Neural correlates of impulsivity in bipolar disorder: A systematic review and clinical implications.

Impulsivity is a common feature of bipolar disorder (BD) with ramifications for functional impairment and premature mortality. This PRISMA-guided systematic review aims to integrate findings on the neurocircuitry associated with impulsivity in BD. We searched for functional neuroimaging studies that examined rapid-response impulsivity and choice impulsivity using the Go/No-Go Task, Stop-Signal Task, and Delay Discounting Task. Findings from 33 studies were synthesized with an emphasis on the effect of mood state of the sample and affective salience of the task. Results suggest trait-like brain activation abnormalities in regions implicated in impulsivity that persist across mood states. During rapid-response inhibition, BD exhibit under-activation of key frontal, insular, parietal, cingulate, and thalamic regions, but over-activation of these regions when the task involves emotional stimuli. Delay discounting tasks with functional neuroimaging in BD are lacking, but hyperactivity of orbitofrontal and striatal regions associated with reward hypersensitivity may be related to difficulty delaying gratification. We propose a working model of neurocircuitry dysfunction underlying behavioral impulsivity in BD. Clinical implications and future directions are discussed.

Frontal lobe functioning during a simple response conflict task in first-episode psychosis and its relationship to treatment response.

Prior functional magnetic resonance imaging (fMRI) studies have investigated the neural mechanisms underlying cognitive control in patients with psychosis with findings of both hypo- and hyperfrontality. One factor that may contribute to inconsistent findings is the use of complex and polyfactorial tasks to investigate frontal lobe functioning. In the current study we employed a simple response conflict task during fMRI to examine differences in brain activation between patients experiencing their first-episode of psychosis (n = 33) and age- and sex-matched healthy volunteers (n = 33). We further investigated whether baseline brain activation among patients predicted changes in symptom severity and treatment response following 12 weeks of controlled antipsychotic treatment. During the task subjects were instructed to press a response button on the same side or opposite side of a circle that appeared on either side of a central fixation point. Imaging data revealed that for the contrast of opposite-side vs. same-side, patients showed significantly greater activation compared with healthy volunteers in the anterior cingulate cortex and intraparietal sulcus. Among patients, greater baseline anterior cingulate cortex, temporal-parietal junction, and superior temporal cortex activation predicted greater symptom reduction and therapeutic response following treatment. All findings remained significant after covarying for task performance. Intact performance on this relatively parsimonious task was associated with frontal hyperactivity suggesting the need for patients to utilize greater neural resources to achieve task performance comparable to healthy individuals. Moreover, frontal hyperactivity observed using a simple fMRI task may provide a biomarker for predicting treatment response in first-episode psychosis.

An Integrative Neuroscience Framework for the Treatment of Chronic Pain: From Cellular Alterations to Behavior.

Chronic pain can result from many pain syndromes including complex regional pain syndrome (CRPS), phantom limb pain and chronic low back pain, among others. On a molecular level, chronic pain syndromes arise from hypersensitization within the dorsal horn of the spinal cord, a process known as central sensitization. Central sensitization involves an upregulation of ionotropic and metabotropic glutamate receptors (mGluRs) similar to that of long-term potentiation (LTP). Regions of the brain in which LTP occurs, such as the amygdala and hippocampus, are implicated in fear- and memory-related brain circuity. Chronic pain dramatically influences patient quality of life. Individuals with chronic pain may develop pain-related anxiety and pain-related fear. The syndrome also alters functional connectivity in the default-mode network (DMN) and salience network. On a cellular/molecular level, central sensitization may be reversed through degradative glutamate receptor pathways. This, however, rarely happens. Instead, cortical brain regions may serve in a top-down regulatory capacity for the maintenance or alleviation of pain. Specifically, the medial prefrontal cortex (mPFC), which plays a critical role in fear-related brain circuits, the DMN, and salience network may be the driving forces in this process. On a cellular level, the mPFC may form new neural circuits through LTP that may cause extinction of pre-existing pain pathways found within fear-related brain circuits, the DMN, and salience network. In order to promote new LTP connections between the mPFC and other key brain structures, such as the amygdala and insula, we propose a holistic rehabilitation program including cognitive behavioral therapy (CBT) and revolving around: (1) cognitive reappraisals; (2) mindfulness meditation; and (3) functional rehabilitation. Unlike current medical interventions focusing upon pain-relieving medications, we do not believe that chronic pain treatment should focus on reversing the effects of central sensitization. Instead, we propose here that it is critical to focus on non-invasive efforts to promote new neural circuits originating from the mPFC.

Neural systems mediating decision-making and response inhibition for social and nonsocial stimuli in autism.

Autism is marked by impairments in social reciprocity and communication, along with restricted, repetitive and stereotyped behaviors. Prior studies have separately investigated social processing and executive function in autism, but little is known about the brain mechanisms of cognitive control for both emotional and nonemotional stimuli. We used functional magnetic resonance imaging to identify differences in neurocircuitry between individuals with high functioning autism (HFA) and neurotypical controls during two versions of a go/no-go task: emotional (fear and happy faces) and nonemotional (English letters). During the letter task, HFA participants showed hypoactivation in the ventral prefrontal cortex. During the emotion task, happy faces elicited activation in the ventral striatum, nucleus accumbens and anterior amygdala in neurotypical, but not HFA, participants. Response inhibition for fear faces compared with happy faces recruited occipitotemporal regions in HFA, but not neurotypical, participants. In a direct contrast of emotional no-go and letter no-go blocks, HFA participants showed hyperactivation in extrastriate cortex and fusiform gyrus. Accuracy for emotional no-go trials was negatively correlated with activation in fusiform gyrus in the HFA group. These results indicate that autism is associated with abnormal processing in socioemotional brain networks, and support the theory that autism is marked by a social motivational deficit.

Abnormal cingulum bundle development in autism: a probabilistic tractography study.

There is now considerable evidence that white matter abnormalities play a role in the neurobiology of autism. Little research has been directed, however, at understanding (a) typical white matter development in autism and how this relates to neurocognitive impairments observed in the disorder. In this study we used probabilistic tractography to identify the cingulum bundle in 21 adolescents and young adults with Autism Spectrum Disorder (ASD), and 21 age- and sex-matched healthy volunteers. We investigated group differences in the relationships between age and fractional anisotropy, a putative measure of white matter integrity, within the cingulum bundle. Moreover, in a preliminary investigation, we examined the relationship between cingulum fractional anisotropy and executive functioning using the Behavior Rating Inventory of Executive Function (BRIEF). The ASD participants demonstrated significantly lower fractional anisotropy within the cingulum bundle compared to the typically developing volunteers. There was a significant group-by-age interaction such that the ASD group did not show the typical age-associated increases in fractional anisotropy observed among healthy individuals. Moreover, lower fractional anisotropy within the cingulum bundle was associated with worse BRIEF behavioral regulation index scores in the ASD group. The current findings implicate a dysregulation in cingulum bundle white matter development occurring in late adolescence and early adulthood in ASD, and suggest that greater disturbances in this trajectory are associated with executive dysfunction in ASD.

The neural circuitry mediating shifts in behavioral response and cognitive set in autism.

BACKGROUND: Recent studies have suggested that the social and cognitive impairments in autism are associated with neural processing deficits in specific brain regions. However, these studies have primarily focused on neural systems responsible for face processing and social behaviors. Although repetitive, stereotyped behaviors are a hallmark of autism, little is known about the neural mechanisms underlying these behaviors in the disorder. METHODS: We used functional magnetic resonance imaging (fMRI) to investigate the neural correlates of shifts in behavioral response and cognitive set in 18 individuals with high-functioning autism and 15 neurotypical control participants. Participants performed a target detection task specifically designed to distinguish shifts in response from shifts in cognitive set. RESULTS: Individuals with autism showed lower accuracy on response shifting trials, independent of whether those trials also required a shift in cognitive set. Compared with control subjects, participants with autism showed reduced activation in frontal, striatal, and parietal regions during these trials. In addition, within the autism group, the severity of restricted, repetitive behaviors was negatively correlated with activation in anterior cingulate and posterior parietal regions. CONCLUSIONS: These results suggest that executive deficits and, by extension, repetitive behaviors associated with autism might reflect a core dysfunction within the brain's executive circuitry.

Frontostriatal connectivity and its role in cognitive control in parent-child dyads with ADHD.

OBJECTIVE: Many studies have linked the structure and function of frontostriatal circuitry to cognitive control deficits in attention deficit hyperactivity disorder (ADHD). Few studies have examined the role of white matter tracts between these structures or the extent to which white matter tract myelination and regularity correlate in family members with the disorder. METHOD: Functional imaging maps from a go/nogo task were used to identify portions of the ventral prefrontal cortex and striatum involved in suppressing an inappropriate action (i.e., cognitive control) in 30 parent-child dyads (N=60), including 20 dyads (N=40) with ADHD and 10 dyads (N=20) without ADHD. An automated fiber-tracking algorithm was used to delineate white matter fibers adjacent to these functionally defined regions based on diffusion tensor images. Fractional anisotropy, an index of white matter tract myelination and regularity derived from diffusion tensor images, was calculated to characterize the associations between white matter tracts and function. RESULTS: Fractional anisotropy in right prefrontal fiber tracts correlated with both functional activity in the inferior frontal gyrus and caudate nucleus and performance of a go/nogo task in parent-child dyads with ADHD, even after controlling for age. Prefrontal fiber tract measures were tightly associated between ADHD parents and their children. CONCLUSIONS: Collectively, these findings support previous studies suggesting heritability of frontostriatal structures among individuals with ADHD and suggest disruption in frontostriatal white matter tracts as one possible pathway to the disorder.

ADHD- and medication-related brain activation effects in concordantly affected parent-child dyads with ADHD.

BACKGROUND: Several studies have documented fronto-striatal dysfunction in children and adolescents with attention deficit/hyperactivity disorder (ADHD) using response inhibition tasks. Our objective was to examine functional brain abnormalities among youths and adults with ADHD and to examine the relations between these neurobiological abnormalities and response to stimulant medication. METHOD: A group of concordantly diagnosed ADHD parent-child dyads was compared to a matched sample of normal parent-child dyads. In addition, ADHD dyads were administered double-blind methylphenidate and placebo in a counterbalanced fashion over two consecutive days of testing. Frontostriatal function was measured using functional magnetic resonance imaging (fMRI) during performance of a go/no-go task. RESULTS: Youths and adults with ADHD showed attenuated activity in fronto-striatal regions. In addition, adults with ADHD appeared to activate non-fronto-striatal regions more than normals. A stimulant medication trial showed that among youths, stimulant medication increased activation in fronto-striatal and cerebellar regions. In adults with ADHD, increases in activation were observed in the striatum and cerebellum, but not in prefrontal regions. CONCLUSIONS: This study extends findings of fronto-striatal dysfunction to adults with ADHD and highlights the importance of frontostriatal and frontocerebellar circuitry in this disorder, providing evidence of an endophenotype for examining the genetics of ADHD.

The interaction of emotional and cognitive neural systems in emotionally guided response inhibition.

The ability to generate appropriate responses in social situations often requires the integration of emotional information conveyed through facial expressions with ongoing cognitive processes. Neuroimaging studies have begun to address how cognitive and emotional neural systems interact, but most of these studies have used emotional oddball stimuli as distractors in order to dissociate emotional from cognitive neural systems. Therefore, the manner in which these systems interact when behavioral responses must be directly guided by the emotional content of stimuli remains elusive. Here, we used functional magnetic resonance imaging (fMRI) to investigate the neural systems involved in response inhibition for faces conveying particular emotions. Participants performed go/no-go tasks involving either letters or happy and sad faces. The fMRI results indicated that inhibiting responses to emotional faces activated inferior frontal/insular cortex, whereas response inhibition during the letter task did not strongly engage this region. In addition, distinct regions of ventral anterior cingulate were preferentially activated for sad faces in the go and no-go conditions. These findings suggest that inhibition within an emotional context recruits a distinct set of brain regions that includes areas beyond those normally activated by response inhibition tasks and that can be modulated by emotional valence.

Dissociation of neural systems mediating shifts in behavioral response and cognitive set.

The ability to generate appropriate behaviors in response to changing situations requires both the alteration of ongoing behavior and the understanding of the global rules governing stimulus categorization in a given context. Neuropsychological tests that have been developed to measure this form of cognitive flexibility, such as the Wisconsin Card Sorting Test, have reliably demonstrated that individuals with lesions in regions of the prefrontal cortex and basal ganglia have difficulty generating a cognitive set and altering rule-governed behavior. Recent neuroimaging studies have supported the role of these brain regions in the performance of response shifting and cognitive set shifting. However, the precise role of these regions in the individual components of these tasks remains a contentious issue. Here, we used event-related functional magnetic resonance imaging (fMRI) to dissociate the neural circuitry involved in the alteration of ongoing behavior and the shifting of cognitive set. Participants viewed geometric shapes as they appeared individually in rapid succession and responded with an appropriate button press based upon whether the individual shape was a predetermined target stimulus. Responses were required for each shape presented. The fMRI results indicated that response shifting specifically activated a dorsal neural circuit comprised of the dorsolateral prefrontal cortex, anterior cingulate, and intraparietal sulcus. Shifts in cognitive set were mediated by ventrolateral prefrontal cortex, anterior cingulate, and striatum. These findings suggest that the alteration of ongoing behavior and shifting of cognitive set are mediated by two distinct neural systems interconnected by the anterior cingulate.

The effects of methylphenidate on neural systems of attention in attention deficit hyperactivity disorder.

OBJECTIVE: Recent studies have suggested that attention deficit hyperactivity disorder (ADHD) is associated with abnormalities in basal ganglia and prefrontal cortical functioning. However, these studies have primarily relied upon cognitive tasks that reflect impulse control rather than attentional mechanisms. METHOD: The authors used functional magnetic resonance imaging to investigate the neural correlates of selective and divided attention in a randomized, double-blind, placebo-controlled pharmacological challenge with methylphenidate in 15 adolescents with ADHD (ages 14-17), eight adolescents with reading disorder (ages 12-17), and four adolescents with both reading disorder and ADHD (ages 14-18) who were scanned during both a methylphenidate and a placebo session. Fourteen healthy comparison subjects (ages 12-20) who were not given methylphenidate served as the primary comparison group. RESULTS: During the divided attention task, unmedicated subjects with ADHD or reading disorder recruited the left ventral basal ganglia significantly less than the healthy comparison subjects. Methylphenidate led to an increase in activation in this region but had no effect on task performance. Subjects with ADHD also recruited the middle temporal gyrus significantly less than the comparison subjects, but methylphenidate did not have a direct effect on activation in this region. CONCLUSIONS: These results suggest that ADHD is associated with abnormal processing in attentional networks, with specific dysfunction in striatal circuitry. Methylphenidate may act to normalize activity within this network.

The role of the parietal cortex in visual feature binding.

When multiple objects are simultaneously present in a scene, the visual system must properly integrate the features associated with each object. It has been proposed that this "binding problem" is solved by selective attention to the locations of the objects [Treisman, A.M. & Gelade, E. (1980) Cogn. Psychol. 12, 97-136]. If spatial attention plays a role in feature integration, it should do so primarily when object location can serve as a binding cue. Using functional MRI (fMRI), we show that regions of the parietal cortex involved in spatial attention are more engaged in feature conjunction tasks than in single feature tasks when multiple objects are shown simultaneously at different locations but not when they are shown sequentially at the same location. These findings suggest that the spatial attention network of the parietal cortex is involved in feature binding but only when spatial information is available to resolve ambiguities about the relationships between object features.