Michael L. Rohan

Preliminary Evidence for White Matter Tract Abnormalities in Young Adults Exposed to Parental Verbal Abuse

BACKGROUND Psychiatric sequelae of exposure to parental verbal abuse (PVA) appear to be comparable with that of nonfamilial sexual abuse and witnessing domestic violence. Diffusion tensor imaging (DTI) was used to ascertain whether PVA was associated with abnormalities in white matter (WM) tract integrity. METHODS 1271 healthy young adults were screened for exposure to childhood adversity. Diffusion tensor imaging was collected on 16 unmedicated subjects with history of high-level exposure to PVA but no other form of maltreatment (4 male/12 female subjects, mean age 21.9 +/- 2.4 years) and 16 healthy control subjects (5 male/11 female subjects, 21.0 +/- 1.6 years). Group differences in fractional anisotropy (FA), covaried by parental education and income, were assessed using tract-based spatial statistics (TBSS). RESULTS Three WM tract regions had significantly reduced FA: 1) arcuate fasciculus in left superior temporal gyrus, 2) cingulum bundle by the posterior tail of the left hippocampus, and 3) the left body of the fornix. Fractional anisotropy in these areas was strongly associated with average PVA scores (r(s) = -.701, -.801, -.524, respectively) and levels of maternal verbal abuse. Across groups, FA in region 1 correlated with verbal IQ and verbal comprehension index. Fractional anisotropy in region 2 was inversely associated with ratings of depression, dissociation, and limbic irritability. Fractional anisotropy in region 3 was inversely correlated with ratings of somatization and anxiety. CONCLUSIONS Exposure to PVA may be associated with alteration in the integrity of neural pathways with implications for language development and psychopathology.

Antidepressant-like effects of cranial stimulation within a low-energy magnetic field in rats

BACKGROUND Evidence suggests that a novel type of magnetic resonance imaging (MRI) scan called echo planar magnetic resonance spectroscopic imaging (EP-MRSI) has mood-elevating actions in humans during the depressive phases of bipolar disorder. We examined whether a low-energy component of EP-MRSI (low-field magnetic stimulation [LFMS]) has antidepressant-like, locomotor-stimulating, or amnestic effects in rats. METHODS We examined the effects of LFMS on immobility in the forced swim test (FST) and activity within an open field in separate groups of rats. After exposure to forced swimming, rats received LFMS (three 20-min sessions at 1.5 G/cm and .75 V/m) before behavioral testing. We also examined the effects of LFMS on fear conditioning (FC), a learning paradigm that also involves exposure to stressful conditions. RESULTS Low-field magnetic stimulation reduced immobility in the FST, an antidepressant-like effect qualitatively similar to that of standard antidepressants. Low-field magnetic stimulation did not alter locomotor activity or FC. CONCLUSIONS Low-field magnetic stimulation has antidepressant-like effects in rats that seem unrelated to locomotor-activating or amnestic effects. These findings raise the possibility that electromagnetic fields can affect the brain biology and might have physiologic consequences that offer novel approaches to therapy for psychiatric disorders. These same consequences might render MRI-based scans more invasive than previously appreciated.

Rapid mood-elevating effects of low field magnetic stimulation in depression.

BACKGROUND We previously reported rapid mood elevation following an experimental magnetic resonance imaging procedure in depressed patients with bipolar disorder (BPD). This prompted the design, construction, and testing of a portable electromagnetic device that reproduces only the rapidly oscillating (1 kHz, <1 V/m) electromagnetic field of the experimental procedure, called low field magnetic stimulation (LFMS). METHODS We used a randomized, double blind, sham controlled treatment protocol to study the effects of LFMS in a large group of stably medicated, depressed patients with either BPD (n = 41) or major depressive disorder (n = 22). Subjects received a single, 20-minute treatment. Change in mood was assessed immediately afterward using a visual analog scale (VAS), the 17-item Hamilton Depression Rating Scale (HDRS-17), and the Positive and Negative Affect Schedule scales. RESULTS Substantial improvement (>10% of baseline) in mood was observed following LFMS treatment relative to sham treatment for both diagnostic subgroups for our primary outcomes, the VAS and the HDRS-17. These differences were not statistically significant in primary analyses stratifying by diagnosis but were significant in secondary analyses combining data across the two diagnostic groups (p = .01 VAS, p = .02 HDRS-17). Rapid improvement in mood was also observed using the Positive and Negative Affect Schedule scales as secondary measures (positive affect scale p = .02 BPD, p = .002 combined group). A finite element method calculation indicates a broad penetration of the LFMS electric field throughout the cerebral cortex. CONCLUSIONS Low field magnetic stimulation may produce rapid changes in mood using a previously unexplored range of electromagnetic fields.

Brain T2 relaxation times correlate with regional cerebral blood volume.

We previously reported cerebellar and putaminal transverse relaxation time (T2) differences in children with ADHD and in adults with childhood trauma. As brain T2 can be altered by deoxyhemoglobin concentration ([dHb]) and because [dHb] is proportional to regional cerebral blood volume (rCBV), at steady state we attributed those differences to rCBV changes. Studies in other species have established a correlation between T2 and rCBV; however this has yet to be demonstrated in human brain. Echo planar imaging (EPI) T2 relaxometry and dynamic susceptibility-contrast (DSC) MRI were used to measure T2 and rCBV in 11 healthy adults. Significant T2-rCBV correlations were observed in both cerebellar vermis and putamen (r=0.759,p=0.007;r=0.782,p=0.004, respectively). These correlations predict 9±3% and 10±3% rCBV changes, respectively, for each 1-msec change in T2. Consequently, brain T2 measurements may be useful for estimating steady-state rCBV.

Stimulation by Time-varying Magnetic Fields

In this review, we present work in progress at Advanced NMR Systems on the stimulation of nerves by time-changing magnetic fields (Wld t ) . The W l d t effects in MRI are caused by the interaction of the time-changing gradient fields with the nerves and muscles of the human body. The mechanism for these effects is that a changing magnetic flux through a conductive surface causes electric fields or voltages to be induced in that conductor; in MRI, the gradient fields have a changing flux through the body of the patient, which results in voltages that may interact with nerves or muscles and cause stimulation. Thresholds for the occurrence of these effects are under investigation. Efforts in the assessment of dBldr effects in MRI are twofold: calculations have been done to model the system using changing, but spatially uniform magnetic fields using an ellipsoidal and homogeneously conductive model for the body; laboratory efforts are under way to find the stimulation thresholds in canines using scaled-down gradient coil systems. This review presents a description of the gradient fields used in MRI imaging for better inclusion in predictions of stimulation, introducing a simple parametrized model for those fields. Additionally, statistics on high speed gradient scanning at Advanced NMR Systems over the last six years are presented to add to the existing information. The analysis methods used to date are based on plane wave magnetic fields such as those produced by transmission lines; the fields used in MRI have several nonzero field components, each of which varies spatially. Furthermore, MRI uses two types of gradient coils (axial and transverse) that have different field distributions and require separate consideration. An additional concern is the geometric considerations that a spatially varying field requires; such a field cannot be characterized by only a peak value, but must be at least scaled by a volumetric form factor. A model for the W l d t situation for a transverse coil is shown in FIGURE 1.

Differential effects of childhood neglect and abuse during sensitive exposure periods on male and female hippocampus

ABSTRACT The hippocampus is a highly stress susceptible structure and hippocampal abnormalities have been reported in a host of psychiatric disorders including major depression and post‐traumatic stress disorder (PTSD). The hippocampus appears to be particularly susceptible to early life stress with a graded reduction in volume based on number of types (multiplicity) or severity of maltreatment. We assessed whether the most important predictors of adult hippocampal volume were multiplicity, severity or duration of exposure or timing of maltreatment during developmental sensitive periods. 3T MRIs were collected on 336 unmedicated, right‐handed subjects (132M/204F, 18–25 years). Exposure to broad categories of abuse and neglect during each year of childhood were assessed using the Maltreatment and Abuse Chronology of Exposure scale and evaluated using artificial intelligence and predictive analytics. Male hippocampal volume was predicted by neglect, but not abuse, up through 7 years of age. Female hippocampal volume was predicted by abuse, but not neglect, at 10, 11, 15 and 16 years. Exposure at peak age had greater predictive importance than multiplicity, severity or duration. There were also marked gender differences in subfields and portions (head, body or tail) affected by exposure. History and symptoms of major depression, PTSD or anxiety disorders were not predictive of hippocampal volume once maltreatment was accounted for. Neglect appears to foster inadequate hippocampal development in males while abuse appears to produce a stress‐related deficit in females. Studies assessing hippocampal volume in psychiatric disorders need to control for the gender‐specific effects of abuse and neglect. HighlightsHippocampal volume in males was predicted by neglect during first seven years.Hippocampal volume in females was predicted by abuse, particular at ages 10 and 11.Neglect at peak age correlated most strongly with volume of the CA1 in males.Abuse at peak age correlated most strongly with volume of CA3 in females.Abuse had greater effects on shape of female hippocampal head and tail than body.

College Binge Drinking Associated with Decreased Frontal Activation to Negative Emotional Distractors during Inhibitory Control

The transition to college is associated with an increase in heavy episodic alcohol use, or binge drinking, during a time when the prefrontal cortex and prefrontal-limbic circuitry continue to mature. Traits associated with this immaturity, including impulsivity in emotional contexts, may contribute to risky and heavy episodic alcohol consumption. The current study used blood oxygen level dependent (BOLD) multiband functional magnetic resonance imaging (fMRI) to assess brain activation during a task that required participants to ignore background images with positive, negative, or neutral emotional valence while performing an inhibitory control task (Go-NoGo). Subjects were 23 college freshmen (seven male, 18–20 years) who engaged in a range of drinking behavior (past 3 months’ binge episodes range = 0–19, mean = 4.6, total drinks consumed range = 0–104, mean = 32.0). Brain activation on inhibitory trials (NoGo) was contrasted between negative and neutral conditions and between positive and neutral conditions using non-parametric testing (5000 permutations) and cluster-based thresholding (z = 2.3), p ≤ 0.05 corrected. Results showed that a higher recent incidence of binge drinking was significantly associated with decreased activation of dorsolateral prefrontal cortex (DLPFC), dorsomedial prefrontal cortex (DMPFC), and anterior cingulate cortex (ACC), brain regions strongly implicated in executive functioning, during negative relative to neutral inhibitory trials. No significant associations between binge drinking and brain activation were observed for positive relative to neutral images. While task performance was not significantly associated with binge drinking in this sample, subjects with heavier recent binge drinking showed decreased recruitment of executive control regions under negative versus neutral distractor conditions. These findings suggest that in young adults with heavier recent binge drinking, processing of negative emotional images interferes more with inhibitory control neurocircuitry than in young adults who do not binge drink often. This pattern of altered frontal lobe activation associated with binge drinking may serve as an early marker of risk for future self-regulation deficits that could lead to problematic alcohol use. These findings underscore the importance of understanding the impact of emotion on cognitive control and associated brain functioning in binge drinking behaviors among young adults.

Cocaine-conditioned odor cues without chronic exposure: Implications for the development of addiction vulnerability

Adolescents are highly vulnerable to addiction and are four times more likely to become addicted at first exposure than at any other age. The dopamine D1 receptor, which is typically overexpressed in the normal adolescent prefrontal cortex, is involved in drug cue responses and is associated with relapse in animal models. In human drug addicts, imaging methods have detected increased activation in response to drug cues in reward- and habit-associated brain regions. These same methods can be applied more quantitatively to rodent models. Here, changes in neuronal activation in response to cocaine-conditioned cues were observed using functional magnetic resonance imaging in juvenile rats that were made to over-express either D1 receptors or green fluorescent protein by viral-mediated transduction. Reduced activation was observed in the amygdala and dopamine cell body regions in the low cue-preferring/control juvenile rats in response to cocaine cues. In contrast, increased activation was observed in the dorsal striatum, nucleus accumbens, prefrontal cortex, and dopamine cell bodies in high cue-preferring/D1 juveniles. The increase in cue salience that is mediated by increased D1 receptor density, rather than excessive cocaine experience, appears to underlie the transition from aversion to reward in cue-induced neural response and may form the basis for habit-forming vulnerability.

Adolescent Hippocampal and Prefrontal Brain Activation during Performance of the Virtual Morris Water Task

The frontal cortex undergoes substantial structural and functional changes during adolescence and significant developmental changes also occur in the hippocampus. Both of these regions are notably vulnerable to alcohol and other substance use, which is typically initiated during adolescence. Identifying measures of brain function during adolescence, particularly before initiation of drug or alcohol use, is critical to understanding how such behaviors may affect brain development, especially in these vulnerable brain regions. While there is a substantial developmental literature on adolescent working memory, less is known about spatial memory. Thus, a virtual Morris water task (vMWT) was applied to probe function of the adolescent hippocampus. Multiband blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) data were acquired at 3T during task performance. Participants included 32 healthy, alcohol- and drug-naïve adolescents, 13–14 years old, examined at baseline of a 3-year longitudinal MRI study. Significantly greater BOLD activation was observed in the hippocampus and surrounding areas, and in prefrontal regions involved in executive function, during retrieval relative to motor performance. In contrast, significantly greater BOLD activation was observed in components of the default mode network, including frontal medial cortex, during the motor condition (when task demands were minimal) relative to the retrieval condition. Worse performance (longer path length) during retrieval was associated with greater activation of angular gyrus/supramarginal gyrus, whereas worse performance (longer path length/latency) during motor control was associated with less activation of frontal pole. Furthermore, while latency (time to complete task) was greater in females than in males, there were no sex differences in path length (accuracy), suggesting that females required more time to navigate the virtual environment, but did so as effectively as males. These findings demonstrate that performance of the vMWT elicits hippocampal and prefrontal activation patterns in early adolescence, similar to activation observed during spatial memory retrieval in adults. Given that this task is sensitive to hippocampal function, and that the adolescent hippocampus is notably vulnerable to the effects of alcohol and other substances, data acquired using this task during healthy adolescent development may provide a framework for understanding neurobiological impact of later initiation of use.