Aberrant Connections Research Articles

Functional connectivity of the vigilant-attention network in children and adolescents with attention-deficit/hyperactivity disorder

The ability to maintain attention to simple tasks (i.e., vigilant attention, VA) is often impaired in attention-deficit/hyperactivity disorder (ADHD), but the underlying pathophysiological mechanisms at the brain network level are not clear yet. We therefore investigated ADHD-related differences in resting-state functional connectivity within a meta-analytically defined brain network of 14 distinct regions subserving VA (comprising 91 connections in total), as well as the association of connectivity with markers of behavioural dysfunction in 17 children (age range: 9–14 years) with a diagnosis of ADHD and 21 age-matched neurotypical controls. Our analyses revealed selective, rather than global, differences in the intrinsic coupling between nodes of the VA-related brain network in children with ADHD, relative to controls. In particular, ADHD patients showed substantially diminished intrinsic coupling for 7 connections and increased coupling for 4 connections, with many differences involving connectivity with the anterior insula. Moreover, connectivity strength of several aberrant connections was found to be associated with core aspects of ADHD symptomatology, such as poor attention, difficulties with social functioning, and impaired cognitive control, attesting to the behavioural relevance of specific connectivity differences observed in the resting state.

Central and non-central networks, cognition, clinical symptoms, and polygenic risk scores in schizophrenia.

Schizophrenia is a complex disorder that may be the result of aberrant connections between specific brain regions rather than focal brain abnormalities. Here, we investigate the relationships between brain structural connectivity as described by network analysis, intelligence, symptoms, and polygenic risk scores (PGRS) for schizophrenia in a group of patients with schizophrenia and a group of healthy controls. Recently, researchers have shown an interest in the role of high centrality networks in the disorder. However, the importance of non-central networks still remains unclear. Thus, we specifically examined network-averaged fractional anisotropy (mean edge weight) in central and non-central subnetworks. Connections with the highest betweenness centrality within the average network (>75% of centrality values) were selected to represent the central subnetwork. The remaining connections were assigned to the non-central subnetwork. Additionally, we calculated graph theory measures from the average network (connections that occur in at least 2/3 of participants). Density, strength, global efficiency, and clustering coefficient were significantly lower in patients compared with healthy controls for the average network (pFDR < 0.05). All metrics across networks were significantly associated with intelligence (pFDR < 0.05). There was a tendency towards significance for a correlation between intelligence and PGRS for schizophrenia (r = -0.508, p = 0.052) that was significantly mediated by central and non-central mean edge weight and every graph metric from the average network. These results are consistent with the hypothesis that intelligence deficits are associated with a genetic risk for schizophrenia, which is mediated via the disruption of distributed brain networks. Hum Brain Mapp 38:5919-5930, 2017. © 2017 Wiley Periodicals, Inc.

Marcus Gunn Syndrome and implications for Oral and Maxillofacial surgery (OMFS)

Introduction Marcus Gunn Syndrome, also known as Jaw Wink Syndrome or trigemino-oculomotor synkinesis, was first reported in 1883. It typically presents at birth with unilateral ptosis and eyelid elevation on jaw opening. Pathophysiology is explained by an oculofacial synkinesis. There is an aberrant connection of the oculomotor nerve and the mandibular branch of the trigeminal nerve resulting in eyelid elevation on mouth opening. The typically congenital syndrome is exceptionally rare. It is often diagnosed in infancy with complete ophthalmic examination and ptosis evaluation. This syndrome does not often require surgical intervention but it may still have an impact in clinical management. Case description A 32-year-old male presented in the OMFS outpatient clinic in Countess of Chester Hospital for extraction of his lower third molars. His past medical history included a known diagnosis of Marcus Gunn Syndrome but he was otherwise fit and well. He had resting ptosis of the left and elevation of the left eyelid on jaw protrusion. Results and conclusions Third molars were removed uneventfully under local anesthesia and no further treatment was required. Literature suggests that patients with Marcus Gunn Syndrome may have an atypical oculocardiac reflex during their surgical procedure and patients are at increased risk of malignant hypothermia. In this case, the procedure was performed under local anesthesia but this condition may impact on surgical planning if general anesthesia was to be considered.

Aberrant connections between climbing fibres and Purkinje cells induce alterations in the timing of an instrumental response in the rat.

Cerebellar participation in timing and sensory-motor sequences has been supported by several experimental and clinical studies. A relevant role of the cerebellum in timing of conditioned responses in the range of milliseconds has been demonstrated, but less is known regarding the role of the cerebellum in supra-second timing of operant responses. A dissociated role of the cerebellum and striatum in timing in the millisecond and second range had been reported, respectively. The climbing fibre-Purkinje cell synapse is crucial in timing models; thus, the aberrant connection between these cellular elements is a suitable model for evaluating the contribution of the cerebellum in timing in the supra-second range. The aberrant connection between climbing fibres and Purkinje cells was induced by administration of the antagonist of NMDA receptors MK-801 to Sprague-Dawley rats at postnatal days 7-14. The timing of an operant response with two fixed intervals (5 and 8s) and egocentric sequential learning was evaluated in 60-day-old adult rats. The aberrant connections caused a reduced accuracy in the timing of the instrumental response that was more evident in the 8-s interval and a reduced number of successive correct responses (responses emitted in the correct second without any other response between them) in the 8-s interval. In addition, an inability to incorporate new information in a sequence previously learned in egocentric-based sequence learning was apparent in rats with aberrant CF-PC synapses. These results support a relevant role for the cerebellum in the fine-tuning of the timing of operant responses in the supra-second range.

Aberrant Insula-Centered Functional Connectivity in Psychogenic Erectile Dysfunction Patients: A Resting-State fMRI Study.

Most previous studies exploring the neural mechanism of psychogenic erectile dysfunction (pED) focused on brain activity under tasks. We suggest that the resting brain activity is equally important in pED studies, in that the patterns of spontaneous neural activities is independent of modalities of sensory input, therefore providing substantial information regarding the central mechanism of pED. Our previous study reported the altered baseline activity in right anterior insula (aINS) in pED patients. Also, the insula is a pivotal region in sexual behavior, which is suggested to be able to directly mediate erection. Therefore, the current study employed resting-state fMRI to examine alterations in functional connectivity (FC) of the aINS comparing pED patients with matched control subjects. After rigorous participant inclusion procedure, 27 pED patients and 27 healthy male controls were enrolled. Our results elucidated the disrupted homogeneity within the right aINS and aberrant connection patterns between the right aINS and the right dorsolateral prefrontal cortex (dlPFC), as well as the right aINS and the right temporoparietal junction (TPJ) respectively in pED group, as compared with the healthy controls. In conclusion, our results demonstrated the aberrant insula-centered FC in pED, which may be related to the abnormal representation of internal bodily state or needs in pED patients and thus further affect the inhibitory control in the sexual context. We hope that these findings may shed new light on the understanding of the central mechanism of pED.

Resting-state connectivity and modulated somatomotor and default-mode networks in Huntington disease.

To analyze brain functional connectivity in the somatomotor and default-mode networks (DMNs) of patients with Huntington disease (HD), its relationship with gray matter (GM) volume loss, and functional changes after pridopidine treatment. Ten patients and ten untreated controls underwent T1-weighted imaging and resting-state functional magnetic resonance imaging (fMRI); four patients were also assessed after 3months of pridopidine treatment (90mg/d). The seed-based functional connectivity patterns from the posterior cingulate cortex and the supplementary motor area (SMA), considered cortical hubs of the DMN and somatomotor networks, respectively, were computed. FMRIB Software Library voxel-based morphometry measured GM volume. Patients had GM volume decrease in all cortical and subcortical areas of the somatomotor network with preservation of the SMA, and increased somatomotor and DMN connectivity. In DMN structures, functional connectivity impairment preceded volume loss. Pridopidine reduced the intensity of these aberrant connections. The abnormal connectivity of the somatomotor and DMN observed in HD patients may represent an early dysfunction marker, as it preceded volume loss in DMN. Pridopidine reduced connectivity of these networks in all four treated patients, suggesting that connectivity is sensitive to treatment response.

Treatment of Enterocutaneous Fistulas, Then and Now.

An enterocutaneous fistula (ECF) is an aberrant connection between the gastrointestinal tract and the skin or atmosphere (enteroatmospheric fistula [EAF]). Multimodal treatment includes surgical procedures, nutrition support, and wound care. We evaluated our practice and compared our outcomes with previous results published from our institution. We performed a retrospective analysis of hospitalized ECF/EAF patients admitted between January 2011 and November 2015. Patients with internal fistulas; active inflammatory bowel disease; malignancy; radiation treatment; end-stage renal, hepatic, or cardiac disease; and active alcoholism were excluded. Data collected included demographics, fistula characteristics, nutrition therapy, treatment, operative success, and hospital mortality. Parametric and nonparametric tests for independent and paired groups were performed. Thirty-one patients were included in the analysis. The median (interquartile range) age was 60 (53-76) years, and 81% were female. Parenteral nutrition was initially prescribed in 80% of patients, but 61% received enteral nutrition (EN) at some point during their hospitalization. Two patients were fed by fistuloclysis. Eighty percent of the patients underwent surgical repair a median of 12 months after diagnosis with 92% operative success. Surgical repair had a modest correlation with home discharge (ρ = 0.517, P = .003). A large proportion of patients (77%) were discharged home. The in-hospital mortality at our institution decreased from 44% in 1960 to 21% in 1970 to 3% in the current study. Modern treatment of ECF/EAF, including EN and advanced local wound care, is associated with improvements in clinical outcomes such as hospital mortality.

Transcranial Direct Current Stimulation Technique: A Need of Bangladesh for Stroke Management

Stroke has been considered as one of the leading cause of death worldwide. It results in reduced excitability, deregulated plastic modifications, and formation of aberrant connections and, these factors hinder recovery from stroke. Transcranial direct current stimulation (tDCS) is a promising technique for the treatment of a wide range of neurological disorders including stroke. Its application could improve the condition of patients having neurological disorders by making functional connections and maintaining existing pathways. In Bangladesh, stroke remains the third leading cause of death with 0.3% prevalence. The number of disability-adjusted life years lost for stroke is 485 per 10000 people, which depicts great economic burden of this disease in the future. Thus, introduction of new technologies such as tDCS in the treatment of stroke will not only improve conditions of stroke patients but also reduce economic burden of this disease in Bangladesh.

Chapter 10 - Surgical management of cerebral dural arteriovenous fistulae

Dural arteriovenous fistulae are high flow, low resistance intracranial vascular malformations defined by an aberrant connection between an artery and dural vein or sinus. Symptomatology and presentation are highly dependent on location, generally categorized as supratentorial, tentorial, or infratentorial, and consist primarily of sequelae secondary to local venous hypertension, insufficiency, and cortical venous reflux. Surgery is generally reserved for high risk or persistently symptomatic lesions that are unamenable or unresponsive to endovascular therapy. For surgical lesions, familiarity with skull base approaches, specific fistula anatomy, and technical nuances based on fistula location offer patients the best chance of a favorable outcome.

Weighted and directed interactions in evolving large-scale epileptic brain networks.

Epilepsy can be regarded as a network phenomenon with functionally and/or structurally aberrant connections in the brain. Over the past years, concepts and methods from network theory substantially contributed to improve the characterization of structure and function of these epileptic networks and thus to advance understanding of the dynamical disease epilepsy. We extend this promising line of research and assess—with high spatial and temporal resolution and using complementary analysis approaches that capture different characteristics of the complex dynamics—both strength and direction of interactions in evolving large-scale epileptic brain networks of 35 patients that suffered from drug-resistant focal seizures with different anatomical onset locations. Despite this heterogeneity, we find that even during the seizure-free interval the seizure onset zone is a brain region that, when averaged over time, exerts strongest directed influences over other brain regions being part of a large-scale network. This crucial role, however, manifested by averaging on the population-sample level only – in more than one third of patients, strongest directed interactions can be observed between brain regions far off the seizure onset zone. This may guide new developments for individualized diagnosis, treatment and control.

The development of an automatically produced cholangiography procedure using the reconstruction of portal-phase multidetector-row computed tomography images: preliminary experience.

Fusion angiography using reconstructed multidetector-row computed tomography (MDCT) images, and cholangiography using reconstructed images from MDCT with a cholangiographic agent include an anatomical gap due to the different periods of MDCT scanning. To conquer such gaps, we attempted to develop a cholangiography procedure that automatically reconstructs a cholangiogram from portal-phase MDCT images. The automatically produced cholangiography procedure utilized an original software program that was developed by the Graduate School of Information Science, Nagoya University. This program structured 5 candidate biliary tracts, and automatically selected one as the candidate for cholangiography. The clinical value of the automatically produced cholangiography procedure was estimated based on a comparison with manually produced cholangiography. Automatically produced cholangiograms were reconstructed for 20 patients who underwent MDCT scanning before biliary drainage for distal biliary obstruction. The procedure showed the ability to extract the 5 main biliary branches and the 21 subsegmental biliary branches in 55 and 25% of the cases, respectively. The extent of aberrant connections and aberrant extractions outside the biliary tract was acceptable. Among all of the cholangiograms, 5 were clinically applied with no correction, 8 were applied with modest improvements, and 3 produced a correct cholangiography before automatic selection. Although our procedure requires further improvement based on the analysis of additional patient data, it may represent an alternative to direct cholangiography in the future.

Aberrant Insular Functional Network Integrity in Patients with Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) is accompanied by tissue injury to the insular cortices, areas that regulate autonomic pain, dyspnea, and mood, all of which are affected in the syndrome. Presumably, the dysregulation of insular-related functions are mediated by aberrant functional connections with other brain regions; however, the integrity of the functional connectivity (FC) to other sites is undescribed. Our aim was to examine resting-state FC of the insular cortices to other brain areas in OSA, relative to control subjects. We collected resting-state functional magnetic resonance imaging (MRI) data from 67 newly diagnosed, treatment-naïve OSA and 75 control subjects using a 3.0-Tesla MRI scanner. After standard processing, data were analyzed for the left and right insular FC. OSA subjects showed complex aberrant insular FC to several brain regions, including frontal, parietal, cingulate, temporal, limbic, basal ganglia, thalamus, occipital, cerebellar, and brainstem regions. Areas of altered FC in OSA showed linear relationships with magnitudes of sleep related and neuropsychologic-related variables, whereas control subjects showed no such relationships with those measures. Brain functional connections from insular sites to other brain regions in OSA subjects represent abnormal autonomic, affective, sensorimotor, and cognitive control networks that may affect both impaired parasympathetic and sympathetic interactions, as well as abnormal sensorimotor integration, affected in the condition. The functional changes likely result from the previously reported structural changes in OSA subjects, as demonstrated by diverse neuroimaging studies.

Aberrant excitatory rewiring of layer V pyramidal neurons early after neocortical trauma

Lesioned neuronal circuits form new functional connections after a traumatic brain injury (TBI). In humans and animal models, aberrant excitatory connections that form after TBI may contribute to the pathogenesis of post-traumatic epilepsy. Partial neocortical isolation (“undercut” or “UC”) leads to altered neuronal circuitry and network hyperexcitability recorded in vivo and in brain slices from chronically lesioned neocortex. Recent data suggest a critical period for maladaptive excitatory circuit formation within the first 3days post UC injury (Graber and Prince 1999, 2004; Li et al. 2011, 2012b). The present study focuses on alterations in excitatory connectivity within this critical period. Immunoreactivity (IR) for growth-associated protein (GAP)-43 was increased in the UC cortex 3days after injury. Some GAP-43-expressing excitatory terminals targeted the somata of layer V pyramidal (Pyr) neurons, a domain usually innervated predominantly by inhibitory terminals. Immunocytochemical analysis of pre- and postsynaptic markers showed that putative excitatory synapses were present on somata of these neurons in UC neocortex. Excitatory postsynaptic currents from UC layer V Pyr cells displayed properties consistent with perisomatic inputs and also reflected an increase in the number of synaptic contacts. Laser scanning photostimulation (LSPS) experiments demonstrated reorganized excitatory connectivity after injury within the UC. Concurrent with these changes, spontaneous epileptiform bursts developed in UC slices. Results suggest that aberrant reorganization of excitatory connectivity contributes to early neocortical hyperexcitability in this model. The findings are relevant for understanding the pathophysiology of neocortical post-traumatic epileptogenesis and are important in terms of the timing of potential prophylactic treatments.

Context-Dependent Gait Choice Elicited by EphA4 Mutation in Lbx1 Spinal Interneurons

The most commonly used locomotor strategy in rodents is left-right limb alternation. Mutation of the axon guidance molecule EphA4 profoundly alters this basic locomotor pattern to synchrony. Here we report that conditional mutation of EphA4 in spinal interneurons expressing the transcription factor Lbx1 degrades the robustness in the expression of left-right alternating gait during development. Lbx1 EphA4 conditional mice exhibit alternating gait when walking on ground, but synchronous gait in environments with decreased weight-load, like swimming and airstepping. Using cell-type-specific, transient pharmacogenetic silencing approaches, we attribute this behavioral gait switch to neuronal activity of dorsal Lbx1 spinal interneurons. We also found that in Lbx1 EphA4 conditional mice these dorsal interneurons form aberrant bilateral connections to motor neurons, thereby indirectly transmitting received unilateral proprioceptive sensory information to both spinal sides. Together, our findings reveal the behavioral and circuit-level impact of conditional EphA4 mutation in a transcriptionally defined spinal interneuron subpopulation.

From the brachial plexus to the hand, multiple connections between the median and ulnar nerves may serve as bypass routes for nerve fibres.

Axons from the median and ulnar nerves can pass to each other through aberrant connections between them. Multiple interconnections between the nerves may provide a detour route for nerve fibres going to the hand. We investigated the incidence of variations and the associations between them in 90 cadaveric upper limbs. In 91% of upper limbs, one to five variations were found, with several statistically significant associations. The contribution of the C8 nerve to the lateral cord was positively associated with an accessory contribution of the lateral cord to the ulnar nerve. The latter variation showed positive association with the occurrence of any of the variations in the hand itself. Ulnar innervation of the superficial head of the flexor pollicis brevis was positively associated with the Riche-Cannieu communication. The co-existence of the variations and their associations may be the explanation for unusual clinical findings related to median and ulnar conduction, which appear contrary to anatomical knowledge.

Transsynaptic Coordination of the Formation of Morphofunctional Contacts between the Brain and the Neurotransplant: an Ulrastructural Study.

We studied the role of neurotransmitter signaling mediated by synaptic vesicles in the formation of aberrant functional connections between fascia dentata grafts and the somatosensory neocortex in adult rats. Quantitative analysis of the different populations of synaptic vesicles in the ectopic giant axonal endings of granular neurons was performed and the results were compared with the normal. Two pools of small clear vesicles (rapidly releasable pool and pool of reserve vesicles circulating in the active zone) and one pool of large dense-core vesicles were analyzed. Significant differences from the control suggest that synaptic integration of the transplants into the recipient brain is coordinated by transsynaptic signaling and mediated by different populations of synaptic vesicles.

Surgical Outcomes in Cases of Marcus-Gunn Jaw-Winking Phenomenon.

Markus-Gunn Jaw-winking Phenomenon (MGJW) is a congenital ptosis associated with synkinetic movement of upper lid on masticating movements of jaw. It results from aberrant connection between motor division of trigeminal nerve and oculomotor nerve. To investigate the clinical characteristics of MGJW phenomenon and evaluate its surgical outcomes of unilateral levator excision and frontalis suspension. It is a retrospective analysis of nine cases of MGJW phenomenon seen from 2007 to 2013 AD. The clinical features were recorded and analysed. Unilateral levator excision and frontalis suspension for the correction of synkinesis and ptosis was done for all the patients. The result of surgery was analysed. MGJW phenomenon was seen more in males. All the cases had unilateral ptosis with jaw winking phenomenon. Ipsilateral hypotropia and refractive errors were seen in 44%. One week post operative margin reflex distance was good in 67% of cases. Persistent jaw-winking was seen in 3 cases, two underwent repeat surgery to abolish the synkinesis. At one year follow up, 33% had good margin reflex distance of more than 4mm and 22% had fairly good margin reflex distance of 3mm. Patients with Marcus Gunn jaw winking synkinesis can present at a wide age range. There may be an associated vertical muscle imbalance, which should be managed before ptosis surgery to avoid ptosis under correction. Unilateral frontalis flap suspension combined levator excision can correct ptosis very well for patients with Marcus-Gunn syndrome.

Current concepts in functional gastrointestinal disorders.

Functional gastrointestinal disorders (FGIDs) are some of the most common and challenging disorders in pediatrics. Recurrent abdominal pain is the central feature of pain-associated FGIDs such as irritable bowel syndrome. A thorough understanding of current pathophysiological concepts is essential to successful management. The brain-gut axis, role of microbiota and the biopsychosocial model are emerging concepts in FGIDs. The biopsychosocial model focuses on the interplay between genes, environment, and physical and psychosocial factors. Interactions between microbiota and the central, enteric and autonomic nervous systems form the link between gut functions and conscious perceptions. Irritable bowel syndrome is the most extensively studied and prototypical pain-associated FGIDs. An aberrant processing of pain or physiologic signals originating from the gut causes a state of visceral hypersensitivity - a central mechanism of functional pain. Psychosocial and autonomic influences also play large roles. Therapy is tailored to the individual patient and comorbid symptoms. This review highlights the complex mechanisms and the aberrant brain-gut neural connections forming the basis of FGIDs. Successful management of FGIDs requires knowledge of the underlying pathophysiology coupled with a multidisciplinary treatment approach. Management should focus on cognitive behavioral therapy, dietary factors along with gastrointestinal motility and psychotropic drug therapy.

Yap and Taz are required for Ret-dependent urinary tract morphogenesis.

Despite the high occurrence of congenital abnormalities of the lower urinary tract in humans, the molecular, cellular and morphological aspects of their development are still poorly understood. Here, we use a conditional knockout approach to inactivate within the nephric duct (ND) lineage the two effectors of the Hippo pathway, Yap and Taz. Deletion of Yap leads to hydronephrotic kidneys with blind-ending megaureters at birth. In Yap mutants, the ND successfully migrates towards, and contacts, the cloaca. However, close analysis reveals that the tip of the Yap(-/-) ND forms an aberrant connection with the cloaca and does not properly insert into the cloaca, leading to later detachment of the ND from the cloaca. Taz deletion from the ND does not cause any defect, but analysis of Yap(-/-);Taz(-/-) NDs indicates that both genes play partially redundant roles in ureterovesical junction formation. Aspects of the Yap(-/-) phenotype resemble hypersensitivity to RET signaling, including excess budding of the ND, increased phospho-ERK and increased expression of Crlf1, Sprouty1, Etv4 and Etv5. Importantly, the Yap(ND) (-/-) ND phenotype can be largely rescued by reducing Ret gene dosage. Taken together, these results suggest that disrupting Yap/Taz activities enhances Ret pathway activity and contributes to pathogenesis of lower urinary tract defects in human infants.

Network Disruption and Cerebrospinal Fluid Amyloid-Beta and Phospho-Tau Levels in Mild Cognitive Impairment.

In this preliminary study, we used magnetoencephalography and an integrative approach to explore the impact of CSF biomarkers, neuropsychological scores, and white matter structural abnormalities on neural function in mild cognitive impairment. Disruption in functional connectivity between several pairs of cortical regions associated with abnormal levels of biomarkers, cognitive deficits, or with impaired axonal integrity of hippocampal tracts. Amyloid deposition and tau protein-related neuronal injury in early Alzheimer's disease are associated with synaptic dysfunction and a dual pattern of cortical network disorganization (i.e., desynchronization and hypersynchronization) that affects key regions of the default mode network and temporal areas.