we aimed to identify aberrant ventrolateral prefronto-basal ganglia-thalamic subnetworks representing direct-indirect imbalance and its association with cognitive inflexibility in patients.
To increase network detection sensitivity, we constructed a cortico-basal ganglia-thalamo-cortical network model incorporating striatal, pallidal and thalamic subregions defined by unsupervised clustering in 105 medication-free patients with obsessive-compulsive disorder (age = 25.05 ± 6.55 years, male/female = 70/35) and 99 healthy controls (age = 23.93 ± 5.80 years, male/female = 64/35). By using the network-based statistic method, we analysed group differences in subnetworks formed by suprathreshold dysconnectivities. Using linear regression models, we tested subnetwork dysconnectivity effects on symptom severity and set-shifting performance assessed by well-validated clinical and cognitive tests.
Compared with the healthy controls, patients were slower to track the Part B sequence of the Trail Making Test when the effects of psychomotor and visuospatial functions were adjusted (t = 3.89, P < 0.001) and made more extradimensional shift errors (t = 4.09, P < 0.001). In addition to reduced fronto-striatal and striato-external pallidal connectivities and hypoconnected striato-thalamic subnetwork [P = 0.001, family-wise error rate (FWER) corrected], patients had hyperconnected fronto-external pallidal (P = 0.012, FWER corrected) and intra-thalamic (P = 0.015, FWER corrected) subnetworks compared with the healthy controls. Among the patients, the fronto-pallidal subnetwork alteration, especially ventrolateral prefronto-external globus pallidal hyperconnectivity, was associated with relatively fewer extradimensional shifting errors (β = −0.30, P = 0.001).
Our findings suggest that the hyperconnected fronto-external pallidal subnetwork may have an opposite effect to the imbalance caused by the reduced indirect pathway (fronto-striato-external pallidal) connectivities in patients. This ventrolateral prefrontal hyperconnectivity may help the external globus pallidus disinhibit basal ganglia output nuclei, which results in behavioural inhibition, so as to compensate for the impaired set shifting. We suggest the ventrolateral prefrontal and external globus pallidus as neuromodulatory targets for inflexible habitual behaviours in obsessive-compulsive disorder.
... Within the basal ganglia, the direct pathway is typically considered movement-activating, while the indirect pathway is typically thought to inhibit movement. Overactivation of CSTC loops is theorized to result in hyperactivity within the direct pathway resulting in impulsivity, repetitive behaviors, and impaired action inhibition observed in OCD patients [61]. ...
Focused ultrasound has emerged as a key tool for neurologic disorders. In this focused review, we discuss the utility in disrupting the blood brain barrier to maximize treatment. This can facilitate creating direct coagulative lesions and aid in the administration of chemotherapy. Furthermore, it can facilitate neuromodulation when used in pulse sequencing. The current literature regarding brain tumors, essential tremor, and obsessive-compulsive disorder is reviewed. Additionally, concepts and experimental outcomes for neurodegenerative disease such as Alzheimer’s is presented. Focused ultrasound as a tool is still in its infancy but the potential for adjuvant and direct therapy is promising. More clinical uses will become apparent in coming decades.
