Neurobiological model of obsessive–compulsive disorder: Evidence from recent neuropsychological and neuroimaging findings

Obsessive–compulsive disorder (OCD) was previously considered refractory to most types of therapeutic intervention. There is now, however, ample evidence that selective serotonin reuptake inhibitors and behavior therapy are highly effective methods for treatment of OCD. Furthermore, recent neurobiological studies of OCD have found a close correlation between clinical symptoms, cognitive function, and brain function. A large number of previous neuroimaging studies using positron emission tomography, single‐photon emission computed tomography or functional magnetic resonance imaging (fMRI) have identified abnormally high activities throughout the frontal cortex and subcortical structures in patients with OCD. Most studies reported excessive activation of these areas during symptom provocation. Furthermore, these hyperactivities were decreased after successful treatment using either selective serotonin reuptake inhibitors or behavioral therapy. Based on these findings, an orbitofronto‐striatal model has been postulated as an abnormal neural circuit that mediates symptomatic expression of OCD. On the other hand, previous neuropsychological studies of OCD have reported cognitive dysfunction in executive function, attention, nonverbal memory, and visuospatial skills. Moreover, recent fMRI studies have revealed a correlation between neuropsychological dysfunction and clinical symptoms in OCD by using neuropsychological tasks during fMRI. The evidence from fMRI studies suggests that broader regions, including dorsolateral prefrontal and posterior regions, might be involved in the pathophysiology of OCD. Further, we should consider that OCD is heterogeneous and might have several different neural systems related to clinical factors, such as symptom dimensions. This review outlines recent neuropsychological and neuroimaging studies of OCD. We will also describe several neurobiological models that have been developed recently. Advanced findings in these fields will update the conventional biological model of OCD.     

Neuroimaging studies in patients with obsessive-compulsive disorder in China

Summary

Obsessive-compulsive disorder (OCD) is a common mental disorder of uncertain etiology. Neuroimaging studies of patients with OCD in China started to appear in the late 1990s, identifying structural abnormalities in the gray matter and white matter of the prefrontal lobe, the corpus striatum, and the thalamus. Studies using positron emission tomography (PET), functional magnetic resonance imaging (fMRI), and magnetic resonance spectroscopy (MRS) have found increased metabolism and activation in these brain regions that are correlated with the duration, severity and cognitive symptoms of OCD. After surgery for OCD the activation in these target areas decreases. These results in China are similar to those presented in previous neuroimaging studies, including several meta-analyses from other countries.     

The neuropsychology of obsessive compulsive disorder: the importance of failures in cognitive and behavioural inhibition as candidate endophenotypic markers

Obsessive compulsive disorder (OCD) is a highly debilitating neuropsychiatric condition with estimated lifetime prevalence of 2-3%, more than twice that of schizophrenia. However, in contrast to other neuropsychiatric conditions of a comparable or lesser prevalence, relatively little is understood about the aetiology, neural substrates and cognitive profile of OCD. Despite strong evidence for OCD being familial, with risk to first-degree relatives much greater than for the background population, its genetic underpinnings have not yet been adequately delineated. Although cognitive dysfunction is evident in the everyday behaviour of OCD sufferers and is central to contemporary psychological models, theory-based studies of neurocognitive function have yet to reveal a reliable cognitive signature, and interpretation has often been confounded by failures to control for co-morbidities. The neuroimaging findings in OCD are amongst the most robust reported in the psychiatric literature, with structural and functional abnormalities frequently reported in orbitofrontal cortex, anterior cingulate cortex, and caudate nucleus. In spite of this, our relative lack of understanding of OCD neurochemical processes continues to impede progress in the development of novel pharmacological treatment approaches. Integrating the neurobiological, cognitive, and clinical findings, we propose that OCD might usefully be conceptualised in terms of lateral orbitofrontal loop dysfunction, and that failures in cognitive and behavioural inhibitory processes appear to underlie many of the symptoms and neurocognitive findings. We highlight existing limitations in the literature, and the potential utility of endophenotypes in overcoming these limitations. We propose that neurocognitive indices of inhibitory functions may represent a useful heuristic in the search for endophenotypes in OCD. This has direct implications not only for OCD but also for putative obsessive-compulsive spectrum conditions including attention deficit hyperactivity disorder, Tourette's syndrome, and trichotillomania (compulsive hair pulling).     

An overview of the first 5 years of the ENIGMA obsessive–compulsive disorder working group: The power of worldwide collaboration

Neuroimaging has played an important part in advancing our understanding of the neurobiology of obsessive–compulsive disorder (OCD). At the same time, neuroimaging studies of OCD have had notable limitations, including reliance on relatively small samples. International collaborative efforts to increase statistical power by combining samples from across sites have been bolstered by the ENIGMA consortium; this provides specific technical expertise for conducting multi‐site analyses, as well as access to a collaborative community of neuroimaging scientists. In this article, we outline the background to, development of, and initial findings from ENIGMA''s OCD working group, which currently consists of 47 samples from 34 institutes in 15 countries on 5 continents, with a total sample of 2,323 OCD patients and 2,325 healthy controls. Initial work has focused on studies of cortical thickness and subcortical volumes, structural connectivity, and brain lateralization in children, adolescents and adults with OCD, also including the study on the commonalities and distinctions across different neurodevelopment disorders. Additional work is ongoing, employing machine learning techniques. Findings to date have contributed to the development of neurobiological models of OCD, have provided an important model of global scientific collaboration, and have had a number of clinical implications. Importantly, our work has shed new light on questions about whether structural and functional alterations found in OCD reflect neurodevelopmental changes, effects of the disease process, or medication impacts. We conclude with a summary of ongoing work by ENIGMA‐OCD, and a consideration of future directions for neuroimaging research on OCD within and beyond ENIGMA.     

Neuroimaging studies in post-traumatic stress disorder.

The authors review some of the advances that have been made in understanding the structural, biochemical, and functional neuroanatomy of post-traumatic stress disorder (PTSD). First, the authors review the primary brain regions that had been hypothesized a priori, from the phenomenology and neurobiology of PTSD, to be implicated in the pathophysiology. Next, they review findings from neuroimaging studies of these brain regions in PTSD, and explain the various experimental methods and imaging technologies used in these studies. A broader perspective, including a discussion of additional brain areas that may be involved in PTSD, is synthesized. The authors conclude with a rationale and approach for studies testing sharply defined hypotheses and those using multidisciplinary strategies that integrate neuroimaging data with other cognitive, biologic, and genetic tools to study this complex disorder.     

Review of structural neuroimaging in patients with refractory obsessivecompulsive disorder

The notion that some special brain regions may be involved in the pathogenesis of obsessive-compulsive disorder (OCD) dates back to the beginning of the twentieth century. Structural neuroimaging studies in the past 2 decades have revealed important findings that facilitate understanding of OCD pathogenesis. Current knowledge based on functional and structural neuroimaging investigations largely emphasizes abnormalities in fronto-striatal-thalamic-cortical and orbitofronto-striato-thalamic circuits in the pathophysiology of OCD. However, these neuroimaging studies did not focus on refractory OCD. The present review mainly focused on structural neuroimaging performed in OCD, which had been ignored previously, and highlighted current evidence supporting that orbito-frontal cortex and thalamus are key brain regions, and that the hippocampus-amygdala complex is associated with refractoriness to the available treatment strategies. However, to fully reveal the neuroanatomy of refractoriness, longitudinal studies with larger samples are required.     

Neuroimaging of cognitive brain function in paediatric obsessive compulsive disorder: a review of literature and preliminary meta-analysis

Obsessive compulsive disorder (OCD) is a frequent psychiatric disorder with a prevalence of 1–3?%, and it places an enormous burden on patients and their relatives. Up to 50?% of all cases suffer from onset in childhood or adolescence, and the disorder often takes a chronic course with a poor long-term prognosis. Paediatric OCD, with its high familiality, is often referred to as a distinct OCD subtype that coincides with a developmental period in which the prefrontal cortex exhibits extensive structural and functional maturation. In the present review, we included all studies examining cognitive brain activation in children and/or adolescents with OCD. We conducted extensive literature searches for relevant articles (Pubmed, ScienceDirect) and summarize, tabulate, and discuss their results. For the eight activation studies using functional magnetic resonance imaging, we also performed preliminary meta-analyses to assess the most consistent hypo- and hyperactivation in paediatric OCD patients during cognitive task performance. The review of literature as well as our preliminary meta-analyses of paediatric studies indicated altered functional activation in the same brain regions of affective and cognitive cortico-striatal-thalamic (CST) circuits as for adult OCD patients despite some variations in the direction of activation difference. The still small number of studies that examined brain activation in paediatric OCD patients thereby largely converged with previous findings in adult patients and with the established neurobiological models of CST circuit dysfunction in OCD.     

White matter abnormalities in obsessive-compulsive disorder: a diffusion tensor imaging study

CONTEXT: Several neurobiological models of obsessive-compulsive disorder (OCD) posit a primary role for dysfunction of the anterior cingulate gyrus. Both functional and structural neuroimaging studies have implicated anterior cingulate gray matter abnormalities in the pathophysiology of OCD, but there has been little investigation of the anterior cingulate white matter in this disorder. OBJECTIVE: To test the hypothesis that patients with OCD have abnormal white matter microstructure in the anterior cingulate gyrus compared with healthy volunteers as inferred from diffusion tensor imaging. Additional analyses examined group differences in white matter integrity across the entire brain. DESIGN, SETTING, AND PARTICIPANTS: Fifteen patients with a DSM-IV diagnosis of OCD and 15 healthy volunteers matched for age, sex, and handedness underwent diffusion tensor imaging and structural magnetic resonance imaging examinations. Fractional anisotropy (FA), a robust intravoxel measure of water self-diffusion, was compared between groups on a voxel-by-voxel basis in the anterior cingulate white matter after standardization in Talairach space. MAIN OUTCOME MEASURES: Clinical ratings of symptom severity (ie, Yale-Brown Obsessive-Compulsive Scale) and FA. RESULTS: Compared with healthy volunteers, patients demonstrated significantly lower FA bilaterally in 3 areas of the anterior cingulate gyrus white matter. Additional analyses conducted across the rest of the brain white matter revealed lower FA bilaterally in the parietal region (supramarginal gyri), right posterior cingulate gyrus, and left occipital lobe (lingual gyrus). No areas of significantly higher FA were observed in patients compared with healthy volunteers. Lower FA in the parietal region correlated significantly with higher Yale-Brown Obsessive-Compulsive Scale scores. CONCLUSIONS: These preliminary findings provide evidence of an abnormality that involves the anterior cingulate white matter in the pathogenesis of OCD and are consistent with neurobiological models that posit a defect in connectivity in the anterior cingulate basal ganglia-thalamocortical circuit. White matter abnormalities in other brain regions may also be implicated in the neurobiology of OCD.     

Hippocampus and amygdalar volumes in patients with refractory obsessive-compulsive disorder

Functional and structural neuroimaging studies have implicated the hippocampus-amygdala complex in the pathophysiology of obsessive-compulsive disorder (OCD), although no consensus has been established. These brain regions have not been investigated in refractory OCD patients. Volumes of the hippocampus, and amygdala were measured by magnetic resonance imaging (MRI) in a sample of 14 refractory OCD patients and 14 healthy comparison subjects. The mean left and right hippocampal and amygdala volumes of the patients were smaller than those of the healthy controls. OCD severity was not correlated with amygdala volumes but was related to the left hippocampus. Duration of illness was correlated with both hippocampus and left amygdala. Our findings suggest that hippocampus and amygdalar abnormalities can be considered in refractoriness to OCD.     

Microstructural and functional MRI studies of cognitive impairment in epilepsy

Cognitive impairment is the most common comorbidity in children with epilepsy, but its pathophysiology and predisposing conditions remain unknown. Clinical epilepsy characteristics are not conclusive in determining cognitive outcome. Because many children with epilepsy do not have macrostructural magnetic resonance imaging (MRI) abnormalities, the underlying substrate for cognitive impairment may be found at the microstructural or functional level. In the last two decades, new MRI techniques have been developed that have the potential to visualize microstructural or functional abnormalities associated with cognitive impairment. These include volumetric MRI, voxel‐based morphometry (VBM), diffusion tensor imaging (DTI), MR spectroscopy (MRS), and functional MRI (fMRI). All of these techniques have shed new light on various aspects associated with, or underlying, cognitive impairment, although their use in epilepsy has been limited and focused mostly on adults. Therefore, in this review, the use of all these different MRI techniques to unravel cognitive impairment in epilepsy is discussed both in adults and children with epilepsy. Volumetric MRI and VBM have revealed significant volume losses in the area of the seizure focus as well as in distant areas. DTI adds evidence of loss of integrity of connections from the seizure focus to distant areas as well as between distant areas. MRS and fMRI have shown impaired function both in the area of the seizure focus as well as in distant structures. For this review we have compiled and compared findings from the various techniques to conclude that cognitive impairment in epilepsy results from a network disorder in which the (micro)structures as well as the functionality can be disturbed.     

Neuroimaging correlates of cognitive and functional outcome after traumatic brain injury

Magnetic resonance imaging (MRI) may provide an estimate of the severity of diffuse axonal injury by quantitative measurements of atrophy of white matter tracts (such as corpus callosum) and of ventricular enlargement (particularly the third ventricle). However, most MRI studies failed to reveal consistent relationships between the pattern of neuropsychological impairments and the site and extent of focal structural lesions after traumatic brain injury. Functional neuroimaging techniques, such as positron emission tomography or functional MRI, may reveal areas of cerebral dysfunction in regions that look structurally intact on MRI. Studies using these techniques have suggested that the cognitive and behavioural disturbances of traumatic brain injury could be related to a defective activation of a prefrontal-cingulate network.     

Mapping of SPECT regional cerebral perfusion abnormalities in obsessive-compulsive disorder

Locations of cerebral perfusion abnormalities in obsessive-compulsive disorder (OCD) were mapped with single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). This report is a new, more thorough analysis of a previous study of these subjects that used region-of-interest methods. Ten obsessive-compulsive patients and seven age- and sex-matched control subjects were studied. Image sets were converted into stereotaxic space, normalized to each subject's mean cerebral value, then group averaged. Difference images were calculated and searched for regions with significant between-group cerebral perfusion differences. Obsessive-compulsive patients had significantly higher relative cerebral perfusion in medial-frontal and right frontal cortex and in cerebellum, and significantly reduced perfusion in right visual association cortex. Increased frontal Perfusion agrees with several prior reports. The caudate nucleus, which has been controversial in neuroimaging studies of OCD, did not display a difference between groups. The results of this study provide information about the locations and extents of cerebral perfusion abnormalities in OCD. Regional abnormalities were compared with those reported in prior functional neuroimaging studies. Issues related to OCD hyperfrontality and frontal lateralization of psychopathology are discussed. Normal caudate nucleus findings are considered in relation to prior functional imaging studies and hypotheses of OCD pathology. © 1994 Wiley-Liss, Inc.     

Functional neuroimaging studies in posttraumatic stress disorder: review of current methods and findings

Posttraumatic stress disorder (PTSD) is an anxiety disorder associated with changes in neural circuitry involving frontal and limbic systems. Altered metabolism in these brain structures after a traumatic event is correlated to PTSD. Developments in the field of neuroimaging have allowed researchers to look at the structural and functional properties of the brain in PTSD. Despite the relative novelty of functional imaging and its application to the field of PTSD, numerous publications have brought to light several of the circuits implied in this disorder. This article summarizes the findings with regard to PTSD in the functional imaging techniques of single-photon emission computed tomography (SPECT), positron emission tomography (PET), and functional magnetic resonance imaging (fMRI). Furthermore, we discuss strengths and weaknesses of the various techniques and studies. Finally, we explore the future potential of functional neuroimaging studies in PTSD.     

Disrupted structural and functional brain connectomes in mild cognitive impairment and Alzheimer’s disease

Alzheimer’s disease (AD) is the most common type of dementia, comprising an estimated 60–80% of all dementia cases. It is clinically characterized by impairments of memory and other cognitive functions. Previous studies have demonstrated that these impairments are associated with abnormal structural and functional connections among brain regions, leading to a disconnection concept of AD. With the advent of a combination of non-invasive neuroimaging (structural magnetic resonance imaging (MRI), diffusion MRI, and functional MRI) and neurophysiological techniques (electroencephalography and magnetoencephalography) with graph theoretical analysis, recent studies have shown that patients with AD and mild cognitive impairment (MCI), the prodromal stage of AD, exhibit disrupted topological organization in large-scale brain networks (i.e., connectomics) and that this disruption is significantly correlated with the decline of cognitive functions. In this review, we summarize the recent progress of brain connectomics in AD and MCI, focusing on the changes in the topological organization of large-scale structural and functional brain networks using graph theoretical approaches. Based on the two different perspectives of information segregation and integration, the literature reviewed here suggests that AD and MCI are associated with disrupted segregation and integration in brain networks. Thus, these connectomics studies open up a new window for understanding the pathophysiological mechanisms of AD and demonstrate the potential to uncover imaging biomarkers for clinical diagnosis and treatment evaluation for this disease.     

Neuroimaging biomarkers and cognitive function in non-CNS cancer and its treatment: Current status and recommendations for future research

Cognitive changes in patients undergoing treatment for non-central nervous system (CNS) cancers have been recognized for several decades, yet the underlying mechanisms are not well understood. Structural, functional and molecular neuroimaging has the potential to help clarify the neural bases of these cognitive abnormalities. Structural magnetic resonance imaging (MRI), functional MRI (fMRI), diffusion tensor imaging (DTI), MR spectroscopy (MRS), and positron emission tomography (PET) have all been employed in the study of cognitive effects of cancer treatment, with most studies focusing on breast cancer and changes thought to be induced by chemotherapy. Articles in this special issue of Brain Imaging and Behavior are devoted to neuroimaging studies of cognitive changes in patients with non-CNS cancer and include comprehensive critical reviews and novel research findings. The broad conclusions that can be drawn from past studies and the present body of new research is that there are structural and functional changes associated with cancer and various treatments, particularly systemic cytotoxic chemotherapy, although some cognitive and fMRI studies have identified changes at pre-treatment baseline. Recommendations to accelerate progress include well-powered multicenter neuroimaging studies, a better standardized definition of the cognitive phenotype and extension to other cancers. A systems biology framework incorporating multimodality neuroimaging, genetics and other biomarkers will be highly informative regarding individual differences in risk and protective factors and disease- and treatment-related mechanisms. Studies of interventions targeting cognitive changes are also needed. These next steps are expected to identify novel protective strategies and facilitate a more personalized medicine for cancer patients.     

Brain-behavior relationships in obsessive-compulsive disorder

Advances in neuroimaging have led to a greater understanding of brain-behavior relationships in obsessive-compulsive disorder (OCD). This article provides an updated review and analysis of the structural and functional neuroimaging studies in OCD published to date and discusses how evidence from various types of neuroimaging studies has been synthesized to generate and test hypotheses regarding these relationships. We also review the basic science literature on the functional neuroanatomy of cortico-basal ganglia-thalamo-cortical circuits and integrate this information with neuroimaging data in OCD, to present a theoretical model of brain mediation of OCD symptoms and response to treatment. Taken together, neuroimaging studies indicate that OCD symptoms are mediated by hyperactivity in orbitofrontal-subcortical circuits, which may be attributable to an imbalance of tone between direct and indirect striato-pallidal pathways. Serotonergic drugs may ameliorate OCD symptoms by changing the relative balance of tone through the indirect versus direct orbitofrontal-subcortical pathways, thereby decreasing activity in the overall circuit that exists in the symptomatic state.     

New approach to obsessive-compulsive disorder: dopaminergic theories

In patients with obsessive-compulsive disorder (OCD), structural and volumetric abnormalities have been identified by up-to-date neuroimaging techniques both in the prefrontal region and in the basal ganglia (striatum, thalamus, amygdala). The dysfunction of these regions also has been proved by neuroimaging techniques. These alterations can be described as dopaminergic hyperfunction in the prefrontal cortex and serotonergic hypofunction in the basal ganglia. The dysfunction of the so-called 'cortico-striato-thalamic' loops is strongly linked to the symptoms of OCD, where the dopamine is the most dominant neurotransmitter. The ascending serotonergic projections from the raphe nuclei restrain and control the function of these loops. Thus, when serotonergic hypofunction is present, the predominantly dopaminergic loops became overactive, which has been confirmed by neuroimaging techniques and by neurocognitive tests as well. The linkage of the two predominant neurotransmitter systems affected in OCD can be the reason for the fact that SSRIs have limited success in the treatment of OCD symptoms. In recent international, multicentric studies, the treatment of SSRI non-responder subgroup of OCD patients were supplemented by antipsychotics with dopaminergic activity. Many studies have confirmed the beneficial effect of these antidopaminergic substances on the hyperactive cortico-striato-thalamic loops in OCD. The investigation of these dysfunctional loops is also connected to the genetic background of OCD, because some of the candidate gene regions of OCD are coding proteins of the dopamine synthesis (for example: COMT). In this paper, we present a detailed overview of these relationships based on recent findings of OCD research.     

Multimodal functional and structural imaging investigations in psychosis research

Substantial pathophysiological questions about the relationship of brain pathologies in psychosis can only be answered by multimodal neuroimaging approaches combining different imaging modalities such as structural MRI (sMRI), functional MRI (fMRI), diffusion tensor imaging (DTI), positron emission tomography (PET) and magnetic-resonance spectroscopy. In particular, the multimodal imaging approach has the potential to shed light on the neuronal mechanisms underlying the major brain structural and functional pathophysiological features of schizophrenia and high-risk states such as prefronto-temporal gray matter reduction, altered higher-order cognitive processing, or disturbed dopaminergic and glutamatergic neurotransmission. In recent years, valuable new findings have been revealed in these fields by multimodal imaging studies mostly reflecting a direct and aligned correlation of brain pathologies in psychosis. However, the amount of multimodal studies is still limited, and further efforts have to be made to consolidate previous findings and to extend the scope to other pathophysiological parameters contributing to the pathogenesis of psychosis. Here, investigating the genetic foundations of brain pathology relationships is a major challenge for future multimodal imaging applications in psychosis research.

     

Advances in longitudinal studies of amnestic mild cognitive impairment and Alzheimer’s disease based on multi-modal MRI techniques

Amnestic mild cognitive impairment (aMCI) is a prodromal stage of Alzheimer’s disease (AD), and 75%–80% of aMCI patients finally develop AD. So, early identification of patients with aMCI or AD is of great significance for prevention and intervention. According to cross-sectional studies, it is known that the hippocampus, posterior cingulate cortex, and corpus callosum are key areas in studies based on structural MRI (sMRI), functional MRI (fMRI), and diffusion tensor imaging (DTI) respectively. Recently, longitudinal studies using each MRI modality have demonstrated that the neuroimaging abnormalities generally involve the posterior brain regions at the very beginning and then gradually affect the anterior areas during the progression of aMCI to AD. However, it is not known whether follow-up studies based on multi-modal neuroimaging techniques (e.g., sMRI, fMRI, and DTI) can help build effective MRI models that can be directly applied to the screening and diagnosis of aMCI and AD. Thus, in the future, large-scale multi-center follow-up studies are urgently needed, not only to build an MRI diagnostic model that can be used on a single person, but also to evaluate the variability and stability of the model in the general population. In this review, we present longitudinal studies using each MRI modality separately, and then discuss the future directions in this field.     

Brain imaging and psychotherapy: methodological considerations and practical implications

The development of psychotherapy has been based on psychological theories and clinical effects. However, an investigation of the neurobiological mechanisms of psychological interventions is also needed in order to improve indication and prognosis, inform the choice of parallel pharmacotherapy, provide outcome measures and potentially even aid the development of new treatment protocols. This neurobiological investigation can be informed by animal models, for example of learning and conditioning, but will essentially need the non-invasive techniques of functional neuroimaging in order to assess psychotherapy effects on patients’ brains, which will be reviewed here. Most research so far has been conducted in obsessive compulsive disorder (OCD), anxiety disorders and depression. Effects in OCD were particularly exciting in that both cognitive behavioural therapy and medication with a selective serotonin inhibitor led to a reduction in blood flow in the caudate nucleus. In phobia, brief courses of behavioural therapy produced marked reductions of paralimbic responses to offensive stimuli in line with the clinical improvement. Findings in depression are less consistent, with both increases and decreases in prefrontal metabolism being reported. However, they are important in pointing to different mechanisms for the clinical effects of pharmacotherapy (more “bottom up”) and psychotherapy (more “top down”). For the future it would be desirable if the findings of psychotherapy changes to brain activation patterns were confirmed in larger groups with homogenous imaging protocols. Functional imaging has already made great contributions to the understanding of the neural correlates of psychopathology. For example, evidence converges to suggest that the subgenual cingulate is crucial for mood regulation. One current clinical application of these findings is deep brain stimulation in areas highlighted by such imaging studies. I will discuss their initial application in depression and OCD, and suggest potential alternative options based on recent developments in neurofeedback technology.