Andrew B. Dodd

Methods for identifying subject‐specific abnormalities in neuroimaging data

Algorithms that are capable of capturing subject‐specific abnormalities (SSA) in neuroimaging data have long been an area of focus for diverse neuropsychiatric conditions such as multiple sclerosis, schizophrenia, and traumatic brain injury. Several algorithms have been proposed that define SSA in patients (i.e., comparison group) relative to image intensity levels derived from healthy controls (HC) (i.e., reference group) based on extreme values. However, the assumptions underlying these approaches have not always been fully validated, and may be dependent on the statistical distributions of the transformed data. The current study evaluated variations of two commonly used techniques (“pothole” method and standardization with an independent reference group) for identifying SSA using simulated data (derived from normal, t and chi‐square distributions) and fractional anisotropy maps derived from 50 HC. Results indicated substantial group‐wise bias in the estimation of extreme data points using the pothole method, with the degree of bias being inversely related to sample size. Statistical theory was utilized to develop a distribution‐corrected z‐score (DisCo‐Z) threshold, with additional simulations demonstrating elimination of the bias and a more consistent estimation of extremes based on expected distributional properties. Data from previously published studies examining SSA in mild traumatic brain injury were then re‐analyzed using the DisCo‐Z method, with results confirming the evidence of group‐wise bias. We conclude that the benefits of identifying SSA in neuropsychiatric research are substantial, but that proposed SSA approaches require careful implementation under the different distributional properties that characterize neuroimaging data. Hum Brain Mapp 35:5457–5470, 2014.

Does incentive-elicited nucleus accumbens activation differ by substance of abuse? An examination with adolescents

Highlights • We measure brain activation during anticipation of reward and loss in adolescents.• We compare incentive responses in six groups formed based on substance use patterns.• No activation differences emerge between the cannabis-only group and the other groups.• Tobacco-only users have less reward response than polysubstance and alcohol-only users.• Tobacco-only users show decreased reward activation compared to the control group.

A Longitudinal Assessment of Structural and Chemical Alterations in Mixed Martial Arts Fighters.

Growing evidence suggests that temporally proximal acute concussions and repetitive subconcussive head injuries may lead to long-term neurological deficits. However, the underlying mechanisms of injury and their relative time-scales are not well documented in human injury models. The current study therefore investigated whether biomarkers of brain chemistry (magnetic resonance [MR] spectroscopy: N-acetylaspartate [NAA], combined glutamate and glutamine [Glx], total creatine [Cre], choline compounds [Cho], and myo-inositol [mI]) and structure (cortical thickness, white matter [WM]/subcortical volume) differed between mixed martial artists (MMA; n = 13) and matched healthy controls (HC) without a history of contact sport participation (HC; n = 14). A subset of participants (MMA = 9; HC = 10) returned for follow-up visits, with MMA (n = 3) with clinician-documented acute concussions also scanned serially. As expected, MMA self-reported a higher incidence of previous concussions and significantly more cognitive symptoms during prior concussion recovery. Fighters also exhibited reduced memory and processing speed relative to controls on neuropsychological testing coupled with cortical thinning in the left posterior cingulate gyrus and right occipital cortex at baseline assessment. Over a 1-year follow-up period, MMA experienced a significant decrease in both WM volume and NAA concentration, as well as relative thinning in the left middle and superior frontal gyri. These longitudinal changes did not correlate with self-reported metrics of injury (i.e., fight diary). In contrast, HC did not exhibit significant longitudinal changes over a 4-month follow-up period (p > 0.05). Collectively, current results provide preliminary evidence of progressive changes in brain chemistry and structure over a relatively short time period in individuals with high exposure to repetitive head hits. These findings require replication in independent samples.

The efficacy of attention bias modification therapy in cocaine use disorders.

ABSTRACT Background: Attentional bias (i.e., differences in reaction time between drug and neutral cues) has been associated with a variety of drug-use behaviors (e.g., craving, abstinence). Reduction of bias may ultimately reduce use. Objective: The current study examined whether attentional bias modification therapy (ABMT) reduced the frequency of drug use behaviors in individuals with cocaine use disorder (CUD). Method: Participants (n = 37) were randomly assigned to ABMT or control therapy, which systematically varied how frequently probes replaced neutral (ABMT = 100%; control therapy = 50%) relative to drug stimuli. Each intervention included 5 training sessions comprising a total of 2640 trials over 4 weeks. Clinical assessments occurred at baseline, post-intervention, 2 weeks and 3 months posttreatment. Results: There were no baseline differences between groups on drug-use behaviors or other clinical measures. Contrary to predictions, both groups exhibited slower rather than faster reaction times for cocaine stimuli (p = 0.005) at baseline, with no relationship between bias and baseline measures of drug-use behavior. Conclusions: ABMT was not more effective than our control therapy at reducing attentional bias, reducing craving or changing other drug use behaviors. Current results suggest additional replication studies are needed to assess ABMT’s efficacy in reducing drug-use behaviors in CUD.

An fMRI study of multimodal selective attention in schizophrenia

BACKGROUND Studies have produced conflicting evidence regarding whether cognitive control deficits in patients with schizophrenia result from dysfunction within the cognitive control network (CCN; top-down) and/or unisensory cortex (bottom-up). AIMS To investigate CCN and sensory cortex involvement during multisensory cognitive control in patients with schizophrenia. METHOD Patients with schizophrenia and healthy controls underwent functional magnetic resonance imaging while performing a multisensory Stroop task involving auditory and visual distracters. RESULTS Patients with schizophrenia exhibited an overall pattern of response slowing, and these behavioural deficits were associated with a pattern of patient hyperactivation within auditory, sensorimotor and posterior parietal cortex. In contrast, there were no group differences in functional activation within prefrontal nodes of the CCN, with small effect sizes observed (incongruent-congruent trials). Patients with schizophrenia also failed to upregulate auditory cortex with concomitant increased attentional demands. CONCLUSIONS Results suggest a prominent role for dysfunction within auditory, sensorimotor and parietal areas relative to prefrontal CCN nodes during multisensory cognitive control.

Look Hear! The Prefrontal Cortex is Stratified by Modality of Sensory Input During Multisensory Cognitive Control

&NA; Parsing multisensory information from a complex external environment is a fundamental skill for all organisms. However, different organizational schemes currently exist for how multisensory information is processed in human (supramodal; organized by cognitive demands) versus primate (organized by modality/cognitive demands) lateral prefrontal cortex (LPFC). Functional magnetic resonance imaging results from a large cohort of healthy controls (N = 64; Experiment 1) revealed a rostral‐caudal stratification of LPFC for auditory versus visual attention during an audio‐visual Stroop task. The stratification existed in spite of behavioral and functional evidence of increased interference from visual distractors. Increased functional connectivity was also observed between rostral LPFC and auditory cortex across independent samples (Experiments 2 and 3) and multiple methodologies. In contrast, the caudal LPFC was preferentially activated during visual attention but functioned in a supramodal capacity for resolving multisensory conflict. The caudal LPFC also did not exhibit increased connectivity with visual cortices. Collectively, these findings closely mirror previous nonhuman primate studies suggesting that visual attention relies on flexible use of a supramodal cognitive control network in caudal LPFC whereas rostral LPFC is specialized for directing attention to auditory inputs (i.e., human auditory fields).

A prospective microstructure imaging study in mixed-martial artists using geometric measures and diffusion tensor imaging: methods and findings

Although diffusion magnetic resonance imaging (dMRI) has been widely used to characterize the effects of repetitive mild traumatic brain injury (rmTBI), to date no studies have investigated how novel geometric models of microstructure relate to more typical diffusion tensor imaging (DTI) sequences. Moreover, few studies have evaluated the sensitivity of different registration pipelines (non-linear, linear and tract-based spatial statistics) for detecting dMRI abnormalities in clinical populations. Results from single-subject analyses in healthy controls (HC) indicated a strong negative relationship between fractional anisotropy (FA) and orientation dispersion index (ODI) in both white and gray matter. Equally important, only moderate relationships existed between all other estimates of free/intracellular water volume fractions and more traditional DTI metrics (FA, mean, axial and radial diffusivity). These findings suggest that geometric measures provide differential information about the cellular microstructure relative to traditional DTI measures. Results also suggest greater sensitivity for non-linear registration pipelines that maximize the anatomical information available in T1-weighted images. Clinically, rmTBI resulted in a pattern of decreased FA and increased ODI, largely overlapping in space, in conjunction with increased intracellular and free water fractions, highlighting the potential role of edema following repeated head trauma. In summary, current results suggest that geometric models of diffusion can provide relatively unique information regarding potential mechanisms of pathology that contribute to long-term neurological damage.

Proactive response inhibition abnormalities in the sensorimotor cortex of patients with schizophrenia.

BACKGROUND Previous studies of response inhibition in patients with schizophrenia have focused on reactive inhibition tasks (e.g., stop-signal, go/no-go), primarily observing lateral prefrontal cortex abnormalities. However, recent studies suggest that purposeful and sustained (i.e., proactive) inhibition may also be affected in these patients. METHODS Patients with chronic schizophrenia and healthy controls underwent fMRI while inhibiting motor responses during multisensory (audiovisual) stimulation. Resting state data were also collected. RESULTS We included 37 patients with schizophrenia and 37 healthy controls in our study. Both controls and patients with schizophrenia successfully inhibited the majority of overt motor responses. Functional results indicated basic inhibitory failure in the lateral premotor and sensorimotor cortex, with opposing patterns of positive (schizophrenia) versus negative (control) activation. Abnormal activity was associated with independently assessed signs of psychomotor retardation. Patients with schizophrenia also exhibited unique activation of the pre-supplementary motor area (pre-SMA)/SMA and precuneus relative to baseline as well as a failure to deactivate anterior nodes of the default mode network. Independent resting-state connectivity analysis indicated reduced connectivity between anterior (task results) and posterior regions of the sensorimotor cortex for patients as well as abnormal connectivity between other regions (cerebellum, thalamus, posterior cingulate gyrus and visual cortex). LIMITATIONS Aside from rates of false-positive responses, true proactive response inhibition tasks do not provide behavioural metrics that can be independently used to quantify task performance. CONCLUSION Our results suggest that basic cortico-cortico and intracortical connections between the sensorimotor cortex and adjoining regions are impaired in patients with schizophrenia and that these impaired connections contribute to inhibitory failures (i.e., a positive rather than negative hemodynamic response).

A functional magnetic resonance imaging study of cognitive control and neurosensory deficits in mild traumatic brain injury.

Mild traumatic brain injury patients (mTBI) frequently report symptoms of increased distractability and sensory disturbances during mutisensory stimulation. These common post‐concussive symptoms could putatively result from dysfunction within the cognitive control network (CCN; top‐down) or from unisensory cortex (bottom‐up) itself. Functional magnetic resonance imaging (fMRI) and high‐resolution structural data were therefore prospectively collected during a multisensory (audio‐visual) cognitive control task from 46 mTBI patients within 3 weeks of injury and 46 matched healthy controls (HC), with a subset of participants returning at 4 months. Multisensory stimuli were presented at two frequencies to manipulate cognitive and perceptual load. Patients self‐reported more cognitive, emotional, somatic, vestibular and visual symptoms relative to HC, which improved, but did not entirely resolve, over the 4 month follow‐up period. There were no group differences in behavior or functional activation during cognitive control (incongruent – congruent trials). In contrast, patients exhibited abnormal activation within different regions of visual cortex that depended on whether attention was focused on auditory or visual information streams. Patients also exhibited increased activation within bilateral inferior parietal lobules during higher cognitive/perceptual loads, suggesting a compensatory mechanism to achieve similar levels of behavioral performance. Functional abnormalities within the visual cortex and inferior parietal lobules were only partially resolved at 4 months post‐injury, suggesting that neural abnormalities may take longer to resolve than behavioral measures used in most clinical settings. In summary, current results indicate that abnormalities within unisensory cortex (particularly visual areas) following mTBI, which likely contribute to deficits commonly reported during multisensory stimulation. Hum Brain Mapp 36:4394–4406, 2015.

Hemodynamic response function abnormalities in schizophrenia during a multisensory detection task

Functional magnetic resonance imaging (fMRI) of the blood oxygen level dependent (BOLD) response has commonly been used to investigate the neuropathology underlying cognitive and sensory deficits in patients with schizophrenia (SP) by examining the positive phase of the BOLD response, assuming a fixed shape for the hemodynamic response function (HRF). However, the individual phases (positive and post‐stimulus undershoot (PSU)) of the HRF may be differentially affected by a variety of underlying pathologies. The current experiment used a multisensory detection task with a rapid event‐related fMRI paradigm to investigate both the positive and PSU phases of the HRF in SP and healthy controls (HC). Behavioral results indicated no significant group differences during task performance. Analyses that examined the shape of the HRF indicated two distinct group differences. First, SP exhibited a reduced and/or prolonged PSU following normal task‐related positive BOLD activation in secondary auditory and visual sensory areas relative to HC. Second, SP did not show task‐induced deactivation in the anterior node of the default‐mode network (aDMN) relative to HC. In contrast, when performing traditional analyses that focus on the positive phase, there were no group differences. Interestingly, the magnitude of the PSU in secondary auditory and visual areas was positively associated with the magnitude of task‐induced deactivation within the aDMN, suggesting a possible common neural mechanism underlying both of these abnormalities (failure in neural inhibition). Results are consistent with recent views that separate neural processes underlie the two phases of the HRF and that they are differentially affected in SP. Hum Brain Mapp 37:745–755, 2016.