Dysfunctional Connectivity Research Articles

Negative symptoms in schizophrenia are associated with aberrant striato-cortical connectivity in a rewarded perceptual decision-making task.

BackgroundNegative symptoms in schizophrenia have been associated with structural and functional changes in the prefrontal cortex. They often persist after treatment with antipsychotic medication which targets, in particular, the ventral striatum (VS). As schizophrenia has been suggested to arise from dysfunctional connectivity between neural networks, it is possible that residual aberrant striato-cortical connectivity in medicated patients plays a role in enduring negative symptomology. The present study examined the relationship between striato-cortical connectivity and negative symptoms in medicated schizophrenia patients.MethodsWe manipulated motivation in a perceptual decision-making task during functional magnetic resonance imaging. Comparing healthy controls (n = 21) and medicated patients with schizophrenia (n = 18) we investigated how motivation-mediated changes in VS activation affected functional connectivity with the frontal cortex, and how changes in connectivity strength from the neutral to motivated condition related to negative symptom severity.ResultsA pattern of aberrant striato-cortical connectivity was observed in the presence of intact VS, but altered left inferior frontal gyrus (IFG) motivation-mediated activation in patients. The more severe the patient's negative symptoms, the less the connectivity strength between the right VS and left IFG changed from the neutral to the motivated condition. Despite aberrant striato-cortical connectivity and altered recruitment of the left IFG among patients, both patients and healthy controls adopted a more liberal response strategy in the motivated compared to the neutral condition.ConclusionsThe present findings suggest that there is a link between dysfunctional striato-cortical connectivity and negative symptom severity, and offer a possible explanation as to why negative symptoms persist after treatment with antipsychotics.

Neural correlates of the Heidelberg Music Therapy: indicators for the regeneration of auditory cortex in tinnitus patients?

Tinnitus, the phenomenon of ringing or buzzing in the ears without an external sound source is one of the most commonly reported symptoms in otorhinolaryngology and affects 10 – 15% of the general population. Models have been developed to account for neural basis of tinnitus, its pathogenesis and its consequences on mental health (deRidder et al., 2013). In most cases tinnitus onset follows a partial hearing impairment. Peripheral sensory deprivation due to cochlear damages may prompt increased neuronal activity in the central auditory system in order to adapt the neural sensitivity to the reduced sensory inputs. This central gain could over amplify the “neural noise” and thus trigger a homeostatic down-regulation of inhibitory synapses in the auditory cortical map leading to specific reorganization of the cortical representation of the tinnitus percept. Dysfunctional feedback connections from limbic regions to auditory brain areas, interacting at the thalamic level, may account for the psychological impairment.

Impaired regulation of emotion: neural correlates of reappraisal and distraction in bipolar disorder and unaffected relatives.

Deficient emotion regulation has been proposed as a crucial pathological mechanism in bipolar disorder (BD). We therefore investigated emotion regulation impairments in BD, the related neural underpinnings and their etiological relevance for the disorder. Twenty-two euthymic patients with bipolar-I disorder and 17 unaffected first-degree relatives of BD-I patients, as well as two groups of healthy gender-, age- and education-matched controls (N=22/17, respectively) were included. Participants underwent functional magnetic resonance imaging while applying two different emotion regulation techniques, reappraisal and distraction, when presented with emotional images. BD patients and relatives showed impaired downregulation of amygdala activity during reappraisal, but not during distraction, when compared with controls. This deficit was correlated with the habitual use of reappraisal. The negative connectivity of amygdala and orbitofrontal cortex (OFC) observed during reappraisal in controls was reversed in BD patients and relatives. There were no significant differences between BD patients and relatives. As being observed in BD patients and unaffected relatives, deficits in emotion regulation through reappraisal may represent heritable neurobiological abnormalities underlying BD. The neural mechanisms include impaired control of amygdala reactivity to emotional stimuli and dysfunctional connectivity of the amygdala to regulatory control regions in the OFC. These are, thus, important aspects of the neurobiological basis of increased vulnerability for BD.

Aberrant amygdala functional connectivity at rest in pediatric anxiety disorders.

BackgroundChildhood onset of anxiety disorders is associated with greater functional impairment and burden across the lifespan. Recent work suggests that generalized anxiety disorder (GAD) is characterized by dysfunctional connectivity in amygdala-based circuits at rest in adolescents, consistent with adults. However, neural mechanisms underlying a broad spectrum of often-comorbid anxiety disorders in children remains unclear and understudied. The current study examines amygdala functional connectivity at rest in children and adolescents across comorbid anxiety disorders (ADs) including youth with primary diagnoses of GAD and social phobia (SP).ResultsCompared with healthy controls (HCs), AD youth exhibited hyperconnectivity between the right amygdala and the insula and hypoconnectivity between the left amygdala and the ventromedial prefrontal cortex (vmPFC) and posterior cingulate cortex (PCC). Within the AD group, connectivity was not correlated with anxiety severity and only the amygdala-PCC connectivity was positively correlated with age.ConclusionsOur findings indicate that youth with comorbid ADs demonstrate aberrant connectivity in the anterior limbic network (ALN) as well as the PCC at rest. This extends upon previous work suggesting alterations in amygdala circuits underlying fear learning, emotion regulation, and the processing of interoceptive states. Presence of these findings within this young, comorbid sample points to underlying common mechanisms across ADs and illuminates future targets for prevention and intervention in childhood.

Undocumented Families in Times of Deportation at the San Diego–Tijuana Border

Immigration policy in recent years has led to the deportation of thousands of undocumented parents of US citizen children. In the first six months of FY 2011, almost 47,000 undocumented parents were deported from the country. This article examines how US policy came to allow, if not prescribe, the separation of undocumented parents from their sons and daughters. Drawing on evidence from the San Diego–Tijuana border, it reviews critical moments in the history of deportation and reflects on how that history laid the groundwork for the complex and dysfunctional connections between the immigration and child welfare systems that have led to forced family separation.

Genetic vulnerability in patients with psychiatric presentations: a neuroscience perspective.

Today’s psychiatry is progressively entering the realm of science. Significant advances in structural neuroimaging and insight in functional as well as dysfunctional connectivity permit us to see the world from a patient’s perspective and generate hypotheses driven by objective brain-based data (1). In addition to these sophisticated imaging tools, human genetic mapping allows us to address an individual’s genetic vulnerabilities in relation to their brain’s development and processing internal and external information. Increasingly, psychiatric clinicians see genetic mapping as a valid and significantly beneficial tool (2). From a simple cheek swab or saliva sample, commercial enterprises give clinicians quick and easy access to a patient’s genetic vulnerabilities, which can be divided in two domains.

IS THE ASSOCIATIVE STRIATUM A LOCUS OF VULNERABILITY FOR TRANSITION TO PSYCHOSIS?

Tourette syndrome (TS) is characterized by dysfunctional connectivity between prefrontal cortex and sub-cortical structures, and altered meso-cortical and/or meso-striatal dopamine release. Since time processing is also regulated by fronto-striatal circuits and modulated by dopaminergic transmission, we hypothesized that time processing is abnormal in TS.We compared time processing abilities between nine children with TS-only (i.e. without major psychiatric comorbidities) and 10 age-matched healthy children, employing a time reproduction task in which subjects actively reproduce different temporal intervals, and a time comparison task in which subjects judge whether a test interval is longer or shorter than a reference interval. IQ, sustained and divided attention, and working memory were assessed in both groups using the Leiter International Performance Scale-Revised, and the Digit Span sub-test of the WISC-R.Children with TS-only reproduced in an overestimated fashion over-second, but not sub-second, time intervals. The precision of over-second intervals reproduction correlated with tic severity, in that the lower the tic severity, the closer the reproduction of over-second time intervals to their real duration. Time reproduction performance did not significantly correlate with IQ, attention and working memory measures in both groups. No differences between groups were documented in the time comparison task.The improvement of time processing in children with TS-only seems specific for the over-second range of intervals, consistent with an enhancement in the ‘cognitively controlled’ timing system, which mainly processes longer duration intervals, and depends upon dysfunctional connectivity between the basal ganglia and the dorso-lateral prefrontal cortex. The absence of between-group differences on time comparison, moreover, suggests that TS patients manifest a selective improvement of ‘motor’ timing abilities, rather than of perceptual time abilities. Our data also support an enhancement of cognitive control processes in TS children, probably facilitated by effortful tic suppression.

English

Psychopathic offenders inevitably violate interpersonal norms and frequently resort to aggressive and criminal behaviour. The affective and cognitive deficits underlying these behaviours have been linked to abnormalities in functional interhemispheric connectivity. However, direct neurophysiological evidence for dysfunctional connectivity in psychopathic offenders is lacking. We used transcranial magnetic stimulation combined with electroencephalography to examine interhemispheric connectivity in the dorsolateral and motor cortex in a sample of psychopathic offenders and healthy controls. We also measured intracortical inhibition and facilitation over the left and right motor cortex to investigate the effects of local cortical processes on interhemispheric connectivity. We enrolled 17 psychopathic offenders and 14 controls in our study. Global abnormalities in right to left functional connectivity were observed in psychopathic offenders compared with controls. Furthermore, in contrast to controls, psychopathic offenders showed increased intracortical inhibition in the right, but not the left, hemisphere. The relatively small sample size limited the sensitivity to show that the abnormalities in interhemispheric connectivity were specifically related to the dorsolateral prefrontal cortex in psychopathic offenders. To our knowledge, this study provides the first neurophysiological evidence for abnormal interhemispheric connectivity in psychopathic offenders and may further our understanding of the disruptive antisocial behaviour of these offenders.

Abnormal brain activity changes in patients with migraine: a short-term longitudinal study.

Background and PurposeWhether or not migraine can cause cumulative brain alterations due to frequent migraine-related nociceptive input in patients is largely unclear. The aim of this study was to characterize longitudinal changes in brain activity between repeated observations within a short time interval in a group of female migraine patients, using resting-state functional magnetic resonance imaging.MethodsNineteen patients and 20 healthy controls (HC) participated in the study. Regional homogeneity (ReHo) and functional interregional connectivity were assessed to determine the focal and global features of brain dysfunction in migraine. The relationship between changes in headache parameters and longitudinal brain alterations were also investigated.ResultsAll patients reported that their headache activity increased over time. Abnormal ReHo changes in the patient group relative to the HC were found in the putamen, orbitofrontal cortex, secondary somatosensory cortex, brainstem, and thalamus. Moreover, these brain regions exhibited longitudinal ReHo changes at the 6-week follow-up examination. These headache activity changes were accompanied by disproportionately dysfunctional connectivity in the putamen in the migraine patients, as revealed by functional connectivity analysis, suggesting that the putamen plays an important role in integrating diverse information among other migraine-related brain regions.ConclusionsThe results obtained in this study suggest that progressive brain aberrations in migraine progress as a result of increased headache attacks.

Altered Resting-State Functional and White Matter Tract Connectivity in Stroke Patients With Dysphagia

Background. Swallowing dysfunction is intractable after acute stroke. Our understanding of the alterations in neural networks of patients with neurogenic dysphagia is still developing. Objective. The aim was to investigate cerebral cortical functional connectivity and subcortical structural connectivity related to swallowing in unilateral hemispheric stroke patients with dysphagia. Methods. We combined a resting-state functional connectivity with a white matter tract connectivity approach, recording 12 hemispheric stroke patients with dysphagia, 12 hemispheric stroke patients without dysphagia, and 12 healthy controls. Comparisons of the patterns in swallowing-related functional connectivity maps between patient groups and control subjects included (a) seed-based functional connectivity maps calculated from the primary motor cortex (M1) and the supplementary motor area (SMA) to the entire brain, (b) a swallowing-related functional connectivity network calculated among 20 specific regions of interest (ROIs), and (c) structural connectivity described by the mean fractional anisotropy of fibers bound through the SMA and M1. Results. Stroke patients with dysphagia exhibited dysfunctional connectivity mainly in the sensorimotor-insula-putamen circuits based on seed-based analysis of the left and right M1 and SMA and decreased connectivity in the bilateral swallowing-related ROIs functional connectivity network. Additionally, white matter tract connectivity analysis revealed that the mean fractional anisotropy of the white matter tract was significantly reduced, especially in the left-to-right SMA and in the corticospinal tract. Conclusions. Our results indicate that dysphagia secondary to stroke is associated with disruptive functional and structural integrity in the large-scale brain networks involved in motor control, thus providing new insights into the neural remodeling associated with this disorder.

Sub-Anesthetic Ketamine Modulates Intrinsic BOLD Connectivity Within the Hippocampal-Prefrontal Circuit in the Rat

Dysfunctional connectivity within the hippocampal-prefrontal circuit (HC-PFC) is associated with schizophrenia, major depression, and neurodegenerative disorders, and both the hippocampus and prefrontal cortex have dense populations of N-methyl-D-aspartate (NMDA) receptors. Ketamine, a potent NMDA receptor antagonist, is of substantial current interest as a mechanistic model of glutamatergic dysfunction in animal and human studies, a psychotomimetic agent and a rapidly acting antidepressant. In this study, we sought to understand the modulatory effect of acute ketamine administration on functional connectivity in the HC-PFC system of the rat brain using resting-state fMRI. Sprague-Dawley rats in four parallel groups (N=9 per group) received either saline or one of three behaviorally relevant, sub-anesthetic doses of S-ketamine (5, 10, and 25 mg/kg, s.c.), and connectivity changes 15- and 30-min post-injection were studied. The strongest effects were dose- and exposure-dependent increases in functional connectivity within the prefrontal cortex and in anterior-posterior connections between the posterior hippocampus and retrosplenial cortex, and prefrontal regions. The increased prefrontal connectivity is consistent with ketamine-induced increases in HC-PFC electroencephalographic gamma band power, possibly reflecting a psychotomimetic aspect of ketamine's effect, and is contrary to the data from chronic schizophrenic patients suggesting that ketamine effect does not necessarily parallel the disease pattern but might rather reflect a hyperglutamatergic state. These findings may help to clarify the brain systems underlying different dose-dependent behavioral profiles of ketamine in the rat.

Task-related fronto-striatal functional connectivity during working memory performance in schizophrenia

Working memory (WM) deficits and associated brain dysfunction are among the most well replicated candidate endophenotypic processes in schizophrenia. However, previous studies demonstrate inconsistent over- and under-activation of dorsolateral and ventrolateral prefrontal cortices (DLPFC; VLPFC), inferior parietal lobule (IPL) during WM performance, as well as subcortical structures including the striatum, and dysfunctional connectivity among fronto-striatal regions in schizophrenia. However, no previous study has investigated task-related functional connectivity (FC) of DLPFC and striatal regions using a seed-based method; here we employed this method to assess patterns of cortical and subcortical functional connectivity among WM structures during a standard 2-back WM task performed by 28 schizophrenia (SZ) and 28 healthy controls (HC). Initial group comparisons of blood oxygenation level dependent (BOLD) responses during the WM task revealed significantly greater bilateral activity in the striatum in SZ relative to HC, but there was no significant group difference in WM cortical activity (right DLPFC, VLPFC or IPL). Analyses of FC within the cortico-subcortical WM network in the HC group revealed positive performance-related FC between the right DLPFC and the right caudate, and between the right VLPFC and the right IPL; this pattern was absent in SZ. In contrast, SZ patients showed negative performance-related functional connectivity between the left putamen and the right VLPFC. Direct group comparisons in functional connectivity showed significantly greater performance-related FC between the VLPFC and bilateral putamen, as well as unilaterally between the VLPFC and the right IPL, in HC. Results suggest a critical dysfunction of cortico-striatal connectivity underpinning information retrieval for SZ patients during WM performance.

Editorial Thematic Issue: Targeting Synaptic Dysfunction and Neural Connectivity in Neurological and Psychiatric Disorders

Editorial Thematic Issue: Targeting Synaptic Dysfunction and Neural Connectivity in Neurological and Psychiatric Disorders

Inferior frontal and insular cortical thinning is related to dysfunctional brain activation/deactivation during working memory task in schizophrenic patients

Although working memory is known to be impaired in schizophrenia the anatomical and functional relationships underlying this deficit remain to be elucidated. A combined imaging approach involving functional and structural magnetic resonance techniques was used, applying independent component analysis and surface-based morphometry to 14 patients with schizophrenia and 14 healthy controls. Neurocognitive functioning was assessed by a neuropsychological test battery that measured executive function. It was hypothesized that working memory dysfunctional connectivity in schizophrenia is related to underlying anatomical abnormalities. Patients with schizophrenia showed cortical thinning in the left inferior frontal gyrus and insula, which explained 57% of blood oxygenation level-dependent signal magnitude in functional magnetic resonance imaging in the central executive network (lateral prefrontal and parietal cortex) over-activation and default mode network (anterior and posterior cingulate) deactivation. No structure-function relationship emerged in the healthy control group. The study provides evidence to suggest that dysfunctional activation/deactivation patterns in schizophrenia may be explained in terms of underlying gray matter deficits.

Whole-brain functional connectivity identification of functional dyspepsia.

Recent neuroimaging studies have shown local brain aberrations in functional dyspepsia (FD) patients, yet little attention has been paid to the whole-brain resting-state functional network abnormalities. The purpose of this study was to investigate whether FD disrupts the patterns of whole-brain networks and the abnormal functional connectivity could reflect the severity of the disease. The dysfunctional interactions between brain regions at rest were investigated in FD patients as compared with 40 age- and gender- matched healthy controls. Multivariate pattern analysis was used to evaluate the discriminative power of our results for classifying patients from controls. In our findings, the abnormal brain functional connections were mainly situated within or across the limbic/paralimbic system, the prefrontal cortex, the tempo-parietal areas and the visual cortex. About 96% of the subjects among the original dataset were correctly classified by a leave one-out cross-validation approach, and 88% accuracy was also validated in a replication dataset. The classification features were significantly associated with the patients’ dyspepsia symptoms, the self-rating depression scale and self-rating anxiety scale, but it was not correlated with duration of FD patients (p>0.05). Our results may indicate the effectiveness of the altered brain functional connections reflecting the disease pathophysiology underling FD. These dysfunctional connections may be the epiphenomena or causative agents of FD, which may be affected by clinical severity and its related emotional dimension of the disease rather than the clinical course.

Altered Effective Connectivity of the Default Mode Network in Resting-State Amnestic Type Mild Cognitive Impairment

Amnestic mild cognitive impairment (aMCI) is the transitional, heterogeneous continuum from normal elderly to Alzheimer's disease (AD). Previous studies have shown that brain functional activity in the default mode network (DMN) is impaired in aMCI patients with saliently cognitive and memory decline. However, the effective connectivity among the spatially isolated, but functionally related areas within the DMN in aMCI patients remains largely unknown. The present study examined dysfunctional connectivity of the DMN by combining an independent component analysis (ICA) approach with multivariate Granger causality analysis (mGCA) in 18 aMCI patients and 18 age-matched cognitively normal elderly. Results from mGCA showed decreased effective connectivity occurred among the middle temporal gyrus (MTG), hippocampus (HC) and fusiform gyrus (FG), as well as between the precuneus/posterior cingulate cortex (PreCN/PCC) and HC in patients with aMCI. Such an impaired connectivity was also correlated with patients' cognitive performance of the auditory verbal learning. Moreover, enhanced effective connectivity within frontal cortex emerged, which may maintain memory functions after attenuated connections within DMN activity. These findings may elucidate the dysfunctional processes in brain networks of aMCI patients, highlighting the importance of connectivity changes in the pathophysiology of aMCI.

Mapping dysfunctional connectivity in brain injury (P02.267)

Mapping dysfunctional connectivity in brain injury (P02.267)

Hierarchical alteration of brain structural and functional networks in female migraine sufferers.

BackgroundLittle is known about the changes of brain structural and functional connectivity networks underlying the pathophysiology in migraine. We aimed to investigate how the cortical network reorganization is altered by frequent cortical overstimulation associated with migraine.Methodology/Principal FindingsGray matter volumes and resting-state functional magnetic resonance imaging signal correlations were employed to construct structural and functional networks between brain regions in 43 female patients with migraine (PM) and 43 gender-matched healthy controls (HC) by using graph theory-based approaches. Compared with the HC group, the patients showed abnormal global topology in both structural and functional networks, characterized by higher mean clustering coefficients without significant change in the shortest absolute path length, which indicated that the PM lost optimal topological organization in their cortical networks. Brain hubs related to pain-processing revealed abnormal nodal centrality in both structural and functional networks, including the precentral gyrus, orbital part of the inferior frontal gyrus, parahippocampal gyrus, anterior cingulate gyrus, thalamus, temporal pole of the middle temporal gyrus and the inferior parietal gyrus. Negative correlations were found between migraine duration and regions with abnormal centrality. Furthermore, the dysfunctional connections in patients' cortical networks formed into a connected component and three dysregulated modules were identified involving pain-related information processing and motion-processing visual networks.ConclusionsOur results may reflect brain alteration dynamics resulting from migraine and suggest that long-term and high-frequency headache attacks may cause both structural and functional connectivity network reorganization. The disrupted information exchange between brain areas in migraine may be reshaped into a hierarchical modular structure progressively.

Aberrant resting-state connectivity in non-psychotic individuals with auditory hallucinations

Although auditory verbal hallucinations (AVH) are a core symptom of schizophrenia, they also occur in non-psychotic individuals, in the absence of other psychotic, affective, cognitive and negative symptoms. AVH have been hypothesized to result from deviant integration of inferior frontal, parahippocampal and superior temporal brain areas. However, a direct link between dysfunctional connectivity and AVH has not yet been established. To determine whether hallucinations are indeed related to aberrant connectivity, AVH should be studied in isolation, for example in non-psychotic individuals with AVH. Resting-state connectivity was investigated in 25 non-psychotic subjects with AVH and 25 matched control subjects using seed regression analysis with the (1) left and (2) right inferior frontal, (3) left and (4) right superior temporal and (5) left parahippocampal areas as the seed regions. To correct for cardiorespiratory (CR) pulsatility rhythms in the functional magnetic resonance imaging (fMRI) data, heartbeat and respiration were monitored during scanning and the fMRI data were corrected for these rhythms using the image-based method for retrospective correction of physiological motion effects RETROICOR. In comparison with the control group, non-psychotic individuals with AVH showed increased connectivity between the left and the right superior temporal regions and also between the left parahippocampal region and the left inferior frontal gyrus. Moreover, this group did not show a negative correlation between the left superior temporal region and the right inferior frontal region, as was observed in the healthy control group. Aberrant connectivity of frontal, parahippocampal and superior temporal brain areas can be specifically related to the predisposition to hallucinate in the auditory domain.

Neural correlates of altered response inhibition and dysfunctional connectivity at rest in obsessive–compulsive disorder

Functional imaging studies of obsessive-compulsive disorder (OCD) have reported altered fronto-striatal activity during executive tasks. Additionally, altered connectivity of these regions during resting state was found. However, the relationship between brain activity during tasks and resting state remains poorly understood. The present study investigated neural correlates associated with abnormal response inhibition in OCD and to examine how resting state functional connectivity relates to task-related activity. Eighteen unmedicated adult OCD patients and 18 age- and sex-matched control subjects underwent functional magnetic resonance imaging scans during both resting state and a response inhibition task. Brain activation during response inhibition was compared between groups. Fronto-striatal regions showing altered task-related activity were used as seeds for connectivity analyses during resting state. During the response inhibition task, OCD patients had lower activation in areas including the cingulate cortex and basal ganglia regions. Compared with control subjects, patients with OCD showed increased functional connectivity of the caudate nucleus with the middle cingulate cortex and precentral gyrus during rest, suggesting hyperactive striatal-cortical connections. This study found altered function in fronto-striatal regions during response inhibition and its relation to resting state functional connectivity in OCD. Our results suggest that dysfunctional striatal-cortical connections even during rest may result in the failure of response inhibition and error monitoring observed in OCD patients.