Association between serotonin denervation and resting‐state functional connectivity in mild cognitive impairment

Resting‐state functional connectivity alterations have been demonstrated in Alzheimer's disease (AD) and mild cognitive impairment (MCI) before the observation of AD neuropathology, but mechanisms driving these changes are not well understood. Serotonin neurodegeneration has been observed in MCI and AD and is associated with cognitive deficits and neuropsychiatric symptoms, but the role of the serotonin system in relation to brain network dysfunction has not been a major focus of investigation. The current study investigated the relationship between serotonin transporter availability (SERT; measured using positron emission tomography) and brain network functional connectivity (measured using resting‐state functional MRI) in 20 participants with MCI and 21 healthy controls. Two SERT regions of interest were selected for the analysis: the Dorsal Raphe Nuclei (DRN) and the precuneus which represent the cell bodies of origin and a cortical target of projections of the serotonin system, respectively. Both regions show decreased SERT in MCI compared to controls and are the site of early AD pathology. Average resting‐state functional connectivity did not differ between MCI and controls. Decreased SERT in DRN was associated with lower hippocampal resting‐state connectivity in MCI participants compared to controls. Decreased SERT in the right precuneus was also associated with lower resting‐state connectivity of the retrosplenial cortex to the dorsal lateral prefrontal cortex and higher resting‐state connectivity of the retrosplenial cortex to the posterior cingulate and in patients with MCI but not in controls. These results suggest that a serotonergic mechanism may underlie changes in brain functional connectivity in MCI. Hum Brain Mapp 38:3391–3401, 2017. © 2017 Wiley Periodicals, Inc.     

Age‐related effect of serotonin transporter genotype on amygdala and prefrontal cortex function in adolescence

The S and L_G alleles of the serotonin transporter‐linked polymorphic region (5‐HTTLPR) lower serotonin transporter expression. These low‐expressing alleles are linked to increased risk for depression and brain activation patterns found in depression (increased amygdala activation and decreased amygdala–prefrontal cortex connectivity). Paradoxically, serotonin transporter blockade relieves depression symptoms. Rodent models suggest that decreased serotonin transporter in early life produces depression that emerges in adolescence, whereas decreased serotonin transporter that occurs later in development ameliorates depression. However, no brain imaging research has yet investigated the moderating influence of human development on the link between 5‐HTTLPR and effect‐related brain function. We investigated the age‐related effect of 5‐HTTLPR on amygdala activation and amygdala–prefrontal cortex connectivity using a well‐replicated probe, an emotional face task, in children and adolescents aged 9–19 years. A significant genotype‐by‐age interaction predicted amygdala activation, such that the low‐expressing genotype (S/S and S/L_G) group showed a greater increase in amygdala activation with age compared to the higher expressing (L_A/L_A and S/L_A) group. Additionally, compared to the higher expressing group, the low‐expressing genotype group exhibited decreased connectivity between the right amygdala and ventromedial prefrontal cortex with age. Findings indicate that low‐expressing genotypes may not result in the corticolimbic profile associated with depression risk until later adolescence. Hum Brain Mapp 35:646–658, 2014. © 2012 Wiley‐Periodicals, Inc.     

Dopaminergic and GABA‐ergic markers of impulsivity in rats: evidence for anatomical localisation in ventral striatum and prefrontal cortex

Accumulating evidence indicates that impulsivity, in its multiple forms, involves cortical and subcortical mechanisms and abnormal dopamine (DA) transmission. Although decreased DA D2/D3 receptor availability in the nucleus accumbens (NAcb) predicts trait‐like impulsivity in rats it is unclear whether this neurochemical marker extends to both the NAcb core (NAcbC) and shell (NAcbS) and whether markers for other neurotransmitter systems implicated in impulsivity such as serotonin (5‐HT), endogenous opioids and γ‐amino‐butyric acid (GABA) are likewise altered in impulsive rats. We therefore used autoradiography to investigate DA transporter (DAT), 5‐HT transporter (5‐HTT) and D1, D2/D3, μ‐opioid and GABA(A) receptor binding in selected regions of the prefrontal cortex and striatum in rats expressing low and high impulsive behaviour on the five‐choice serial reaction‐time task. High‐impulsive (HI) rats exhibited significantly lower binding for DAT and D2/D3 receptors in the NAcbS and for D1 receptors in the NAcbC compared with low‐impulsive (LI) rats. HI rats also showed significantly lower GABA(A) receptor binding in the anterior cingulate cortex. For all regions where receptor binding was altered in HI rats, binding was inversely correlated with impulsive responding on task. There were no significant differences in binding for 5‐HTT or μ‐opioid receptors in any of the regions investigated. These results indicate that altered D2/D3 receptor binding is localised to the NAcbS of trait‐like impulsive rats and is accompanied by reduced binding for DAT. Alterations in binding for D1 receptors in the NAcbC and GABA(A) receptors in the anterior cingulate cortex demonstrate additional markers and putative mechanisms underlying the expression of behavioural impulsivity.     

Ultralow concentrations of bupivacaine exert anti‐inflammatory effects on inflammation‐reactive astrocytes

Bupivacaine is a widely used, local anesthetic agent that blocks voltage‐gated Na⁺ channels when used for neuro‐axial blockades. Much lower concentrations of bupivacaine than in normal clinical use, < 10^?8 m , evoked Ca²⁺ transients in astrocytes from rat cerebral cortex, that were inositol trisphosphate receptor‐dependent. We investigated whether bupivacaine exerts an influence on the Ca²⁺ signaling and interleukin‐1β (IL‐1β) secretion in inflammation‐reactive astrocytes when used at ultralow concentrations, < 10^?8 m . Furthermore, we wanted to determine if bupivacaine interacts with the opioid‐, 5‐hydroxytryptamine‐ (5‐HT) and glutamate‐receptor systems. With respect to the μ‐opioid‐ and 5‐HT‐receptor systems, bupivacaine restored the inflammation‐reactive astrocytes to their normal non‐inflammatory levels. With respect to the glutamate‐receptor system, bupivacaine, in combination with an ultralow concentration of the μ‐opioid receptor antagonist naloxone and μ‐opioid receptor agonists, restored the inflammation‐reactive astrocytes to their normal non‐inflammatory levels. Ultralow concentrations of bupivacaine attenuated the inflammation‐induced upregulation of IL‐1β secretion. The results indicate that bupivacaine interacts with the opioid‐, 5‐HT‐ and glutamate‐receptor systems by affecting Ca²⁺ signaling and IL‐1β release in inflammation‐reactive astrocytes. These results suggest that bupivacaine may be used at ultralow concentrations as an anti‐inflammatory drug, either alone or in combination with opioid agonists and ultralow concentrations of an opioid antagonist.     

Serotonin‐transporter‐linked promoter region polymorphism and serotonin transporter binding in drug‐naïve patients with major depression

Aims: Both the serotonin transporter and its genetic regulation by the serotonin‐transporter‐linked polymorphic region have a role in the pathophysiology of depression. Most of the previous studies have found no influence of serotonin‐transporter‐linked polymorphic region allelic variation on serotonin transporter binding in healthy controls or patients with major depression. Due to the inconsistency of the previous findings, we compared single photon emission computed tomography imaging with the serotonin‐transporter‐linked polymorphic region genotype in patients with major depressive disorder. Methods: A total of 23 drug‐naïve patients with major depressive disorder were genotyped and brain imaged with ^[123I]nor‐β‐CIT single photon emission computed tomography. The severity of depression was evaluated with the 17‐item Hamilton depression rating scale. Results: Depressed patients homozygous for the short allele had lower ^[123I]nor‐β‐CIT binding in the medial prefrontal cortex, but not in the midbrain, compared with the other genotypes. Conclusion: The decreased medial prefrontal cortical serotonin transporter binding in the patients homozygous for the short allele may be linked to altered function of the serotonin‐transporter‐linked polymorphic region gene expressed in these patients, especially in the medial prefrontal cortex.     

Developmental vitamin D deficiency alters multiple neurotransmitter systems in the neonatal rat brain

BackgroundEpidemiological evidence suggests that developmental vitamin D (DVD) deficiency is a risk factor for neuropsychiatric disorders, such as schizophrenia. DVD deficiency in rats is associated with altered brain structure and adult behaviours indicating alterations in dopamine and glutamate signalling. Developmental alterations in dopamine neurotransmission have also been observed in DVD-deficient rats but a comprehensive assessment of brain neurochemistry has not been undertaken. Thus, the current study determined the regional concentrations of dopamine, noradrenaline, serotonin, glutamine, glutamate and γ-aminobutyric acid (GABA), and associated metabolites, in DVD-deficient neonates.MethodsSprague-Dawley rats were fed a vitamin D deficient diet or control diet six weeks prior to mating until birth and housed under UVB-free lighting conditions. Neurotransmitter concentration was assessed by high-performance liquid chromatography on post-mortem neonatal brain tissue.ResultsUbiquitous reductions in the levels of glutamine (12–24%) were observed in DVD-deficient neonates compared with control neonates. Similarly, in multiple brain regions DVD-deficient neonates had increased levels of noradrenaline and serine compared with control neonates. In contrast, increased levels of dopamine and decreased levels of serotonin in DVD-deficient neonates were limited to striatal subregions compared with controls.ConclusionsOur results confirm that DVD deficiency leads to changes in multiple neurotransmitter systems in the neonate brain. Importantly, this regionally-based assessment in DVD-deficient neonates identified both widespread neurotransmitter changes (glutamine/noradrenaline) and regionally selective neurotransmitter changes (dopamine/serotonin). Thus, vitamin D may have both general and local actions depending on the neurotransmitter system being investigated. Taken together, these data suggest that DVD deficiency alters neurotransmitter systems relevant to schizophrenia in the developing rat brain.     

Adult attachment style is associated with cerebral μ‐opioid receptor availability in humans

Human attachment behavior mediates establishment and maintenance of social relationships. Adult attachment characteristically varies on anxiety and avoidance dimensions, reflecting the tendencies to worry about the partner breaking the social bond (anxiety) and feeling uncomfortable about depending on others (avoidance). In primates and other mammals, the endogenous μ‐opioid system is linked to long‐term social bonding, but evidence of its role in human adult attachment remains more limited. We used in vivo positron emission tomography to reveal how variability in μ‐opioid receptor (MOR) availability is associated with adult attachment in humans. We scanned 49 healthy subjects using a MOR‐specific ligand [¹¹C]carfentanil and measured their attachment avoidance and anxiety with the Experiences in Close Relationships‐Revised scale. The avoidance dimension of attachment correlated negatively with MOR availability in the thalamus and anterior cingulate cortex, as well as the frontal cortex, amygdala, and insula. No associations were observed between MOR availability and the anxiety dimension of attachment. Our results suggest that the endogenous opioid system may underlie interindividual differences in avoidant attachment style in human adults, and that differences in MOR availability are associated with the individuals’ social relationships and psychosocial well‐being. Hum Brain Mapp 36:3621–3628, 2015. © 2015 Wiley Periodicals, Inc.     

Low‐ and high‐frequency transcutaneous electrical acupoint stimulation induces different effects on cerebral μ‐opioid receptor availability in rhesus monkeys

Although systematic studies have demonstrated that acupuncture or electroacupuncture (EA) analgesia is based on their accelerating endogenous opioid release to activate opioid receptors and that EA of different frequencies is mediated by different opioid receptors in specific areas of the central nervous system, there is little direct, real‐time evidence to confirm this in vivo. The present study was designed to investigate the effects of transcutaneous electrical acupoint stimulation (TEAS), an analogue of EA, at low and high frequencies on μ‐opioid receptor (MOR) availability in the brain of rhesus monkeys. Monkeys underwent 95‐min positron emission tomography (PET) with ¹¹C‐carfentanil three times randomly while receiving 0, 2, or 100 Hz TEAS, respectively. Each TEAS was administered in the middle 30 min during the 95‐min PET scan, and each session of PET and TEAS was separated by at least 2 weeks. The results revealed that 2 Hz but not 100 Hz TEAS evoked a significant increase in MOR binding potential in the anterior cingulate cortex, the caudate nucleus, the putamen, the temporal lobe, the somatosensory cortex, and the amygdala compared with 0 Hz TEAS. The effect remained after the end of TEAS in the anterior cingulate cortex and the temporal lobe. The selective increase in MOR availability in multiple brain regions related to pain and sensory processes may play a role in mediating low‐frequency TEAS efficacy. © 2014 Wiley Periodicals, Inc.     

Resting-state functional connectivity abnormalities in patients with obsessive–compulsive disorder and their healthy first-degree relatives

Background

Obsessive–compulsive disorder (OCD) is a common, heritable neuropsychiatric disorder, hypothetically underpinned by dysfunction of brain cortical–striatal–thalamic–cortical (CSTC) circuits; however, the extent of brain functional abnormalities in individuals with OCD is unclear, and the genetic basis of this disorder is poorly understood. We determined the whole brain functional connectivity patterns in patients with OCD and their healthy first-degree relatives.

Methods

We used resting-state fMRI to measure functional connectivity strength in patients with OCD, their healthy first-degree relatives and healthy controls. Whole brain functional networks were constructed by measuring the temporal correlations of all brain voxel pairs and further analyzed using a graph theory approach.

Results

We enrolled 39 patients with OCD, 20 healthy first-degree relatives and 39 healthy controls in our study. Compared with healthy controls, patients with OCD showed increased functional connectivity primarily within the CSTC circuits and decreased functional connectivity in the occipital cortex, temporal cortex and cerebellum. Moreover, patients with OCD and their first-degree relatives exhibited overlapping increased functional connectivity strength in the bilateral caudate nucleus, left orbitofrontal cortex (OFC) and left middle temporal gyrus.

Limitations

Potential confounding factors, such as medication use, heterogeneity in symptom clusters and comorbid disorders, may have impacted our findings.

Conclusion

Our preliminary results suggest that patients with OCD have abnormal resting-state functional connectivity that is not limited to CSTC circuits and involves abnormalities in additional large-scale brain systems, especially the limbic system. Moreover, resting-state functional connectivity strength abnormalities in the left OFC, bilateral caudate nucleus and left middle temporal gyrus may be neuroimaging endophenotypes for OCD.     

Development of insula connectivity between ages 12 and 30 revealed by high angular resolution diffusion imaging

The insula, hidden deep within the Sylvian fissures, has proven difficult to study from a connectivity perspective. Most of our current information on the anatomical connectivity of the insula comes from studies of nonhuman primates and post mortem human dissections. To date, only two neuroimaging studies have successfully examined the connectivity of the insula. Here we examine how the connectivity of the insula develops between ages 12 and 30, in 307 young adolescent and adult subjects scanned with 4‐Tesla high angular resolution diffusion imaging (HARDI). The density of fiber connections between the insula and the frontal and parietal cortex decreased with age, but the connection density between the insula and the temporal cortex generally increased with age. This trajectory is in line with well‐known patterns of cortical development in these regions. In addition, males and females showed different developmental trajectories for the connection between the left insula and the left precentral gyrus. The insula plays many different roles, some of them affected in neuropsychiatric disorders; this information on the insula's connectivity may help efforts to elucidate mechanisms of brain disorders in which it is implicated. Hum Brain Mapp 35:1790–1800, 2014. © 2013 Wiley Periodicals, Inc.     

BDNF Val66met and 5‐HTTLPR polymorphisms predict a human in vivo marker for brain serotonin levels

Brain‐derived neurotrophic factor (BDNF) has been implicated in multiple aspects of brain function including regulation of serotonin signaling. The BDNF val66met polymorphism (rs6265) has been linked to aspects of serotonin signaling in humans but its effects are not well understood. To address this, we evaluated whether BDNF val66met was predictive of a putative marker of brain serotonin levels, serotonin 4 receptor (5‐HT₄) binding assessed with [¹¹C]SB207145 positron emission tomography, which has also been associated with the serotonin‐transporter‐linked polymorphic region (5‐HTTLPR) polymorphism. We applied a linear latent variable model (LVM) using regional 5‐HT₄ binding values (neocortex, amygdala, caudate, hippocampus, and putamen) from 68 healthy humans, allowing us to explicitly model brain‐wide and region‐specific genotype effects on 5‐HT₄ binding. Our data supported an LVM wherein BDNF val66met significantly predicted a LV reflecting [¹¹C]SB207145 binding across regions (P = 0.005). BDNF val66met met‐carriers showed 2–9% higher binding relative to val/val homozygotes. In contrast, 5‐HTTLPR did not predict the LV but S‐carriers showed 7% lower neocortical binding relative to LL homozygotes (P = 7.3 × 10^?6). We observed no evidence for genetic interaction. Our findings indicate that BDNF val66met significantly predicts a common regulator of brain [¹¹C]SB207145 binding, which we hypothesize reflects brain serotonin levels. In contrast, our data indicate that 5‐HTTLPR specifically affects 5‐HT₄ binding in the neocortex. These findings implicate serotonin signaling as an important molecular mediator underlying the effects of BDNF val66met and 5‐HTTLPR on behavior and related risk for neuropsychiatric illness in humans. Hum Brain Mapp, 36:313–323, 2015. © 2014 Wiley Periodicals, Inc .     

The effects of methylphenidate on whole brain intrinsic functional connectivity

Methylphenidate (MPH) is an indirect dopaminergic and noradrenergic agonist that is used to treat attention deficit hyperactivity disorder and that has shown therapeutic potential in neuropsychiatric diseases such as depression, dementia, and Parkinson's disease. While effects of MPH on task‐induced brain activation have been investigated, little is known about how MPH influences the resting brain. To investigate the effects of 40 mg of oral MPH on intrinsic functional connectivity, we used resting state fMRI in 54 healthy male subjects in a double‐blind, randomized, placebo‐controlled study. Functional connectivity analysis employing ICA revealed seven resting state networks (RSN) of interest. Connectivity strength between the dorsal attention network and the thalamus was increased after MPH intake. Other RSN located in association cortex areas, such as the left and right frontoparietal networks and the executive control network, showed MPH‐induced connectivity increase to sensory‐motor and visual cortex regions and connectivity decrease to cortical and subcortical components of cortico‐striato‐thalamo‐cortical circuits (CST). RSN located in sensory‐motor cortex areas showed the opposite pattern with MPH‐induced connectivity increase to CST components and connectivity decrease to sensory‐motor and visual cortex regions. Our results provide evidence that MPH does not only alter intrinsic connectivity between brain areas involved in sustained attention, but that it also induces significant changes in the cortico‐cortical and cortico‐subcortical connectivity of many other cognitive and sensory‐motor RSN. Hum Brain Mapp 35:5379–5388, 2014. © 2014 Wiley Periodicals, Inc.     

Neurotransmitter changes by interferon-alpha and therapeutic implications

Interferon alpha (IFN-alpha) is a cytokine that is widely used for the treatment of chronic viral infection or malignant disorders. During treatment with IFN-alpha, severe neuropsychiatric syndromes may occur such as depression with suicidal ideation, paranoid psychoses or confusional states. The neurobiological correlates of these side effects are widely unknown. Besides induction of other cytokines and hormonal changes, IFN-alpha has been shown to modulate the opioid, serotonin, dopamine and glutamate neurotransmitter system. Positive therapeutic effects of antidepressants such as selective serotonin-reuptake-inhibitors (SSRI) or of opioid receptor antagonists support the hypothesis that neurotransmitter changes play an important role in the development of IFN-alpha associated neuropsychiatric side effects. We review recent research about IFN-associated neurotransmitter changes in the central nervous system and discuss treatment strategies.     

Quantitative analysis of immunolabeling for serotonin and for glutamate transporters after administration of imipramine and citalopram

Serotonin (5-hydroxytryptamine, 5-HT) is an amine neurotransmitter derived from tryptophan and is important in brain systems regulating mood, emotional behavior, and sleep. Selective serotonin reuptake inhibitor (SSRI) drugs are used to treat disorders such as depression, stress, eating disorders, autism, and schizophrenia. It is thought that these drugs act to prolong the action of 5-HT by blocking reuptake. This may lead to decreased 5-HT content in the nerve fibers themselves; however, this has not previously been directly demonstrated. We have studied the effects of administration of two drugs, imipramine and citalopram, on levels of 5-HT in nerve fibers in the murine brain. Quantitative analysis of the areal density of 5-HT fibers throughout the brain was performed using ImageJ software. While a high density of fibers was observed in mid- and hind-brain regions and areas such as thalamus and hypothalamus, densities were far lower in areas such as cortex, where SSRIs might be thought to exert their actions. As anticipated, imipramine and citalopram produced a decline in 5-HT levels in nerve fibers, but the result was not uniform. Areas such as inferior colliculus showed significant reduction whereas little, if any, change was observed in the adjacent superior colliculus. The reason for, and significance of, this regionality is unclear. It has been proposed that serotonin effects in the brain might be linked to changes in glutamatergic transmission. Extracellular glutamate levels are regulated primarily by glial glutamate transporters. Qualitative evaluation of glutamate transporter immunolabeling in cortex of control and drug-treated mice revealed no discernable difference in intensity of glutamate transporter immunoreactivity. These data suggest that changes in intracellular and extracellular levels of serotonin do not cause concomitant changes in astroglial glutamate transporter expression, and thus cannot represent a mechanism for the delayed efficacy of antidepressants when administered clinically.     

Cortical chemoarchitecture shapes macroscale effective functional connectivity patterns in macaque cerebral cortex

The mammalian cortex is a complex system of—at the microscale level—interconnected neurons and—at the macroscale level—interconnected areas, forming the infrastructure for local and global neural processing and information integration. While the effects of regional chemoarchitecture on local cortical activity are well known, the effect of local neurotransmitter receptor organization on the emergence of large scale region‐to‐region functional interactions remains poorly understood. Here, we examined reports of effective functional connectivity—as measured by the action of strychnine administration acting on the chemical balance of cortical areas—in relation to underlying regional variation in microscale neurotransmitter receptor density levels in the macaque cortex. Linking cortical variation in microscale receptor density levels to collated information on macroscale functional connectivity of the macaque cortex, we show macroscale patterns of effective corticocortical functional interactions—and in particular, the strength of connectivity of efferent macroscale pathways—to be related to the ratio of excitatory and inhibitory neurotransmitter receptor densities of cortical areas. Our findings provide evidence for the microscale chemoarchitecture of cortical areas to have a direct stimulating influence on the emergence of macroscale functional connectivity patterns in the mammalian brain. Hum Brain Mapp 37:1856–1865, 2016. © 2016 Wiley Periodicals, Inc.     

CYTOKINE TARGETS IN THE BRAIN: IMPACT ON NEUROTRANSMITTERS AND NEUROCIRCUITS

Increasing attention has been paid to the role of inflammation in a host of illnesses including neuropsychiatric disorders such as depression and anxiety. Activation of the inflammatory response leads to release of inflammatory cytokines and mobilization of immune cells both of which have been shown to access the brain and alter behavior. The mechanisms of the effects of inflammation on the brain have become an area of intensive study. Data indicate that cytokines and their signaling pathways including p38 mitogen‐activated protein kinase have significant effects on the metabolism of multiple neurotransmitters such as serotonin, dopamine, and glutamate through impact on their synthesis, release, and reuptake. Cytokines also activate the kynurenine pathway, which not only depletes tryptophan, the primary amino acid precursor of serotonin, but also generates neuroactive metabolites that can significantly influence the regulation of dopamine and glutamate. Through their effects on neurotransmitter systems, cytokines impact neurocircuits in the brain including the basal ganglia and anterior cingulate cortex, leading to significant changes in motor activity and motivation as well as anxiety, arousal, and alarm. In the context of environmental challenge from the microbial world, these effects of inflammatory cytokines on the brain represent an orchestrated suite of behavioral and immune responses that subserve evolutionary priorities to shunt metabolic resources away from environmental exploration to fighting infection and wound healing, while also maintaining vigilance against attack, injury, and further pathogen exposure. Chronic activation of this innate behavioral and immune response may lead to depression and anxiety disorders in vulnerable individuals.     

Brain stimulation‐induced neuroplasticity underlying therapeutic response in phantom sounds

Noninvasive brain stimulation can modify phantom sounds for longer periods by modulating neural activity and putatively inducing regional neuroplastic changes. However, treatment response is limited and there are no good demographic or clinical predictors for treatment outcome. We used state‐of‐the‐art voxel‐based morphometry (VBM) to investigate whether transcranial magnetic stimulation‐induced neuroplasticity determines therapeutic outcome. Sixty subjects chronically experiencing phantom sounds (i.e., tinnitus) received repetitive transcranial magnetic stimulation (rTMS) of left dorsolateral prefrontal and temporal cortex according to a protocol that has been shown to yield a significantly higher number of treatment responders than sham stimulation and previous stimulation protocols. Structural magnetic resonance imaging was performed before and after rTMS. In VBM whole‐brain analyses (P < 0.05, FWE corrected), we assessed longitudinal gray matter changes as well as structural connectivity between the ensuing regions. We observed longitudinal mesoscopic gray matter changes of left dorsolateral prefontal (DLPFC), left operculo‐insular, and right inferior temporal cortex (ITC) in responders (N = 22) but not nonresponders (N = 38), as indicated by a group × time interaction and post‐hoc tests. These results were neither influenced by age, sex, hearing loss nor by tinnitus laterality, duration, and severity at baseline. Furthermore, we found robust DLPFC–insula and insula–ITC connectivity in responders, while only relatively weak DLPFC–insula connectivity and no insula–ITC connectivity could be demonstrated in nonresponders. Our results reinforce the implication of nonauditory brain regions in phantom sounds and suggest the dependence of therapeutic response on their neuroplastic capabilities. The latter in turn may depend on (differences in) their individual structural connectivity. Hum Brain Mapp 39:554–562, 2018. © 2017 Wiley Periodicals, Inc.     

Neuropsychiatric symptoms in Alzheimer's disease are related to functional connectivity alterations in the salience network

Neuropsychiatric syndromes are highly prevalent in Alzheimer's disease (AD), but their neurobiology is not completely understood. New methods in functional magnetic resonance imaging, such as intrinsic functional connectivity or “resting‐state” analysis, may help to clarify this issue. Using such approaches, alterations in the default‐mode and salience networks (SNs) have been described in Alzheimer's, although their relationship with specific symptoms remains unclear. We therefore carried out resting‐state functional connectivity analysis with 20 patients with mild to moderate AD, and correlated their scores on neuropsychiatric inventory syndromes (apathy, hyperactivity, affective syndrome, and psychosis) with maps of connectivity in the default mode network and SN. In addition, we compared network connectivity in these patients with that in 17 healthy elderly control subjects. All analyses were controlled for gray matter density and other potential confounds. Alzheimer's patients showed increased functional connectivity within the SN compared with controls (right anterior cingulate cortex and left medial frontal gyrus), along with reduced functional connectivity in the default‐mode network (bilateral precuneus). A correlation between increased connectivity in anterior cingulate cortex and right insula areas of the SN and hyperactivity syndrome (agitation, irritability, aberrant motor behavior, euphoria, and disinhibition) was found. These findings demonstrate an association between specific network changes in AD and particular neuropsychiatric symptom types. This underlines the potential clinical significance of resting state alterations in future diagnosis and therapy. Hum Brain Mapp 35:1237–1246, 2014. © 2013 Wiley Periodicals, Inc.