Potential sensitive period effects of maltreatment on amygdala, hippocampal and cortical response to threat.

Childhood maltreatment is a leading risk factor for psychopathology, though it is unclear why some develop risk averse disorders, such as anxiety and depression, and others risk-taking disorders including substance abuse. A critical question is whether the consequences of maltreatment depend on the number of different types of maltreatment experienced at any time during childhood or whether there are sensitive periods when exposure to particular types of maltreatment at specific ages exert maximal effects. Retrospective information on severity of exposure to ten types of maltreatment during each year of childhood was collected using the Maltreatment and Abuse Chronology of Exposure scale. Artificial Intelligence predictive analytics were used to delineate the most important type/time risk factors. BOLD activation fMRI response to threatening versus neutral facial images was assessed in key components of the threat detection system (i.e., amygdala, hippocampus, anterior cingulate, inferior frontal gyrus and ventromedial and dorsomedial prefrontal cortices) in 202 healthy, unmedicated, participants (84 M/118 F, 23.2 ± 1.7 years old). Emotional maltreatment during teenage years was associated with hyperactive response to threat whereas early childhood exposure, primarily to witnessing violence and peer physical bullying, was associated with an opposite pattern of greater activation to neutral than fearful faces in all regions. These findings strongly suggest that corticolimbic regions have two different sensitive period windows of enhanced plasticity when maltreatment can exert opposite effects on function. Maltreatment needs to be viewed from a developmental perspective in order to fully comprehend its enduring neurobiological and clinical consequences.

The effects of childhood maltreatment on brain structure, function and connectivity.

Maltreatment-related childhood adversity is the leading preventable risk factor for mental illness and substance abuse. Although the association between maltreatment and psychopathology is compelling, there is a pressing need to understand how maltreatment increases the risk of psychiatric disorders. Emerging evidence suggests that maltreatment alters trajectories of brain development to affect sensory systems, network architecture and circuits involved in threat detection, emotional regulation and reward anticipation. This Review explores whether these alterations reflect toxic effects of early-life stress or potentially adaptive modifications, the relationship between psychopathology and brain changes, and the distinction between resilience, susceptibility and compensation.

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

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.

Childhood maltreatment is associated with alteration in global network fiber-tract architecture independent of history of depression and anxiety.

Childhood maltreatment is a major risk factor for psychopathology. It is also associated with alterations in the network architecture of the brain, which we hypothesized may play a significant role in the development of psychopathology. In this study, we analyzed the global network architecture of physically healthy unmedicated 18-25 year old subjects (n=262) using diffusion tensor imaging (DTI) MRI and tractography. Anatomical networks were constructed from fiber streams interconnecting 90 cortical or subcortical regions for subjects with no-to-low (n=122) versus moderate-to-high (n=140) exposure to maltreatment. Graph theory analysis revealed lower degree, strength, global efficiency, and maximum Laplacian spectra, higher pathlength, small-worldness and Laplacian skewness, and less deviation from artificial networks in subjects with moderate-to-high exposure to maltreatment. On balance, local clustering was similar in both groups, but the different clusters were more strongly interconnected in the no-to-low exposure group. History of major depression, anxiety and attention deficit hyperactivity disorder did not have a significant impact on global network measures over and above the effect of maltreatment. Maltreatment is an important factor that needs to be taken into account in studies examining the relationship between network differences and psychopathology.

Childhood maltreatment is associated with reduced volume in the hippocampal subfields CA3, dentate gyrus, and subiculum.

Childhood maltreatment or abuse is a major risk factor for mood, anxiety, substance abuse, psychotic, and personality disorders, and it is associated with reduced adult hippocampal volume, particularly on the left side. Translational studies show that the key consequences of stress exposure on the hippocampus are suppression of neurogenesis in the dentate gyrus (DG) and dendritic remodeling in the cornu ammonis (CA), particularly the CA3 subfield. The hypothesis that maltreatment is associated with volume reductions in 3-T MRI subfields containing the DG and CA3 was assessed and made practical by newly released automatic segmentation routines for FreeSurfer. The sample consisted of 193 unmedicated right-handed subjects (38% male, 21.9 ± 2.1 y of age) selected from the community. Maltreatment was quantified using the Adverse Childhood Experience study and Childhood Trauma Questionnaire scores. The strongest associations between maltreatment and volume were observed in the left CA2-CA3 and CA4-DG subfields, and were not mediated by histories of major depression or posttraumatic stress disorder. Comparing subjects with high vs. low scores on the Childhood Trauma Questionnaire and Adverse Childhood Experience study showed an average volume reduction of 6.3% and 6.1% in the left CA2-CA3 and CA4-DG, respectively. Volume reductions in the CA1 and fimbria were 44% and 60% smaller than in the CA2-CA3. Interestingly, maltreatment was associated with 4.2% and 4.3% reductions in the left presubiculum and subiculum, respectively. These findings support the hypothesis that exposure to early stress in humans, as in other animals, affects hippocampal subfield development.

Sensitive periods of amygdala development: the role of maltreatment in preadolescence.

The amygdala is vulnerable to stress-dependent disruptions in neural development. Animal models have shown that stress increases dendritic arborization leading to larger amygdala volumes. Human studies of early stress and amygdala volume, however, remain inconclusive. This study compared amygdala volume in adults with childhood maltreatment to that in healthy controls. Eighteen participants from a longitudinal cohort and 33 cross-sectional controls (17 M/34 F, 25.5±3.1 years) completed a structural magnetic resonance imagining scan and the Maltreatment and Abuse Chronology of Exposure scale. Random forest regression with conditional trees was used to assess relative importance of exposure to adversity at each age on amygdala, thalamic or caudate volume. Severity of exposure to adversity across age accounted for 27% of the variance in right amygdala volume. Peak sensitivity occurred at 10-11 years of age, and importance of exposure at this time was highly significant based on permutation tests (p=0.003). The regression model showed that exposure during this sensitive period resulted in steep dose-response function with maximal response to even modest levels of exposure. Subjects in the highest exposure quartile (MACE-11, range=11-54) had a 9.1% greater right amygdala volume than subjects in the lowest exposure quartile (MACE-11, ≤3.5). No associations emerged between age of exposure and volume of the left amygdala or bilateral caudate or thalamus. Severity of adversity experienced at age 10-11 contributed to larger right but not left amygdala volume in adulthood. Results provide preliminary evidence that the amygdala may have a developmental sensitive period in preadolescence.

Sex and sensitive period differences in potential effects of maltreatment on axial versus radial diffusivity in the corpus callosum.

Corpus callosum (CC) abnormalities have been observed in several psychiatric disorders. Maltreatment has also been associated with marked differences in CC anatomy and microstructure, though rarely controlled for in psychiatric neuroimaging studies. The aim of this study was to identify type and timing of maltreatment associated with alterations in CC microstructure and to ascertain if they differ by sex. T1 and diffusion-weighted MRIs were obtained from 345 (135 M/210 F) healthy 18-25-year-olds. The Maltreatment and Abuse Chronology of Exposure scale provided retrospective data on exposure to ten types of maltreatment across each year of childhood. AI predictive analytics were used to identify the most significant type and time risk factors. The most striking maltreatment-associated alterations in males were in axial diffusivity and were most specifically associated with exposure to emotional abuse or neglect during segment-specific sensitive periods. In contrast, maltreatment was associated with marked alteration in radial diffusivity and fractional anisotropy in females and was most specifically associated with early physical neglect during one common sensitive period involving all segments except the splenium. Overall sex differences, controlling for maltreatment, brain size, and sociodemographic factors were limited to the genu with greater fractional anisotropy in males and radial diffusivity in females. These findings suggest that maltreatment may target myelinization in females and axonal development in males and that these sex differences need to be taken into account in studies seeking to delineate the contribution of CC abnormalities and interhemispheric communication to psychiatric disorders.

Individual Differences in Hemispheric Emotional Valence by Computerized Test Correlate with Lateralized Differences in Nucleus Accumbens, Hippocampal and Amygdala Volumes.

Purpose: Conventional theories of hemispheric emotional valence (HEV) postulate fixed hemispheric differences in emotional processing. Schiffer's dual brain psychology proposes that there are prominent individual differences with a substantial subset showing a reversed laterality pattern. He further proposed that hemispheric differences were more akin to differences in personality than in emotional processing. This theory is supported by findings that unilateral treatments, such as transcranial magnetic stimulation, are effective if they accurately target individual differences in laterality. The aim of this paper was to assess if a computer test of hemispheric emotional valence (CTHEV) could effectively identify individual differences in HEV and to ascertain if these individual differences were associated with underlying differences in brain structure and connectivity. Patients and Methods: The CTHEV was administered to 50 (18 male/32 female) right-handed participants, aged 18-19 years, enrolled in a study assessing the neurobiological effects of childhood maltreatment. Based on a literature review, we determined whether CTHEV correlated with lateralized volumes of the nucleus accumbens, amygdala, hippocampus, and subgenual anterior cingulate as well as volume of the corpus callosum. Results: CTHEV scores correlated with laterality indices of the nucleus accumbens (p = 0.00016), amygdala (p = 0.0138) and hippocampus (p = 0.031). A positive left hemispheric valence was associated with a larger left-sided nucleus accumbens and hippocampus and a smaller left amygdala. We identified four eigenvector network centrality DTI measures that predict CTHEV, most notably the left amygdala, and found that CTHEV results correlated with total and segment-specific corpus callosal volumes. Conclusion: Individual differences in HEV can be readily assessed by computer test and correlate with differences in brain structure and connectivity that could provide a mechanistic understanding. These findings provide further support for a revised understanding of HEV and provide a tool that could be used to guide lateralized brain treatments.

Harsh corporal punishment is associated with increased T2 relaxation time in dopamine-rich regions.

Harsh corporal punishment (HCP) was defined as frequent parental administration of corporal punishment (CP) for discipline, with occasional use of objects such as straps, or paddles. CP is linked to increased risk for depression and substance abuse. We examine whether long-term exposure to HCP acts as sub-traumatic stressor that contributes to brain alterations, particularly in dopaminergic pathways, which may mediate their increased vulnerability to drug and alcohol abuse. Nineteen young adults who experienced early HCP but no other forms of maltreatment and twenty-three comparable controls were studied. T2 relaxation time (T2-RT) measurements were performed with an echo planar imaging TE stepping technique and T2 maps were calculated and analyzed voxel-by-voxel to locate regional T2-RT differences between groups. Previous studies indicated that T2-RT provides an indirect index of resting cerebral blood volume. Region of interest (ROI) analyses were also conducted in caudate, putamen, nucleus accumbens, anterior cingulate cortex, dorsolateral prefrontal cortex, thalamus, globus pallidus and cerebellar hemispheres. Voxel-based relaxometry showed that HCP was associated with increased T2-RT in right caudate and putamen. ROI analyses also revealed increased T2-RT in dorsolateral prefrontal cortex, substantia nigra, thalamus and accumbens but not globus pallidus or cerebellum. There were significant associations between T2-RT measures in dopamine target regions and use of drugs and alcohol, and memory performance. Alteration in the paramagnetic or hemodynamic properties of dopaminergic cell body and projection regions were observed in subjects with HCP, and these findings may relate to their increased risk for drug and alcohol abuse.

Cerebellar lingula size and experiential risk factors associated with high levels of alcohol and drug use in young adults.

Previous studies have reported cerebellar abnormalities or static ataxia associated with risk for chronic use of alcohol and drugs. Adverse childhood experience is another strong risk factor for later substance abuse. We therefore sought to ascertain the relationship between morphological phenotypes of the lingula (lobule I) of the anterior cerebellar vermis, and exposure to emotional (EM) versus physical (PM) maltreatment, on the degree of ongoing alcohol or drug use. The study design consisted of a cross-sectional in vivo neuroimaging study, utilizing retrospective assessment of maltreatment history and self-reports of alcohol and substance use. Study participants were 153 subjects (54 M/99F, 21.9 +/- 2.2 years) selected for imaging from a database of 1,402 community participants 18-25 years of age, who completed a detailed online screening instrument and met rigorous inclusion/exclusion criteria. Subjects were exposed to only physical abuse or harsh corporal punishment (HCP; PM group, n = 37) and parental verbal abuse and/or witnessing domestic violence (EM group, n = 58) or had no history of maltreatment or axis I disorders (n = 58). The main outcome measures consisted of the gray matter volume of lobule I as measured by manual tracing, number and type of alcoholic beverages consumed during a drinking session, number of sessions per month, and monthly drug use, along with family history of drug and alcohol abuse. Lingula thickness was not attenuated by alcohol use or maltreatment history. However, increased lingula thickness was associated with greater consumption of drugs and hard liquor, particularly in physically maltreated subjects who consumed 2.5- and 2.7-fold more alcohol and used drugs 6.1- and 7.8-fold more frequently than controls or EM subjects, respectively. In conclusion, physical maltreatment was observed to interact with cerebellar morphology resulting in a strong association with alcohol and substance use. Lingula thickness may represent a novel, experientially sensitive, phenotypic risk factor for enhanced alcohol and drug use that perhaps modulates sensitivity to these agents.

Association of Prepubertal and Postpubertal Exposure to Childhood Maltreatment With Adult Amygdala Function.

Importance: Abnormalities in amygdala response to threatening faces have been observed in anxiety disorders, autism, bipolar disorder, depression, posttraumatic stress disorder, and schizophrenia. Abnormally hyperactive and hypoactive responses have typically been associated with anxiety and inhibition vs risk taking and inappropriate social behaviors. Maltreatment is a major risk factor for most of these disorders and is associated with abnormal amygdala function. Objective: To identify the type and age of exposure to childhood maltreatment that are associated with hyperactive and hypoactive amygdala responses in young adulthood. Design, Setting, and Participants: Data collection for this retrospective cohort study took place from November 8, 2010, to August 23, 2012. Data analyses were conducted from September 20, 2012, to June 27, 2018. Participants were recruited from the urban and suburban Boston vicinity without diagnostic restrictions based on exposure history. Exposures: The Maltreatment and Abuse Chronology of Exposure (MACE) scale was used to retrospectively assess type and age of exposure to childhood maltreatment. Main Outcomes and Measures: Activation and pattern information functional magnetic resonance imaging were used to assess bilateral amygdala response to angry and fearful faces vs neutral faces or shapes, and sensitive exposure periods were identified using cross-validated artificial intelligence predictive analytics (50 averaged randomized iterations with training on 63.3% and testing on 36.7% of the sample). Results: Of the 202 participants (mean [SD] age, 23.2 [1.7] years; 118 [58.4%] female), 52 (25.7%) reported no exposure to maltreatment and 150 (74.3%) reported exposure to 1 or more maltreatment types. Eight participants (15.1%) with a MACE score of 0 and 51 (34.2%) with a MACE score of 1 or higher had a history of major depression (odds ratio, 2.40; 95% CI, 1.05-6.06; P = .03); 8 unexposed participants (15.1%) and 46 with MACE scores of 1 or higher (30.9%) had a history of 1 or more anxiety disorders (odds ratio, 2.45; 95% CI, 1.03-6.50; P = .03). Retrospective self-report of physical maltreatment between 3 and 6 years of age and peer emotional abuse at 13 and 15 years were associated with amygdala activation to emotional faces vs shapes. Early exposure was associated with blunted response (ß = -0.17, P < .001), whereas later exposure was associated with augmented response (ß = 0.16, P < .001). Prepubertal vs postpubertal maltreatment was associated with an opposite response on the voxelwise response pattern in clustering stimuli of the same type (eg, mean [SD] emotional ellipse areas for physical maltreatment at age 4 years vs nonverbal emotional abuse at 13 years: 1.41 [1.05] vs 0.25 [0.10], P < .001) and in distinguishing between stimuli of different types (eg, mean [SD] emotional vs neutral faces distance for peer emotional abuse at age 6 years vs 13 years: 1.89 [0.75] vs 0.80 [0.39], P < .001). Conclusions and Relevance: The findings suggest that prepubertal vs postpubertal developmental differences in the association between maltreatment and amygdala response to threatening or salient stimuli exist. Understanding the role of adversity in different sensitive exposure periods and the potential adaptive significance of attenuated vs enhanced amygdala response may help explain why maltreatment may be a risk factor for many different disorders and foster creation of targeted interventions to preempt the emergence of psychopathology in at-risk youths.

Susceptibility or Resilience to Maltreatment Can Be Explained by Specific Differences in Brain Network Architecture.

BACKGROUND: Childhood maltreatment is a major risk factor for psychopathology. However, some maltreated individuals appear remarkably resilient to the psychiatric effects while manifesting the same array of brain abnormalities as maltreated individuals with psychopathology. Hence, a critical aim is to identify compensatory brain alterations that enable resilient individuals to maintain mental well-being despite alterations in stress-susceptible regions. METHODS: Network models were constructed from diffusion tensor imaging and tractography in physically healthy unmedicated 18- to 25-year-old participants (N = 342, n = 192 maltreated) to develop network-based explanatory models. RESULTS: First, we determined that susceptible and resilient individuals had the same alterations in global fiber stream network architecture using two different definitions of resilience: 1) no lifetime history of Axis I or II disorders, and 2) no clinically significant symptoms of anxiety, depression, anger-hostility, or somatization. Second, we confirmed an a priori hypothesis that right amygdala nodal efficiency was lower in asymptomatic resilient than in susceptible participants or control subjects. Third, we identified eight other nodes with reduced nodal efficiency in resilient individuals and showed that nodal efficiency moderated the relationship between maltreatment and psychopathology. Fourth, we found that models based on global network architecture and nodal efficiency could delineate group membership (control, susceptible, resilient) with 75%, 82%, and 80% cross-validated accuracy. CONCLUSIONS: Together these findings suggest that sparse fiber networks with increased small-worldness following maltreatment render individuals vulnerable to psychopathology if abnormalities occur in specific nodes, but that decreased ability of certain nodes to propagate information throughout the network mitigates the effects and leads to resilience.

Does sleep disruption mediate the effects of childhood maltreatment on brain structure?

Background: Childhood maltreatment is associated with alterations in morphology of stress susceptible brain regions. Maltreatment is also known to markedly increase risk for psychopathology and to have an enduring disruptive effect on sleep. Objective: To determine whether abnormalities in sleep continuity have effects on brain morphometry and to evaluate the extent to which sleep impairments mediate the effects of maltreatment on brain structure. Method: Maltreatment and Abuse Chronology of Exposure (MACE) scale ratings, actigraph-assessed sleep and 3T MRI were obtained on N = 37 18-19-year-old participants recruited from the community (N = 34 with neuroimaging). Results: Fourteen participants had no history of maltreatment while N = 23 were exposed, on average, to 4.7 types of maltreatment. Multiplicity of maltreatment was strongly associated with reduced sleep efficiency, increased wake after sleep onset time and number/duration of awakenings, which were independent of effects of maltreatment on depression and anxiety. The most important predictors of impaired sleep were exposure to parental non-verbal emotional abuse at 9-10 years of age. Reduced sleep efficiency correlated with reduced grey matter volume in hippocampus including CA1 subfield, molecular layer and dentate gyrus as well as inferior frontal gyrus and insula. Sleep mediated 39-46% of the effects of maltreatment on volume of hippocampal structures and inferior frontal gyrus. Conclusions: Actigraph-assessed sleep is disrupted in maltreated late teens and mediates a significant portion of the effects of maltreatment on hippocampal volume. Studies are needed to assess whether efforts to enhance sleep in maltreated children can pre-empt or ameliorate neurobiological consequences of maltreatment.

Objetivo: determinar si las anomalías en la continuidad del sueño tienen efectos sobre la morfometría cerebral y evaluar en qué medida las alteraciones del sueño intervienen en los efectos del maltrato sobre la estructura del cerebro. Método: Se obtuvieron las puntuaciones de la Escala de cronología de la exposición al maltrato y al abuso (MACE, por sus siglas en inglés), sueño evaluado por actigraph y 3T MRI en N = 37 participantes de 18-19 años reclutados en la comunidad (N = 34 con neuroimagen). Resultados: Catorce participantes no tenían antecedentes de malos tratos mientras que N = 23 habían estado expuestos, de media, a 4.7 tipos de maltrato. La multiplicidad de los malos tratos se asoció fuertemente con una menor eficiencia del sueño, tiempo mayor de vigilia después de la hora de inicio del sueño y el número / duración de despertares, que fueron independientes de los efectos del maltrato sobre la depresión y la ansiedad. Los predictores más importantes de problemas de sueño fueron la exposición al abuso emocional no verbal de los padres a los 9-10 años de edad. La reducción de la eficiencia del sueño se correlacionó con la reducción del volumen de la materia gris en el hipocampo, incluido el subcampo CA1, la capa molecular y la circunvolución dentada, así como la circunvolución frontal inferior y la ínsula. El sueño mediaba en el 39-46% de los efectos del maltrato sobre el volumen de las estructuras del hipocampo y la circunvolución frontal inferior. Conclusiones: el sueño evaluado por Actigraph se ve alterado en adolescentes mayores maltratados y media en una parte importante de los efectos del maltrato sobre el volumen del hipocampo. Se necesitan estudios para evaluar si los esfuerzos para mejorar el sueño en los niños maltratados pueden adelantar o mejorar las consecuencias neurobiológicas del maltrato.

Cerebellar vermis involvement in cocaine-related behaviors.

Although the cerebellum is increasingly being viewed as a brain area involved in cognition, it typically is excluded from circuitry considered to mediate stimulant-associated behaviors since it is low in dopamine. Yet, the primate cerebellar vermis (lobules II-III and VIII-IX) has been reported to contain axonal dopamine transporter immunoreactivity (DAT-IR). We hypothesized that DAT-IR-containing vermis areas would be activated in cocaine abusers by cocaine-related cues and, in healthy humans, would accumulate DAT-selective ligands. We used BOLD fMRI to determine whether cocaine-related cues activated DAT-IR-enriched vermis regions in cocaine abusers and positron emission tomography imaging of healthy humans to determine whether the DAT-selective ligand [11C]altropane accumulated in those vermis regions. Cocaine-related cues selectively induced BOLD activation in lobules II-III and VIII-IX in cocaine users, and, at early time points after ligand administration, we found appreciable [11C]altropane accumulation in lobules VIII-IX, possibly indicating DAT presence in this region. These data suggest that parts of cerebellar vermis mediate cocaine's persisting and acute effects. In light of prior findings illustrating vermis connections to midbrain dopamine cell body regions, established roles for the vermis as a locus of sensorimotor integration and motor planning, and findings of increased vermis activation in substance abusers during reward-related and other cognitive tasks, we propose that the vermis be considered one of the structures involved in cocaine- and other incentive-related behaviors.

Emotional task-dependent low-frequency fluctuations and methylphenidate: Wavelet scaling analysis of 1/f-type fluctuations in fMRI of the cerebellar vermis.

UNLABELLED: Ion channel currents, neural firing patterns, and brain BOLD signals display 1/f-type fluctuations or fractal properties in time. By design, fMRI methods attempt to minimize the contribution of variance from low-frequency physiological 1/f-noise. New fMRI methods are described to visualize and measure 1/f-type BOLD fluctuations in volunteers recalling affectively neutral or emotional memories or meditating (i.e., attending to breathing) then retrospectively rating emotional content. A wavelet scaling exponent (alpha) was used to characterize signals from 0.015625 to 0.5Hz in cerebellar lobules VIII to X of the vermis (posterior inferior vermis; PIV), a region coordinating balance, eye tracking, locomotion, and vascular tone, and a possible site of pathology in attention deficit hyperactivity disorder (ADHD). RESULTS: Changes in alpha and emotional measures were correlated in PIV voxels (r = 0.622, d.f .= 14, P < 0.0005), but not other regions examined. In contrast, conventional means and standard deviations of PIV voxels were unchanged. Methylphenidate, shown to decrease slow oscillations in rodent basal ganglia [Ruskin DN, Bergstrom DA, Shenker A, Freeman LE, Baek D, Walters JR. Drugs used in the treatment of attention-deficit/hyperactivity disorder affect postsynaptic firing rate and oscillation without preferential dopamine autoreceptor action. Biol Psychiatry 2001;49:340-50.], abolished task-dependent alpha changes in the PIV of an adult with ADHD. Wavelet analysis of long BOLD time series appears well suited to fractal physiology and studies of pharmacologically modulated cerebellar-thalamic-cortical function in ADHD or other psychiatric disorders.

The neurobiological consequences of early stress and childhood maltreatment.

Early severe stress and maltreatment produces a cascade of neurobiological events that have the potential to cause enduring changes in brain development. These changes occur on multiple levels, from neurohumoral (especially the hypothalamic-pituitary-adrenal [HPA] axis) to structural and functional. The major structural consequences of early stress include reduced size of the mid-portions of the corpus callosum and attenuated development of the left neocortex, hippocampus, and amygdala. Major functional consequences include increased electrical irritability in limbic structures and reduced functional activity of the cerebellar vermis. There are also gender differences in vulnerability and functional consequences. The neurobiological sequelae of early stress and maltreatment may play a significant role in the emergence of psychiatric disorders during development.

Effects of methylphenidate on functional magnetic resonance relaxometry of the cerebellar vermis in boys with ADHD.

OBJECTIVE: The authors used functional magnetic resonance imaging (fMRI) to test the effects of methylphenidate on steady-state blood volume in the midline vermis of the cerebellum in boys with attention deficit hyperactivity disorder (ADHD). This region was selected as it has been observed to be significantly smaller in children with ADHD. Also, in preclinical studies, the vermis has been shown to modulate forebrain dopamine systems, to influence locomotor activity, and to contain a significant density of dopamine transporters. METHOD: T(2) relaxometry was used to indirectly assess blood volume in the cerebellum (hemispheres and midline vermis) of 10 boys with ADHD who were administered placebo or one of three different doses of methylphenidate continuously for 1 week. T(2) relaxation time values are inversely proportional to local cerebral blood volume. After each week of treatment, and within 1-3 hours of the boys' afternoon dose, testing for drug efficacy was performed by using objective measures of activity. RESULTS: Moderate and high doses of methylphenidate increased T(2) relaxation time in a rate-dependent manner-increasing T(2) relaxation time in the most active children with ADHD and reducing T(2) relaxation time in subjects with ADHD who were not objectively hyperactive. CONCLUSIONS: This preliminary study supports a role for the vermis in ADHD and suggests that further research is needed to clarify the relationship between vermal size, vermal blood flow, stimulant response, and the developmental pathophysiology of ADHD.

Abnormal T2 relaxation time in the cerebellar vermis of adults sexually abused in childhood: potential role of the vermis in stress-enhanced risk for drug abuse.

Recent studies suggest that childhood sexual abuse (CSA) elicits a cascade of neurohumoral events that affect brain development and is also a risk factor for the later development of substance abuse. We hypothesize that the cerebellar vermis may be a key region linking these observations. The vermis has a protracted ontogeny and a high density of glucocorticoid receptors, rendering it highly susceptible to early stress. The vermis modulates dopamine turnover in the accumbens and receives direct dopamine input through fibers with dopamine transporters. To test this hypothesis, steady-state functional magnetic resonance imaging (fMRI) (T2 relaxometry) was performed to assess resting blood flow in the vermis of 24 young adults (18-22 years) selected by screening from a large community sample. Eight subjects had a history of repeated CSA but were unmedicated and not under psychiatric care. Sixteen subjects were age-matched controls who had no personal or family history of Axis I psychiatric disorders. All subjects were screened to exclude known abnormalities affecting brain development, and any history of drug or alcohol abuse. CSA subjects had higher T2 relaxation time (T2-RT) than controls in the vermis but not in cerebral or cerebellar hemispheres. Vermal T2-RT correlated strongly with Limbic System Checklist (LSCL-33) ratings of temporal lobe epilepsy (TLE)-like symptomatology. From 537 prescreened young adults we found that their frequency of substance use was associated with a monotonic increase in LSCL-33 ratings and depression scores. Together these findings suggest that early trauma may interfere with the development of the vermis, and produce neuropsychiatric symptoms associated with drug use.

Developmental neurobiology of childhood stress and trauma.

Severe early stress and maltreatment produces a cascade of events that have the potential to alter brain development. The first stage of the cascade involves the stress-induced programming of the glucocorticoid, noradrenergic, and vasopressin-oxytocin stress response systems to augment stress responses. These neurohumors then produce effects on neurogenesis, synaptic overproduction and pruning, and myelination during specific sensitive periods. Major consequences include reduced size of the mid-portions of the corpus callosum; attenuated development of the left neocortex, hippocampus, and amygdala along with abnormal frontotemporal electrical activity; and reduced functional activity of the cerebellar vermis. These alterations, in turn, provide the neurobiological framework through which early abuse increases the risk of developing post-traumatic stress disorder (PTSD), depression, symptoms of attention-deficit/hyperactivity, borderline personality disorder, dissociative identity disorder, and substance abuse.

Oral methylphenidate challenge selectively decreases putaminal T2 in healthy subjects.

Despite the recent rise in oral methylphenidate (MPH) abuse, few studies have characterized the time course of oral MPH brain effects in human subjects. Accordingly, this study assessed the hemodynamic effects of oral MPH effects in 11 healthy young adults (six women), by measuring brain transverse relaxation times (T2). T2 can be interpreted as a surrogate marker for, and inversely correlated with, steady-state cerebral blood volume (CBV). Data were acquired from the caudate nucleus, putamen, and thalamus, using a 1.5 T MRI scanner at baseline and serially for 2 h following oral MPH administration (0.5 mg/kg). Physiological and subjective measures and plasma MPH levels also were examined. MPH induced a selective T2 decrease (-1.65+/-0.53 ms) in the putamen (F(6,54)=2.68, P<0.03). Heartrate, blood pressure and plasma MPH levels increased significantly after drug administration, as well as subjective ratings of "feeling drug effect". T2 decreases may reflect MPH-induced increases in putaminal blood volume. These data suggest that T2 relaxometry can be used to study the time course of regional cerebral blood volume responses to MPH and perhaps to other stimulant drugs.