Christine C. Guo

Altered network connectivity in frontotemporal dementia with C9orf72 hexanucleotide repeat expansion.

Hexanucleotide repeat expansion in C9orf72 represents the most common genetic cause of familial and sporadic behavioural variant frontotemporal dementia. Previous studies show that some C9orf72 carriers with behavioural variant frontotemporal dementia exhibit distinctive atrophy patterns whereas others show mild or undetectable atrophy despite severe behavioural impairment. To explore this observation, we examined intrinsic connectivity network integrity in patients with or without the C9orf72 expansion. We studied 28 patients with behavioural variant frontotemporal dementia, including 14 C9orf72 mutation carriers (age 58.3 ± 7.7 years, four females) and 14 non-carriers (age 60.8 ± 6.9 years, four females), and 14 age- and sex-matched healthy controls. Both patient groups included five patients with comorbid motor neuron disease. Neuropsychological data, structural brain magnetic resonance imaging, and task-free functional magnetic resonance imaging were obtained. Voxel-based morphometry delineated atrophy patterns, and seed-based intrinsic connectivity analyses enabled group comparisons of the salience, sensorimotor, and default mode networks. Single-patient analyses were used to explore network imaging as a potential biomarker. Despite contrasting atrophy patterns in C9orf72 carriers versus non-carriers, patient groups showed topographically similar connectivity reductions in the salience and sensorimotor networks. Patients without C9orf72 expansions exhibited increases in default mode network connectivity compared to controls and mutation carriers. Across all patients, behavioural symptom severity correlated with diminished salience network connectivity and heightened default mode network connectivity. In C9orf72 carriers, salience network connectivity reduction correlated with atrophy in the left medial pulvinar thalamic nucleus, and this region further showed diminished connectivity with key salience network hubs. Single-patient analyses revealed salience network disruption and default mode network connectivity enhancement in C9orf72 carriers with early-stage or slowly progressive symptoms. The findings suggest that patients with behavioural variant frontotemporal dementia with or without the C9orf72 expansion show convergent large-scale network breakdowns despite distinctive atrophy patterns. Medial pulvinar degeneration may contribute to the behavioural variant frontotemporal dementia syndrome in C9orf72 carriers by disrupting salience network connectivity. Task-free functional magnetic resonance imaging shows promise in detecting early-stage disease in C9orf72 carriers and may provide a unifying biomarker across diverse anatomical variants.

Intrinsic connectivity network disruption in progressive supranuclear palsy

Progressive supranuclear palsy (PSP) has been conceptualized as a large‐scale network disruption, but the specific network targeted has not been fully characterized. We sought to delineate the affected network in patients with clinical PSP.

Disrupted Effective Connectivity of Cortical Systems Supporting Attention and Interoception in Melancholia

IMPORTANCE Patients with melancholia report a distinct and intrusive dysphoric state during internally generated thought. Melancholia has long been considered to have a strong biological component, but evidence for its specific neurobiological origins is limited. The distinct neurocognitive, psychomotor, and mood disturbances observed in melancholia do, however, suggest aberrant coordination of frontal-subcortical circuitry, which may best be captured through analysis of complex brain networks. OBJECTIVE To investigate the effective connectivity between spontaneous (resting-state) brain networks in melancholia, focusing on networks underlying attention and interoception. DESIGN, SETTING, AND PARTICIPANTS We performed a cross-sectional, observational, resting-state functional magnetic resonance imaging study of 16 participants with melancholia, 16 with nonmelancholic depression, and 16 individuals serving as controls at a hospital-based research institute between August 30, 2010, and June 27, 2012. We identified 5 canonical resting-state networks (default mode, executive control, left and right frontoparietal attention, and bilateral anterior insula) and inferred spontaneous interactions among these networks using dynamic causal modeling. MAIN OUTCOMES AND MEASURES Graph theoretic measures of brain connectivity, namely, in-degree and out-degree of each network and edge connectivity, between regions composed our principal between-group contrasts. RESULTS Melancholia was characterized by a pervasive disconnection involving anterior insula and attentional networks compared with participants in the control (Mann-Whitney, 189.00; z = 2.38; P = .02) and nonmelancholic depressive (Mann-Whitney, 203.00; z = 2.93; P = .004) groups. Decreased effective connectivity between the right frontoparietal and insula networks was present in participants with melancholic depression compared with those with nonmelancholic depression (χ2 = 8.13; P = .004). Reduced effective connectivity between the insula and executive networks was found in individuals with melancholia compared with healthy controls (χ2 = 8.96; P = .003). CONCLUSIONS AND RELEVANCE We observed reduced effective connectivity in resting-state functional magnetic resonance imaging between key networks involved in attention and interoception in melancholia. We propose that these abnormalities underlie the impoverished variety and affective quality of internally generated thought in this disorder.

Network-selective vulnerability of the human cerebellum to Alzheimer’s disease and frontotemporal dementia

SEE SCHMAHMANN DOI101093/BRAIN/AWW064 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Neurodegenerative diseases are associated with distinct and distributed patterns of atrophy in the cerebral cortex. Emerging evidence suggests that these atrophy patterns resemble intrinsic connectivity networks in the healthy brain, supporting the network-based degeneration framework where neuropathology spreads across connectivity networks. An intriguing yet untested possibility is that the cerebellar circuits, which share extensive connections with the cerebral cortex, could be selectively targeted by major neurodegenerative diseases. Here we examined the structural atrophy in the cerebellum across common types of neurodegenerative diseases, and characterized the functional connectivity patterns of these cerebellar atrophy regions. Our results showed that Alzheimers disease and frontotemporal dementia are associated with distinct and circumscribed atrophy in the cerebellum. These cerebellar atrophied regions share robust and selective intrinsic connectivity with the atrophied regions in the cerebral cortex. These findings for the first time demonstrated the selective vulnerability of the cerebellum to common neurodegenerative disease, extending the network-based degeneration framework to the cerebellum. Our work also has direct implications on the cerebellar contribution to the cognitive and affective processes that are compromised in neurodegeneration as well as the practice of using the cerebellum as reference region for ligand neuroimaging studies.

The anterior insula shows heightened interictal intrinsic connectivity in migraine without aura

Objective: We sought to explore whether patients with migraine show heightened interictal intrinsic connectivity within primary sensory networks, the salience network, and a network anchored by the dorsal pons, a region known to be active during migraine attacks. Methods: Using task-free fMRI and a region-of-interest analysis, we compared intrinsic connectivity patterns in 15 migraineurs without aura to 15 age- and sex-matched healthy controls, focusing on networks anchored by the calcarine cortex, Heschl gyrus, right anterior insula, and dorsal pons, a region active during migraine attacks. We also examined the relationship between network connectivity, migraine frequency, and sensory sensitivity symptoms. Results: Migraineurs showed increased connectivity between primary visual and auditory cortices and the right dorsal anterior insula, between the dorsal pons and the bilateral anterior insulae, and between the right and left ventral anterior insulae. Increased connectivity showed no clinical correlation with migraine frequency or sensory sensitivity. Conclusions: Patients with migraine display interictal changes in the topology of intrinsic connections, with greater connectivity between primary sensory cortices, the pons, and the anterior insula, a region involved in representing and coordinating responses to emotional salience.

The integration of the internal and external milieu in the insula during dynamic emotional experiences.

Whilst external events trigger emotional responses, interoception (the perception of internal physiological states) is fundamental to core emotional experience. By combining high resolution functional neuroimaging with concurrent physiological recordings, we investigated the neural mechanisms of interoceptive integration during free listening to an emotionally salient audio film. We found that cardiac activity, a key interoceptive signal, was robustly synchronised across participants and centrally represented in the posterior insula. Effective connectivity analysis revealed that the anterior insula, specifically tuned to the emotionally salient moments of the audio stream, serves as an integration hub of interoceptive processing: interoceptive states represented in the posterior insula are integrated with exteroceptive representations by the anterior insula to highlight these emotionally salient moments. Our study for the first time demonstrates the insular hierarchy for interoceptive processing during natural emotional experience. These findings provide an ecologically-valid framework for elucidating the neural underpinnings of emotional deficits in neuropsychiatric disorders.

Dominant hemisphere lateralization of cortical parasympathetic control as revealed by frontotemporal dementia

Significance Brain–body interactions are fundamental to physical and mental health. Here, we used a unique brain lesion model to elucidate the neural localization and lateralization of cerebro-cardiac control. Our data revealed that the salience network, an intrinsic connectivity network anchored by the anterior insula and cingulate, is crucial for maintaining basal parasympathetic outflow. Specifically, dominant hemisphere-predominant salience network damage undermined parasympathetic control of the heart. The findings suggest that balanced functional integrity of both hemispheres is vital to maintaining bodily homeostasis. The brain continuously influences and perceives the physiological condition of the body. Related cortical representations have been proposed to shape emotional experience and guide behavior. Although previous studies have identified brain regions recruited during autonomic processing, neurological lesion studies have yet to delineate the regions critical for maintaining autonomic outflow. Even greater controversy surrounds hemispheric lateralization along the parasympathetic–sympathetic axis. The behavioral variant of frontotemporal dementia (bvFTD), featuring progressive and often asymmetric degeneration that includes the frontoinsular and cingulate cortices, provides a unique lesion model for elucidating brain structures that control autonomic tone. Here, we show that bvFTD is associated with reduced baseline cardiac vagal tone and that this reduction correlates with left-lateralized functional and structural frontoinsular and cingulate cortex deficits and with reduced agreeableness. Our results suggest that networked brain regions in the dominant hemisphere are critical for maintaining an adaptive level of baseline parasympathetic outflow.

Rivastigmine is Associated with Restoration of Left Frontal Brain Activity in Parkinson’s Disease

The objective of this study was to investigate how acetylcholinesterase inhibitor (ChEI) treatment affects brain function in Parkinsons disease (PD). Twelve patients with PD and either dementia or mild cognitive impairment underwent task‐free functional magnetic resonance imaging before and after 3 months of ChEI treatment and were compared with 15 age‐ and sex‐matched neurologically healthy controls. Regional spontaneous brain activity was measured using the fractional amplitude of low‐frequency fluctuations. At baseline, patients showed reduced spontaneous brain activity in regions important for motor control (eg, caudate, supplementary motor area, precentral gyrus, thalamus), attention and executive functions (eg, lateral prefrontal cortex), and episodic memory (eg, precuneus, angular gyrus, hippocampus). After treatment, the patients showed a similar but less extensive pattern of reduced spontaneous brain activity relative to controls. Spontaneous brain activity deficits in the left premotor cortex, inferior frontal gyrus, and supplementary motor area were restored such that the activity was increased posttreatment compared with baseline and was no longer different from controls. Treatment‐related increases in left premotor and inferior frontal cortex spontaneous brain activity correlated with parallel reaction time improvement on a test of controlled attention. PD patients with cognitive impairment show numerous regions of decreased spontaneous brain function compared with controls, and rivastigmine is associated with performance‐related normalization in the left frontal cortex function.

Test-retest reliability of functional connectivity networks during naturalistic fMRI paradigms.

Functional connectivity analysis has become a powerful tool for probing the human brain function and its breakdown in neuropsychiatry disorders. So far, most studies adopted resting‐state paradigm to examine functional connectivity networks in the brain, thanks to its low demand and high tolerance that are essential for clinical studies. However, the test–retest reliability of resting‐state connectivity measures is moderate, potentially due to its low behavioral constraint. On the other hand, naturalistic neuroimaging paradigms, an emerging approach for cognitive neuroscience with high ecological validity, could potentially improve the reliability of functional connectivity measures. To test this hypothesis, we characterized the test–retest reliability of functional connectivity measures during a natural viewing condition, and benchmarked it against resting‐state connectivity measures acquired within the same functional magnetic resonance imaging (fMRI) session. We found that the reliability of connectivity and graph theoretical measures of brain networks is significantly improved during natural viewing conditions over resting‐state conditions, with an average increase of almost 50% across various connectivity measures. Not only sensory networks for audio–visual processing become more reliable, higher order brain networks, such as default mode and attention networks, but also appear to show higher reliability during natural viewing. Our results support the use of natural viewing paradigms in estimating functional connectivity of brain networks, and have important implications for clinical application of fMRI. Hum Brain Mapp 38:2226–2241, 2017.

Out-of-sync: disrupted neural activity in emotional circuitry during film viewing in melancholic depression

While a rich body of research in controlled experiments has established changes in the neural circuitry of emotion in major depressive disorders, little is known as to how such alterations might translate into complex, naturalistic settings - namely involving dynamic multimodal stimuli with rich contexts, such as those provided by films. Neuroimaging paradigms employing dynamic natural stimuli alleviate the anxiety often associated with complex tasks and eschew the need for laboratory-style abstractions, hence providing an ecologically valid means of elucidating neural underpinnings of neuropsychiatric disorders. To probe the neurobiological signature of refined depression subtypes, we acquired functional neuroimaging data in patients with the melancholic subtype of major depressive disorder during free viewing of emotionally salient films. We found a marked disengagement of ventromedial prefrontal cortex during natural viewing of a film with negative emotional valence in patients with melancholia. This effect significantly correlated with depression severity. Such changes occurred on the background of diminished consistency of neural activity in visual and auditory sensory networks, as well as higher-order networks involved in emotion and attention, including bilateral intraparietal sulcus and right anterior insula. These findings may reflect a failure to re-allocate resources and diminished reactivity to external emotional stimuli in melancholia.