Neural correlates of drinking reduction during a clinical trial of cognitive behavioral therapy for alcohol use disorder.

BACKGROUND: Cognitive behavioral therapy (CBT) is an effective treatment for alcohol use disorder (AUD). We hypothesized that the dorsolateral prefrontal cortex (DLPFC), a region implicated in cognitive control and goal-directed behavior, plays a role in behavior change during CBT by facilitating the regulation of craving (ROC). METHODS: Treatment-seeking participants with AUD (N = 22) underwent functional magnetic resonance imaging (fMRI) scanning both before and after a 12-week, single-arm trial of CBT, using an ROC task that was previously shown to engage the DLPFC. RESULTS: We found that both the percentage of heavy drinking days (PHDD) and the overall self-reported alcohol craving measured during the ROC task were significantly reduced from pre- to post-CBT. However, we did not find significant changes over time in either the ability to regulate craving or regulation-related activity in any brain region. We found a significant 3-way interaction between the effects of cue-induced craving, cue-induced brain activity and timepoint of assessment (pre- or post-CBT) on PHDD in the left DLPFC. Follow-up analysis showed that cue-induced craving was associated with cue-induced activity in the left DLPFC among participants who ceased heavy drinking during CBT, both at pre-CBT and post-CBT timepoints. No such associations were present at either timepoint among participants who continued to drink heavily. CONCLUSIONS: These results suggest that patients in whom DLPFC functioning is more strongly related to cue-induced craving may preferentially respond to CBT.

The Road Not Taken: Disconnection of a Human-Unique Cortical Pathway Underlying Naturalistic Social Perception in Schizophrenia.

Background: Efficient processing of complex and dynamic social scenes relies on intact connectivity of many underlying cortical areas and networks, but how connectivity anomalies affect the neural substrates of social perception remains unknown. Here we measured these relationships using functionally based localization of social perception areas, resting-state functional connectivity, and movie-watching data. Methods: In 42 participants with schizophrenia (SzPs) and 41 healthy control subjects, we measured the functional connectivity of areas localized by face-emotion processing, theory-of-mind (ToM), and attention tasks. We quantified the weighted shortest path length between visual and medial prefrontal ToM areas in both populations to assess the impact of these changes in functional connectivity on network structure. We then correlated connectivity along the shortest path in each group with movie-evoked activity in a key node of the ToM network (posterior temporoparietal junction [TPJp]). Results: SzPs had pronounced decreases in connectivity in TPJ/posterior superior temporal sulcus (TPJ-pSTS) areas involved in face-emotion processing (t81 = 4.4, p = .00002). In healthy control subjects, the shortest path connecting visual and medial prefrontal ToM areas passed through TPJ-pSTS, whereas in SzPs, the shortest path passed through the prefrontal cortex. While movie-evoked TPJp activity correlated with connectivity along the TPJ-pSTS pathway in both groups (r = 0.43, p = .002), it additionally correlated with connectivity along the prefrontal cortex pathway only in SzPs (rSzP = 0.56, p = .003). Conclusions: These results suggest that connectivity along the human-unique TPJ-pSTS pathway affects both the network architecture and functioning of areas involved in processing complex dynamic social scenes. These results demonstrate how focal connectivity anomalies can have widespread impacts across the cortex.

Neural correlates of drinking reduction during cognitive behavioral therapy for alcohol use disorder.

Cognitive behavioral therapy (CBT) is an effective treatment for alcohol use disorder (AUD). We hypothesized that the dorsolateral prefrontal cortex (DLPFC), a brain region implicated in cognitive control and goal-directed behavior, plays a role behavior change during CBT by facilitating regulation of craving. To examine this, treatment-seeking participants with AUD (N=22) underwent functional MRI scanning both before and after a 12-week single-arm trial of CBT, using a regulation of craving (ROC) fMRI task designed to measure an individual's ability to control alcohol craving and previously shown to engage the DLPFC. We found that both the number of heavy drinking days (NHDD, the primary clinical outcome) and the self-reported alcohol craving measured during the ROC paradigm were significantly reduced from pre- to post-CBT [NHDD: t=15.69, p<0.0001; alcohol craving: (F(1,21)=16.16; p=0.0006)]. Contrary to our hypothesis, there was no change in regulation effects on self-reported craving over time (F(1,21)=0.072; p=0.79), nor was there was a significant change in regulation effects over time on activity in any parcel. Searching the whole brain for neural correlates of reductions in drinking and craving after CBT, we found a significant 3-way interaction between the effects of cue-induced alcohol craving, cue-induced brain activity and timepoint of assessment (pre- or post-CBT) on NHDD in a parcel corresponding to area 46 of the right DLPFC (ß=-0.37, p=0.046, FDR corrected). Follow-up analyses showed that reductions in cue-induced alcohol craving from pre- to post-CBT were linearly related to reductions in alcohol cue-induced activity in area 46 only among participants who ceased heavy drinking during CBT (r=0.81, p=0.005) but not among those who continued to drink heavily (r=0.28, p=0.38). These results are consistent with a model in which CBT impacts heavy drinking by increasing the engagement of the DLPFC during cue-induced craving.

Brain connectivity at rest predicts individual differences in normative activity during movie watching.

When exposed to the same sensory event, some individuals are bound to have less typical experiences than others. Previous research has investigated this phenomenon by showing that the typicality of one's sensory experience is associated with the typicality of their stimulus-evoked brain activity (as measured by intersubject correlation, or ISC). Individual differences in ISC have recently been attributed to variability in focal neural processing. However, the extent to which these differences reflect purely intra-regional variability versus variation in the brain's baseline ability to transmit information between regions has yet to be established. Here, we show that an individual's degree and spatial distribution of ISC are closely related to their brain's functional organization at rest. Using resting state and movie watching fMRI data from the Human Connectome Project, we reveal that resting state functional connectivity (RSFC) profiles can be used to predict cortex-wide ISC. Similar region-level analyses demonstrate that the levels of ISC exhibited by brain regions during movie watching are associated with their connectivity to other regions at rest, and that the nature of these connectivity-activity relationships varies as a function of regional roles in sensory information processing. Finally, we show that an individual's unique spatial distribution of ISC, independent of its magnitude, is also related to their RSFC profile. These findings contextualize reports of localized individual differences in ISC as potentially reflecting larger, network-level alterations in resting brain function and detail how the brain's ability to process complex sensory information is linked to its baseline functional organization.

Drinking reduction during cognitive behavioral therapy for alcohol use disorder is associated with a reduction in anterior insula-bed nucleus of the stria terminalis resting-state functional connectivity.

BACKGROUND: Connectivity between the anterior insula (AI) and the bed nucleus of the stria terminalis (BNST) may play a role in negative emotions that drive compulsive drinking in patients with alcohol use disorder (AUD). We hypothesized that reductions in drinking during cognitive behavioral therapy (CBT), an effective treatment that teaches regulation (coping) skills for managing negative emotions during abstinence, would be associated with reductions in resting-state functional connectivity (RSFC) between the AI and the BNST. METHODS: We included 18 patients with a Diagnostic and Statistical Manual of Mental Disorders, fifth edition diagnosis of AUD who were (1) seeking treatment and (2) drinking heavily at baseline. We measured RSFC as Pearson's correlation between the BNST and multiple regions of interest in the insula at baseline and after completion of 12 weeks of a single-arm clinical trial of outpatient CBT. We also assessed the number of heavy drinking days over the previous 28 days (NHDD) at both time points. We used 1-sample t-tests to evaluate AI-BNST RSFC at baseline, paired t-tests to evaluate changes in AI-BNST RSFC from pre-CBT to post-CBT, and linear regression to evaluate the relationship between changes in AI-BNST RSFC and NHDD. RESULTS: We found a significant positive RSFC between the AI and the BNST at baseline (p = 0.0015). While there were no significant changes in AI-BNST RSFC from pre- to post-CBT at the group level (p = 0.42), we found that individual differences in reductions in AI-BNST RSFC from pre- to post-CBT were directly related to reductions in NHDD from pre- to post-CBT (r = 0.73, p = 0.0008). CONCLUSIONS: These findings provide preliminary evidence that reduced AI-BNST RSFC may be a mechanism of drinking reduction in AUD and that AI-BNST RSFC may be a target for CBT and possibly other treatments.

Failure to engage the temporoparietal junction/posterior superior temporal sulcus predicts impaired naturalistic social cognition in schizophrenia.

Schizophrenia is associated with marked impairments in social cognition. However, the neural correlates of these deficits remain unclear. Here we use naturalistic stimuli to examine the role of the right temporoparietal junction/posterior superior temporal sulcus (TPJ-pSTS)-an integrative hub for the cortical networks pertinent to the understanding complex social situations-in social inference, a key component of social cognition, in schizophrenia. Twenty-seven schizophrenia participants and 21 healthy control subjects watched a clip of the film The Good, the Bad and the Ugly while high resolution multiband functional MRI images were collected. We used inter-subject correlation to measure the evoked activity, which we then compared to social cognition as measured by The Awareness of Social Inference Test (TASIT). We also compared between groups the TPJ-pSTS blood oxygen level-dependent activity (i) relationship with the motion content in the film; (ii) synchronization with other cortical areas involved in the viewing of the movie; and (iii) relationship with the frequency of saccades made during the movie. Activation deficits were greatest in middle TPJ (TPJm) and correlated significantly with impaired TASIT performance across groups. Follow-up analyses of the TPJ-pSTS revealed decreased synchronization with other cortical areas, decreased correlation with the motion content of the movie, and decreased correlation with the saccades made during the movie. The functional impairment of the TPJm, a hub area in the middle of the TPJ-pSTS, predicts deficits in social inference in schizophrenia participants by disrupting the integration of visual motion processing into the TPJ. This disrupted integration then affects the use of the TPJ to guide saccades during the visual scanning of the movie clip. These findings suggest that the TPJ may be a treatment target for improving deficits in a key component of social cognition in schizophrenia participants.

What you see is what you get: visual scanning failures of naturalistic social scenes in schizophrenia.

BACKGROUND: Impairments in social cognition contribute significantly to disability in schizophrenia patients (SzP). Perception of facial expressions is critical for social cognition. Intact perception requires an individual to visually scan a complex dynamic social scene for transiently moving facial expressions that may be relevant for understanding the scene. The relationship of visual scanning for these facial expressions and social cognition remains unknown. METHODS: In 39 SzP and 27 healthy controls (HC), we used eye-tracking to examine the relationship between performance on The Awareness of Social Inference Test (TASIT), which tests social cognition using naturalistic video clips of social situations, and visual scanning, measuring each individual's relative to the mean of HC. We then examined the relationship of visual scanning to the specific visual features (motion, contrast, luminance, faces) within the video clips. RESULTS: TASIT performance was significantly impaired in SzP for trials involving sarcasm (p < 10-5). Visual scanning was significantly more variable in SzP than HC (p < 10-6), and predicted TASIT performance in HC (p = 0.02) but not SzP (p = 0.91), differing significantly between groups (p = 0.04). During the visual scanning, SzP were less likely to be viewing faces (p = 0.0001) and less likely to saccade to facial motion in peripheral vision (p = 0.008). CONCLUSIONS: SzP show highly significant deficits in the use of visual scanning of naturalistic social scenes to inform social cognition. Alterations in visual scanning patterns may originate from impaired processing of facial motion within peripheral vision. Overall, these results highlight the utility of naturalistic stimuli in the study of social cognition deficits in schizophrenia.

Disease-Specific Contribution of Pulvinar Dysfunction to Impaired Emotion Recognition in Schizophrenia.

One important aspect for managing social interactions is the ability to perceive and respond to facial expressions rapidly and accurately. This ability is highly dependent upon intact processing within both cortical and subcortical components of the early visual pathways. Social cognitive deficits, including face emotion recognition (FER) deficits, are characteristic of several neuropsychiatric disorders including schizophrenia (Sz) and autism spectrum disorders (ASD). Here, we investigated potential visual sensory contributions to FER deficits in Sz (n = 28, 8/20 female/male; age 21-54 years) and adult ASD (n = 20, 4/16 female/male; age 19-43 years) participants compared to neurotypical (n = 30, 8/22 female/male; age 19-54 years) controls using task-based fMRI during an implicit static/dynamic FER task. Compared to neurotypical controls, both Sz (d = 1.97) and ASD (d = 1.13) participants had significantly lower FER scores which interrelated with diminished activation of the superior temporal sulcus (STS). In Sz, STS deficits were predicted by reduced activation of early visual regions (d = 0.85, p = 0.002) and of the pulvinar nucleus of the thalamus (d = 0.44, p = 0.042), along with impaired cortico-pulvinar interaction. By contrast, ASD participants showed patterns of increased early visual cortical (d = 1.03, p = 0.001) and pulvinar (d = 0.71, p = 0.015) activation. Large effect-size structural and histological abnormalities of pulvinar have previously been documented in Sz. Moreover, we have recently demonstrated impaired pulvinar activation to simple visual stimuli in Sz. Here, we provide the first demonstration of a disease-specific contribution of impaired pulvinar activation to social cognitive impairment in Sz.

Deficits and compensation: Attentional control cortical networks in schizophrenia.

Visual processing and attention deficits are responsible for a substantial portion of the disability caused by schizophrenia, but the source of these deficits remains unclear. In 35 schizophrenia patients (SzP) and 34 healthy controls (HC), we used a rapid serial visual presentation (RSVP) visual search task designed to activate/deactivate the cortical components of the attentional control system (i.e. the dorsal and ventral attention networks, lateral prefrontal regions in the frontoparietal network, and cingulo-opercular/salience networks), along with resting state functional connectivity, to examine the integrity of these components. While we find that behavioral performance and activation/deactivation of the RSVP task are largely similar between groups, SzP exhibited decreased functional connectivity within late visual components and between prefrontal and other components. We also find that performance correlates with the deactivation of the ventral attention network in SzP only. This relationship is mediated by the functional connectivity of critical components of the attentional control system. In summary, our results suggest that the attentional control system is potentially used to compensate for visual cortex deficits. Furthermore, prefrontal deficits in SzP may interfere with this compensatory use of the attentional control system. In addition to highlighting focal deficits and potential compensatory mechanisms in visual processing and attention, our findings point to the attentional control system as a potential target for rehabilitation and neuromodulation-based treatments for visual processing deficits in SzP.

Individual-specific functional connectivity of the amygdala: A substrate for precision psychiatry.

The amygdala is central to the pathophysiology of many psychiatric illnesses. An imprecise understanding of how the amygdala fits into the larger network organization of the human brain, however, limits our ability to create models of dysfunction in individual patients to guide personalized treatment. Therefore, we investigated the position of the amygdala and its functional subdivisions within the network organization of the brain in 10 highly sampled individuals (5 h of fMRI data per person). We characterized three functional subdivisions within the amygdala of each individual. We discovered that one subdivision is preferentially correlated with the default mode network; a second is preferentially correlated with the dorsal attention and fronto-parietal networks; and third subdivision does not have any networks to which it is preferentially correlated relative to the other two subdivisions. All three subdivisions are positively correlated with ventral attention and somatomotor networks and negatively correlated with salience and cingulo-opercular networks. These observations were replicated in an independent group dataset of 120 individuals. We also found substantial across-subject variation in the distribution and magnitude of amygdala functional connectivity with the cerebral cortex that related to individual differences in the stereotactic locations both of amygdala subdivisions and of cortical functional brain networks. Finally, using lag analyses, we found consistent temporal ordering of fMRI signals in the cortex relative to amygdala subdivisions. Altogether, this work provides a detailed framework of amygdala-cortical interactions that can be used as a foundation for models relating aberrations in amygdala connectivity to psychiatric symptoms in individual patients.

Deficits in Pre-attentive Processing of Spatial Location and Negative Symptoms in Subjects at Clinical High Risk for Schizophrenia.

Deficits in mismatch negativity (MMN) generation are among the best-established biomarkers for cognitive dysfunction in schizophrenia and predict conversion to schizophrenia (Sz) among individuals at symptomatic clinical high risk (CHR). Impairments in MMN index dysfunction at both subcortical and cortical components of the early auditory system. To date, the large majority of studies have been conducted using deviants that differ from preceding standards in either tonal frequency (pitch) or duration. By contrast, MMN to sound location deviation has been studied to only a limited degree in Sz and has not previously been examined in CHR populations. Here, we evaluated location MMN across Sz and CHR using an optimized, multi-deviant pattern that included a location-deviant, as defined using interaural time delay (ITD) stimuli along with pitch, duration, frequency modulation (FM) and intensity deviants in a sample of 42 Sz, 33 CHR and 28 healthy control (HC) subjects. In addition, we obtained resting state functional connectivity (rsfMRI) on CHR subjects. Sz showed impaired MMN performance across all deviant types, along with strong correlation between MMN deficits and impaired neurocognitive function. In this sample of largely non-converting CHR subjects, no deficits were observed in either pitch or duration MMN. By contrast, CHR subjects showed significant impairments in location MMN generation particularly over right hemisphere and significant correlation between impaired location MMN and negative symptoms including deterioration of role function. In addition, significant correlations were observed between location MMN and rsfMRI involving brainstem circuits. In general, location detection using ITD stimuli depends upon precise processing within midbrain regions and provides a rapid and robust reorientation of attention. Present findings reinforce the utility of MMN as a pre-attentive index of auditory cognitive dysfunction in Sz and suggest that location MMN may index brain circuits distinct from those indexed by other deviant types.

Neural and functional correlates of impaired reading ability in schizophrenia.

Deficits in early auditory processing (EAP) are a core component of schizophrenia (SZ) and contribute significantly to impaired overall function. Here, we evaluate the potential contributions of EAP-related impairments in reading to functional capacity and outcome, relative to effects of auditory social cognitive and general neurocognitive dysfunction. Participants included 30-SZ and 28-controls of similar age, sex, and educational achievement. EAP was assessed using an auditory working memory (tone-matching) task. Phonological processing and reading Fluency were assessed using the Comprehensive Test of Phonological Processing and Woodcock-Johnson reading batteries, respectively. Auditory-related social cognition was assessed using measures of emotion/sarcasm recognition. Functional capacity and outcome were assessed using the UCSD Performance-based Skills Assessment and Specific Level of Functioning scale, respectively. fMRI resting-state functional-connectivity (rsFC) was used to evaluate potential underlying substrates. As predicted, SZ patients showed significant and interrelated deficits in both phonological processing (d = 0.74, p = 0.009) and reading fluency (d = 1.24, p < 0.00005). By contrast, single word reading (d = 0.35, p = 0.31) was intact. In SZ, deficits in EAP and phonological reading ability significantly predicted reduced functional capacity, but not functional outcome. By contrast, deficits in reading fluency significantly predicted impairments in both functional capacity and functional outcome. Moreover, deficits in reading fluency correlated with rsFC alterations among auditory thalamus, early auditory and auditory association regions. These findings indicate significant contributions of EAP deficits and functional connectivity changes in subcortical and early auditory regions to reductions in reading fluency, and of impaired reading ability to impaired functional outcome in SZ.

Bimodal distribution of tone-matching deficits indicates discrete pathophysiological entities within the syndrome of schizophrenia.

To date, no measures are available that permit differentiation of discrete, clinically distinct subtypes of schizophrenia (SZ) with potential differential underlying pathophysiologies. Over recent years, there has been increasing recognition that SZ is heterogeneously associated with deficits in early auditory processing (EAP), as demonstrated using clinically applicable tasks such as tone-matching task (TMT). Here, we pooled TMT performances across 310 SZ individuals and 219 healthy controls (HC), along with clinical, cognitive, and resting-state functional-connectivity MRI (rsFC-MRI) measures. In addition, TMT was measured in a group of 24 patients at symptomatic clinical high risk (CHR) for SZ and 24 age-matched HC (age range 7-27 years). We provide the first demonstration that the EAP deficits are bimodally distributed across SZ subjects (P < 0.0001 vs. unimodal distribution), with one group showing entirely unimpaired TMT performance (SZ-EAP+), and a second showing an extremely large TMT impairment (SZ-EAP-), relative to both controls (d = 2.1) and SZ-EAP+ patients (d = 3.4). The SZ-EAP- group predominated among samples drawn from inpatient sites, showed higher levels of cognitive symptoms (PANSS), worse social cognition and a differential deficit in neurocognition (MATRICS battery), and reduced functional capacity. rsFC-MRI analyses showed significant reduction in SZ-EAP- relative to controls between subcortical and cortical auditory regions. As opposed to SZ, CHR patients showed intact EAP function. In HC age-matched to CHR, EAP ability was shown to increase across the age range of vulnerability preceding SZ onset. These results indicate that EAP measure segregates between discrete SZ subgroups. As TMT can be readily implemented within routine clinical settings, its use may be critical to account for the heterogeneity of clinical outcomes currently observed across SZ patients, as well as for pre-clinical detection and efficacious treatment selection.

The evolution of the temporoparietal junction and posterior superior temporal sulcus.

The scale at which humans can handle complex social situations is massively increased compared to other animals. However, the neural substrates of this scaling remain poorly understood. In this review, we discuss how the expansion and rearrangement of the temporoparietal junction and posterior superior temporal sulcus (TPJ-pSTS) may have played a key role in the growth of human social abilities. Comparing the function and anatomy of the TPJ-pSTS in humans and macaques, which are thought to be separated by 25 million years of evolution, we find that the expansion of this region in humans has shifted the architecture of the dorsal and ventral processing streams. The TPJ-pSTS contains areas related to face-emotion processing, attention, theory of mind operations, and memory; its expansion has allowed for the elaboration and rearrangement of the cortical areas contained within, and potentially the introduction of new cortical areas. Based on the arrangement and the function of these areas in the human, we propose that the TPJ-pSTS is the basis of a third frontoparietal processing stream that underlies the increased social abilities in humans. We then describe a model of how the TPJ-pSTS areas interact as a hub that coordinates the activities of multiple brain networks in the exploration of the complex dynamic social scenes typical of the human social experience.

Functional evolution of new and expanded attention networks in humans.

Macaques are often used as a model system for invasive investigations of the neural substrates of cognition. However, 25 million years of evolution separate humans and macaques from their last common ancestor, and this has likely substantially impacted the function of the cortical networks underlying cognitive processes, such as attention. We examined the homology of frontoparietal networks underlying attention by comparing functional MRI data from macaques and humans performing the same visual search task. Although there are broad similarities, we found fundamental differences between the species. First, humans have more dorsal attention network areas than macaques, indicating that in the course of evolution the human attention system has expanded compared with macaques. Second, potentially homologous areas in the dorsal attention network have markedly different biases toward representing the contralateral hemifield, indicating that the underlying neural architecture of these areas may differ in the most basic of properties, such as receptive field distribution. Third, despite clear evidence of the temporoparietal junction node of the ventral attention network in humans as elicited by this visual search task, we did not find functional evidence of a temporoparietal junction in macaques. None of these differences were the result of differences in training, experimental power, or anatomical variability between the two species. The results of this study indicate that macaque data should be applied to human models of cognition cautiously, and demonstrate how evolution may shape cortical networks.

Topographic organization in the brain: searching for general principles.

The neurons comprising many cortical areas have long been known to be arranged topographically such that nearby neurons have receptive fields at nearby locations in the world. Although this type of organization may be universal in primary sensory and motor cortex, in this review we demonstrate that associative cortical areas may not represent the external world in a complete and continuous fashion. After reviewing evidence for novel principles of topographic organization in macaque lateral intraparietal area (LIP) - one of the most-studied associative areas in the parietal cortex - we explore the implications of these new principles for brain function.

Topographic organization of macaque area LIP.

Despite several attempts to define retinotopic maps in the macaque lateral intraparietal area (LIP) using histological, electrophysiological, and neuroimaging methods, the degree to which this area is topographically organized remains controversial. We recorded blood oxygenation level-dependent signals with functional MRI from two macaques performing a difficult visual search task on stimuli presented at the fovea or in the periphery of the visual field. The results revealed the presence of a single topographic representation of the contralateral hemifield in the ventral subdivision of the LIP (LIPv) in both hemispheres of both monkeys. Also, a foveal representation was localized in rostral LIPv rather than in dorsal LIP (LIPd) as previous experiments had suggested. Finally, both LIPd and LIPv responded only to contralateral stimuli. In contrast, human studies have reported multiple topographic maps in intraparietal cortex and robust responses to ipsilateral stimuli. These blood oxygenation level-dependent functional MRI results provide clear evidence for the topographic organization of macaque LIP that complements the results of previous electrophysiology studies, and also reveal some unexpected characteristics of this organization that have eluded these previous studies. The results also delineate organizational differences between LIPv and LIPd, providing support for these two histologically defined areas may subserve different visuospatial functions. Finally, these findings point to potential evolutionary differences in functional organization with human posterior parietal cortex.