INTRODUCTION: Abnormal language functions, including difficulty with word association tasks, and ... more INTRODUCTION: Abnormal language functions, including difficulty with word association tasks, and verbal fluency, have been repeatedly demonstrated in schizophrenic patients. In a previous investigation (1) differences in activation of the superior temporal gyms were detected between normal controls and schizophrenic patients with functional MRI during word production tasks. Recent hypotheses regarding the neurobiological correlates of schizophrenia have suggested that schizophrenic males may be characterized by extreme forms of sexual dimorphism (2). In this study, we have applied fMRI during verbal recall in order to examine temporal lobe activation in schizophrenic patients and normal controls during a subspan word task.
Rationale Methylene-dioxymethamphetamine (MDMA) is known to cause degeneration of serotonin nerve... more Rationale Methylene-dioxymethamphetamine (MDMA) is known to cause degeneration of serotonin nerve terminals after acute doses in animals. Similarly, behavioral studies in human MDMA users regularly find abnormalities in memory, mood, and impulse control. However, studies of brain function using brain imaging in MDMA users have been less consistent. Objectives The purpose of this study was to determine, using functional magnetic
Wnts were previously shown to regulate the neurogenesis of neural stem or progenitor cells. Here,... more Wnts were previously shown to regulate the neurogenesis of neural stem or progenitor cells. Here, we explored the underlying molecular mechanisms through which Wnt signaling regulates neurotrophins (NTs) in the NT-induced neuronal differentiation of human mesenchymal stem cells (hMSCs). NTs can increase the expression of Wnt1 and Wnt7a in hMSCs. However, only Wnt7a enables the expression of synapsin-1, a synaptic marker in mature neurons, to be induced and triggers the formation of cholinergic and dopaminergic neurons. Human recombinant (hr)Wnt7a and general neuron makers were positively correlated in a dose-and time-dependent manner. In addition, the expression of synaptic markers and neurites was induced by Wnt7a and lithium, a glycogen synthase kinase-3b inhibitor, in the NT-induced hMSCs via the canonical/bcatenin pathway, but was inhibited by Wnt inhibitors and frizzled-5 (Frz5) blocking antibodies. In addition, hrWnt7a triggered the formation of cholinergic and dopaminergic neurons via the non-canonical/c-jun N-terminal kinase (JNK) pathway, and the formation of these neurons was inhibited by a JNK inhibitor and Frz9 blocking antibodies. In conclusion, hrWnt7a enhances the synthesis of synapse and facilitates neuronal differentiation in hMSCS through various Frz receptors. These mechanisms may be employed widely in the transdifferentiation of other adult stem cells.
Magnetic resonance spectroscopy (MRS) provides a noninvasive means to monitor the concentration o... more Magnetic resonance spectroscopy (MRS) provides a noninvasive means to monitor the concentration of several important brain metabolites. In previous work (Charles et al.,1992; Renshaw et al.,1993) we have'reported a markedly elevated choline resonance in ! H MR spectra obtained from the basal ganglia, in the present study, we are evaluating a series of patients before and after eight weeks of treatment with fluoxetine. Patients with unipolar depression (N ,=25) were recruited from those participating in standardized treatment trials at McLean Hospital and the Massachusetts General Hospital. patients underwent MRS prior to the initiation of treatment with fluoxetine, 20 rag/day, and again after eight weeks of treatment (N = 13). Normal control subjects were recruited from the hospital staff (N=I5). Proton MRS was performed using a i.5 T magnetic resonance whole body imaging device and a modified STEAM pulse sequence. The intensity of the basal ganglia IH MRS choline resonance, expressed as the area ratio of the choline peak to the creatine peak (Cho/ Or), was significantly higher in untreated, depressed subjects (0.80 +/-0.34) than in normal controls (0.47 +/-0.21) (p -.0009). With treatment, mean Hamilton Depression scores (HAM-D) decreased significantly (20 +/-4 vs. 9 +/-6; p-.002) as did Cho/Cr ratios (0.62 +/-0.35; p-.008). There was a trend for the decrease in HAM-D scores with treatment to con'elate with the decrease in Cho/Cr ratios (p-.08). This study replicates our previous finding of an increased basal ganglia ! H MRS choline resonance in depressed subjects and suggests that clinical improvement is associated with a relative normalization of this biochemical alteration.
Differences in proton MRS T 2 values for phosphocreatine (PCr) and creatine (Cr) methyl groups (3... more Differences in proton MRS T 2 values for phosphocreatine (PCr) and creatine (Cr) methyl groups (3.0 ppm) were investigated in studies of phantoms and human brain. Results from phantom studies revealed that T 2 of PCr in solution is significantly shorter than T 2 of Cr. Curve-fitting results indicated that the amplitude-TE curves of the total Cr resonance at 3.0 ppm in human brain (N ؍ 26) fit a biexponential decay model significantly better than a monoexponential decay model (P < 0.006), yielding mean T 2 values of 117 ؎ 21 ms and 309 ؎ 21 ms. Using a localized, long-TE (272 ms) point-resolved spectroscopy (PRESS) proton MRS during 2 min of photic stimulation (PS), an increase of 12.1% ؎ 3.5% in the mean intensity of the total Cr resonance in primary visual cortex (VI) was observed at the end of stimulation (P < 0.021). This increase is consistent with the conversion of 26% of PCr in VI to Cr, which is concordant with 31 P MRS findings reported by other investigators. These results suggest a significantly shorter T 2 for PCr than for Cr in vivo. This difference possibly could be exploited to quantify regional activation in functional spectroscopy studies, and could also lead to inaccuracies in some circumstances when the Cr resonance is used as an internal standard for 1 H MRS studies in vivo. Magn Reson Med 47:232-238, 2002.
A dramatic increase in the use and dependence of prescription opioids has occurred within the las... more A dramatic increase in the use and dependence of prescription opioids has occurred within the last 10 years. The consequences of long-term prescription opioid use and dependence on the brain are largely unknown, and any speculation is inferred from heroin and methadone studies. Thus, no data have directly demonstrated the effects of prescription opioid use on brain structure and function in humans. To pursue this issue, we used structural magnetic resonance imaging, diffusion tensor imaging and resting-state functional magnetic resonance imaging in a highly enriched group of prescription opioid-dependent patients [(n = 10); from a larger study on prescription opioid dependent patients (n = 133)] and matched healthy individuals (n = 10) to characterize possible brain alterations that may be caused by long-term prescription opioid use. Criteria for patient selection included: (i) no dependence on alcohol or other drugs; (ii) no comorbid psychiatric or neurological disease; and (iii) no medical conditions, including pain. In comparison to control subjects, individuals with opioid dependence displayed bilateral volumetric loss in the amygdala. Prescription opioid-dependent subjects had significantly decreased anisotropy in axonal pathways specific to the amygdala (i.e. stria terminalis, ventral amygdalofugal pathway and uncinate fasciculus) as well as the internal and external capsules. In the patient group, significant decreases in functional connectivity were observed for seed regions that included the anterior insula, nucleus accumbens and amygdala subdivisions. Correlation analyses revealed that longer duration of prescription opioid exposure was associated with greater changes in functional connectivity. Finally, changes in amygdala Downloaded from functional connectivity were observed to have a significant dependence on amygdala volume and white matter anisotropy of efferent and afferent pathways of the amygdala. These findings suggest that prescription opioid dependence is associated with structural and functional changes in brain regions implicated in the regulation of affect and impulse control, as well as in reward and motivational functions. These results may have important clinical implications for uncovering the effects of long-term prescription opioid use on brain structure and function. Abbreviations: FA = fractional anisotropy; fMRI = functional magnetic resonance imaging; GLM = General Linear Model; MNI = Montré al Neurological Institute; TBSS = tract-based spatial statistics Brain and prescription opioids Brain Downloaded from OD = opioid-dependent subject; H = age/gender/handedness matched healthy control.
Proton magnetic resonance spectra (MRS) were acquired from 1.5 x 1.5 x 1.5-cm voxels in the left ... more Proton magnetic resonance spectra (MRS) were acquired from 1.5 x 1.5 x 1.5-cm voxels in the left and right mesial temporal lobes of 20 schizophrenic patients and 20 non-psychiatric comparison subjects. Choline (Cho) to creatine (and phosphocreatine) (Cr(PCr)) ratios were estimated as were the percent gray matter, white matter and CSF contributing to the voxel. The Cho/Cr(PCr) metabolite ratio was significantly lower in the left temporal lobe than in the right temporal lobe for both the schizophrenia subjects and control group. This difference was greater in the schizophrenia subjects. Left temporal lobe gray matter voxel content was significantly higher and white matter content was significantly lower than in the right temporal lobe for both the schizophrenia subjects and control group. This difference was the same for the schizophrenia subjects and control group. Left voxel gray matter and white matter content correlated with Cho/Cr(PCr) metabolite ratios for the schizophrenic subjects but not for the control subjects. No such correlations were noted on the right side. No significant difference was found between Cho/Cr(PCr) in the left temporal lobe or in the right temporal lobe of the schizophrenia subjects vs. the control group.
Internet gaming disorder (IGD) and alcohol dependence (AD) have been reported to share clinical c... more Internet gaming disorder (IGD) and alcohol dependence (AD) have been reported to share clinical characteristics including craving and over-engagement despite negative consequences. However, there are also clinical factors that differ between individuals with IGD and those with AD in terms of chemical intoxication, prevalence age, and visual and auditory stimulation. We assessed brain functional connectivity within the prefrontal, striatum, and temporal lobe in 15 patients with IGD and in 16 patients with AD. Symptoms of depression, anxiety, and the attention deficit hyperactivity disorder were assessed in patients with IGD and in patients with AD. Both AD and IGD subjects have positive functional connectivity between the dorsolateral prefrontal cortex (DLPFC), cingulate, and cerebellum. In addition, both groups have negative functional connectivity between the DLPFC and the orbitofrontal cortex. However, the AD subjects have positive functional connectivity between the DLPFC, temporal lobe and striatal areas while IGD subjects have negative functional connectivity between the DLPFC, temporal lobe and striatal areas. AD and IGD subjects may share deficits in executive function, including problems with self-control and adaptive responding. However, the negative connectivity between the DLPFC and the striatal areas in IGD subjects, different from the connectivity observed in AD subjects, may be due to the earlier prevalence age, different comorbid diseases as well as visual and auditory stimulation.
Non-invasive measures of brain gamma-aminobutyric acid (GABA) concentrations may be especially us... more Non-invasive measures of brain gamma-aminobutyric acid (GABA) concentrations may be especially useful in the identification of cocaine-related changes in brain chemistry that can be used to guide the development of future treatments for cocaine-dependent persons. This study assessed whether brain GABA levels in cocaine-dependent subjects with and without an alcohol disorder differ from GABA levels in healthy comparison subjects. Two-dimensional, proton magnetic resonance spectroscopy was used to determine GABA levels in the left prefrontal lobe of cocaine-dependent subjects (N=35) recruited from a National Institute on Drug Abuse (NIDA)-sponsored treatment trial of cocaine dependence and a comparison group (N=20). At treatment baseline, mean GABA concentrations were 0.93+/-0.27 mM/kg in cocaine-dependent subjects and 1.32+/-0.44 mM/kg in the comparison sample (t [d.f.=53]=3.65, P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001). Cocaine-dependent subjects with a history of a co-morbid alcohol disorder (N=23) had significantly lower baseline GABA levels (0.87 mM/kg) (t [d.f.=41]=4.31, P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001) than the comparison group. However, cocaine-dependent subjects without an alcohol disorder (N=12) also had lower GABA levels (1.04 mM/kg) than the comparison subjects (t [d.f.=30]=2.09, P=0.045), suggesting that cocaine dependence alone can decrease GABA levels.
Magnetic resonance spectroscopy (MRS) provides a noninvasive means to monitor the concentration o... more Magnetic resonance spectroscopy (MRS) provides a noninvasive means to monitor the concentration of several important brain metabolites. In previous work (Charles et al.,1992; Renshaw et al.,1993) we have'reported a markedly elevated choline resonance in ! H MR spectra obtained from the basal ganglia, in the present study, we are evaluating a series of patients before and after eight weeks of treatment with fluoxetine. Patients with unipolar depression (N ,=25) were recruited from those participating in standardized treatment trials at McLean Hospital and the Massachusetts General Hospital. patients underwent MRS prior to the initiation of treatment with fluoxetine, 20 rag/day, and again after eight weeks of treatment (N = 13). Normal control subjects were recruited from the hospital staff (N=I5). Proton MRS was performed using a i.5 T magnetic resonance whole body imaging device and a modified STEAM pulse sequence. The intensity of the basal ganglia IH MRS choline resonance, expressed as the area ratio of the choline peak to the creatine peak (Cho/ Or), was significantly higher in untreated, depressed subjects (0.80 +/-0.34) than in normal controls (0.47 +/-0.21) (p -.0009). With treatment, mean Hamilton Depression scores (HAM-D) decreased significantly (20 +/-4 vs. 9 +/-6; p-.002) as did Cho/Cr ratios (0.62 +/-0.35; p-.008). There was a trend for the decrease in HAM-D scores with treatment to con'elate with the decrease in Cho/Cr ratios (p-.08). This study replicates our previous finding of an increased basal ganglia ! H MRS choline resonance in depressed subjects and suggests that clinical improvement is associated with a relative normalization of this biochemical alteration.
Recent studies suggest that childhood sexual abuse (CSA) elicits a cascade of neurohumoral events... more 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. ∅⊃
Ž . This study sought to identify whether subjects with a family history FHq of alcoholism had ch... more Ž . This study sought to identify whether subjects with a family history FHq of alcoholism had changes in regional Ž . cerebral blood volume rCBV after an alprazolam challenge which distinguished them from subjects without a Ž . Ž . family history FHy of alcoholism using functional MRI fMRI . Twelve FHq and eight FHy subjects were challenged with 1 mg of alprazolam or placebo in a double-blind crossover design. FMRI scans were obtained at baseline, 1 and 2 h after the challenge using the dynamic susceptibility contrast method with gadolinium. Mood scales, the Tufts Addiction Research Center Inventory-Morphine Benzedrine Group Scale and the drug liking scale, were administered every 30 min to assess drug effects. Global analysis of CBV showed a treatment by time decrease on alprazolam relative to placebo, but no effect by family history. The FHq group showed rCBV decreases at 1 h in the left caudate and left inferior prefrontal region, while the FHy group showed rCBV decreases at 2 h in the right inferior prefrontal region and anterior cingulate in response to alprazolam relative to placebo. FHq subjects reported more mood enhancement with alprazolam. This fMRI technique detected global and regional CBV changes induced by alprazolam. The location and rate of alprazolam-induced rCBV changes differed between FHq and FHy subjects. These changes may be related to the increased mood enhancement found in subjects genetically predisposed to alcoholism. ᮊ
Attempts to identify biological response predictors generally have met with limited success, part... more Attempts to identify biological response predictors generally have met with limited success, particularly where the goal is to develop clinically useful indices. This article reviews the biological approaches to predicting treatment response, beginning with neuroendocrine studies and electroencephalogram analysis and concluding with structural and functional neuroimaging. The article describes the designs of typical studies to aid in interpreting their results and concludes by addressing some of the problems and limitations associated with these approaches and suggesting future directions for this research.
The methionine variant of Val66Met brain-derived neurotrophic factor BDNF met and catecholamine-O... more The methionine variant of Val66Met brain-derived neurotrophic factor BDNF met and catecholamine-O-methyltransferase (COMT L) is associated with a deficit in attention and aggravation of delusions in schizophrenia. We hypothesized that the BDNF-COMT gene interaction would affect the symptoms and cognition in schizophrenia. Ninety-six schizophrenic patients and 79 control participants were recruited. The patients who were BDNF met/met x COMT L carriers had the highest scores of delusion of Positive Symptoms and the Scale for Assessment of Negative Symptoms, word reading of the color word test, and trail-making test B time, compared with the other three genotype interactions. The current results suggest that patients with the BDNF met/met x COMT L allele had more delusional symptoms and poorer cognitive flexibility, compared with the other three genotype interactions.
Magnetic Resonance Materials in Physics, Biology and Medicine, 2005
We previously reported cerebellar and putaminal transverse relaxation time (T2) differences in ch... more 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.
A proton magnetic resonance spectral editing technique is presented that uses PRESS excitation to... more A proton magnetic resonance spectral editing technique is presented that uses PRESS excitation to achieve spatially localized measurements of brain gamma-aminobutyric acid (GABA). The homonuclear difference spectroscopy technique employs a frequency selective inversion pulse to suppress the creatine resonance at 3.0 ppm. The timing of this pulse is optimized to maximize the suppression of creatine by minimizing the effect of the editing pulse on the 3.0 ppm resonances. The PRESS excitation achieves three dimensional spatial localization in a single acquisition making it less sensitive to patient motion than multiple acquisition techniques. The performance and utility of this technique were evaluated by phantom experiments and by in vivo measurements of brain GABA concentration in 10 normal subjects.
Journal of the American Academy of Child & Adolescent Psychiatry, 1999
Objective: To examine further the role of the amygdala in the recognition of facial expression in... more Objective: To examine further the role of the amygdala in the recognition of facial expression in adolescents. Method:
To investigate the feasibility of using 1 H and 23 Na MRI to detect fluid levels in the lower leg... more To investigate the feasibility of using 1 H and 23 Na MRI to detect fluid levels in the lower leg muscle.
INTRODUCTION: Abnormal language functions, including difficulty with word association tasks, and ... more INTRODUCTION: Abnormal language functions, including difficulty with word association tasks, and verbal fluency, have been repeatedly demonstrated in schizophrenic patients. In a previous investigation (1) differences in activation of the superior temporal gyms were detected between normal controls and schizophrenic patients with functional MRI during word production tasks. Recent hypotheses regarding the neurobiological correlates of schizophrenia have suggested that schizophrenic males may be characterized by extreme forms of sexual dimorphism (2). In this study, we have applied fMRI during verbal recall in order to examine temporal lobe activation in schizophrenic patients and normal controls during a subspan word task.
Rationale Methylene-dioxymethamphetamine (MDMA) is known to cause degeneration of serotonin nerve... more Rationale Methylene-dioxymethamphetamine (MDMA) is known to cause degeneration of serotonin nerve terminals after acute doses in animals. Similarly, behavioral studies in human MDMA users regularly find abnormalities in memory, mood, and impulse control. However, studies of brain function using brain imaging in MDMA users have been less consistent. Objectives The purpose of this study was to determine, using functional magnetic
Wnts were previously shown to regulate the neurogenesis of neural stem or progenitor cells. Here,... more Wnts were previously shown to regulate the neurogenesis of neural stem or progenitor cells. Here, we explored the underlying molecular mechanisms through which Wnt signaling regulates neurotrophins (NTs) in the NT-induced neuronal differentiation of human mesenchymal stem cells (hMSCs). NTs can increase the expression of Wnt1 and Wnt7a in hMSCs. However, only Wnt7a enables the expression of synapsin-1, a synaptic marker in mature neurons, to be induced and triggers the formation of cholinergic and dopaminergic neurons. Human recombinant (hr)Wnt7a and general neuron makers were positively correlated in a dose-and time-dependent manner. In addition, the expression of synaptic markers and neurites was induced by Wnt7a and lithium, a glycogen synthase kinase-3b inhibitor, in the NT-induced hMSCs via the canonical/bcatenin pathway, but was inhibited by Wnt inhibitors and frizzled-5 (Frz5) blocking antibodies. In addition, hrWnt7a triggered the formation of cholinergic and dopaminergic neurons via the non-canonical/c-jun N-terminal kinase (JNK) pathway, and the formation of these neurons was inhibited by a JNK inhibitor and Frz9 blocking antibodies. In conclusion, hrWnt7a enhances the synthesis of synapse and facilitates neuronal differentiation in hMSCS through various Frz receptors. These mechanisms may be employed widely in the transdifferentiation of other adult stem cells.
Magnetic resonance spectroscopy (MRS) provides a noninvasive means to monitor the concentration o... more Magnetic resonance spectroscopy (MRS) provides a noninvasive means to monitor the concentration of several important brain metabolites. In previous work (Charles et al.,1992; Renshaw et al.,1993) we have'reported a markedly elevated choline resonance in ! H MR spectra obtained from the basal ganglia, in the present study, we are evaluating a series of patients before and after eight weeks of treatment with fluoxetine. Patients with unipolar depression (N ,=25) were recruited from those participating in standardized treatment trials at McLean Hospital and the Massachusetts General Hospital. patients underwent MRS prior to the initiation of treatment with fluoxetine, 20 rag/day, and again after eight weeks of treatment (N = 13). Normal control subjects were recruited from the hospital staff (N=I5). Proton MRS was performed using a i.5 T magnetic resonance whole body imaging device and a modified STEAM pulse sequence. The intensity of the basal ganglia IH MRS choline resonance, expressed as the area ratio of the choline peak to the creatine peak (Cho/ Or), was significantly higher in untreated, depressed subjects (0.80 +/-0.34) than in normal controls (0.47 +/-0.21) (p -.0009). With treatment, mean Hamilton Depression scores (HAM-D) decreased significantly (20 +/-4 vs. 9 +/-6; p-.002) as did Cho/Cr ratios (0.62 +/-0.35; p-.008). There was a trend for the decrease in HAM-D scores with treatment to con'elate with the decrease in Cho/Cr ratios (p-.08). This study replicates our previous finding of an increased basal ganglia ! H MRS choline resonance in depressed subjects and suggests that clinical improvement is associated with a relative normalization of this biochemical alteration.
Differences in proton MRS T 2 values for phosphocreatine (PCr) and creatine (Cr) methyl groups (3... more Differences in proton MRS T 2 values for phosphocreatine (PCr) and creatine (Cr) methyl groups (3.0 ppm) were investigated in studies of phantoms and human brain. Results from phantom studies revealed that T 2 of PCr in solution is significantly shorter than T 2 of Cr. Curve-fitting results indicated that the amplitude-TE curves of the total Cr resonance at 3.0 ppm in human brain (N ؍ 26) fit a biexponential decay model significantly better than a monoexponential decay model (P < 0.006), yielding mean T 2 values of 117 ؎ 21 ms and 309 ؎ 21 ms. Using a localized, long-TE (272 ms) point-resolved spectroscopy (PRESS) proton MRS during 2 min of photic stimulation (PS), an increase of 12.1% ؎ 3.5% in the mean intensity of the total Cr resonance in primary visual cortex (VI) was observed at the end of stimulation (P < 0.021). This increase is consistent with the conversion of 26% of PCr in VI to Cr, which is concordant with 31 P MRS findings reported by other investigators. These results suggest a significantly shorter T 2 for PCr than for Cr in vivo. This difference possibly could be exploited to quantify regional activation in functional spectroscopy studies, and could also lead to inaccuracies in some circumstances when the Cr resonance is used as an internal standard for 1 H MRS studies in vivo. Magn Reson Med 47:232-238, 2002.
A dramatic increase in the use and dependence of prescription opioids has occurred within the las... more A dramatic increase in the use and dependence of prescription opioids has occurred within the last 10 years. The consequences of long-term prescription opioid use and dependence on the brain are largely unknown, and any speculation is inferred from heroin and methadone studies. Thus, no data have directly demonstrated the effects of prescription opioid use on brain structure and function in humans. To pursue this issue, we used structural magnetic resonance imaging, diffusion tensor imaging and resting-state functional magnetic resonance imaging in a highly enriched group of prescription opioid-dependent patients [(n = 10); from a larger study on prescription opioid dependent patients (n = 133)] and matched healthy individuals (n = 10) to characterize possible brain alterations that may be caused by long-term prescription opioid use. Criteria for patient selection included: (i) no dependence on alcohol or other drugs; (ii) no comorbid psychiatric or neurological disease; and (iii) no medical conditions, including pain. In comparison to control subjects, individuals with opioid dependence displayed bilateral volumetric loss in the amygdala. Prescription opioid-dependent subjects had significantly decreased anisotropy in axonal pathways specific to the amygdala (i.e. stria terminalis, ventral amygdalofugal pathway and uncinate fasciculus) as well as the internal and external capsules. In the patient group, significant decreases in functional connectivity were observed for seed regions that included the anterior insula, nucleus accumbens and amygdala subdivisions. Correlation analyses revealed that longer duration of prescription opioid exposure was associated with greater changes in functional connectivity. Finally, changes in amygdala Downloaded from functional connectivity were observed to have a significant dependence on amygdala volume and white matter anisotropy of efferent and afferent pathways of the amygdala. These findings suggest that prescription opioid dependence is associated with structural and functional changes in brain regions implicated in the regulation of affect and impulse control, as well as in reward and motivational functions. These results may have important clinical implications for uncovering the effects of long-term prescription opioid use on brain structure and function. Abbreviations: FA = fractional anisotropy; fMRI = functional magnetic resonance imaging; GLM = General Linear Model; MNI = Montré al Neurological Institute; TBSS = tract-based spatial statistics Brain and prescription opioids Brain Downloaded from OD = opioid-dependent subject; H = age/gender/handedness matched healthy control.
Proton magnetic resonance spectra (MRS) were acquired from 1.5 x 1.5 x 1.5-cm voxels in the left ... more Proton magnetic resonance spectra (MRS) were acquired from 1.5 x 1.5 x 1.5-cm voxels in the left and right mesial temporal lobes of 20 schizophrenic patients and 20 non-psychiatric comparison subjects. Choline (Cho) to creatine (and phosphocreatine) (Cr(PCr)) ratios were estimated as were the percent gray matter, white matter and CSF contributing to the voxel. The Cho/Cr(PCr) metabolite ratio was significantly lower in the left temporal lobe than in the right temporal lobe for both the schizophrenia subjects and control group. This difference was greater in the schizophrenia subjects. Left temporal lobe gray matter voxel content was significantly higher and white matter content was significantly lower than in the right temporal lobe for both the schizophrenia subjects and control group. This difference was the same for the schizophrenia subjects and control group. Left voxel gray matter and white matter content correlated with Cho/Cr(PCr) metabolite ratios for the schizophrenic subjects but not for the control subjects. No such correlations were noted on the right side. No significant difference was found between Cho/Cr(PCr) in the left temporal lobe or in the right temporal lobe of the schizophrenia subjects vs. the control group.
Internet gaming disorder (IGD) and alcohol dependence (AD) have been reported to share clinical c... more Internet gaming disorder (IGD) and alcohol dependence (AD) have been reported to share clinical characteristics including craving and over-engagement despite negative consequences. However, there are also clinical factors that differ between individuals with IGD and those with AD in terms of chemical intoxication, prevalence age, and visual and auditory stimulation. We assessed brain functional connectivity within the prefrontal, striatum, and temporal lobe in 15 patients with IGD and in 16 patients with AD. Symptoms of depression, anxiety, and the attention deficit hyperactivity disorder were assessed in patients with IGD and in patients with AD. Both AD and IGD subjects have positive functional connectivity between the dorsolateral prefrontal cortex (DLPFC), cingulate, and cerebellum. In addition, both groups have negative functional connectivity between the DLPFC and the orbitofrontal cortex. However, the AD subjects have positive functional connectivity between the DLPFC, temporal lobe and striatal areas while IGD subjects have negative functional connectivity between the DLPFC, temporal lobe and striatal areas. AD and IGD subjects may share deficits in executive function, including problems with self-control and adaptive responding. However, the negative connectivity between the DLPFC and the striatal areas in IGD subjects, different from the connectivity observed in AD subjects, may be due to the earlier prevalence age, different comorbid diseases as well as visual and auditory stimulation.
Non-invasive measures of brain gamma-aminobutyric acid (GABA) concentrations may be especially us... more Non-invasive measures of brain gamma-aminobutyric acid (GABA) concentrations may be especially useful in the identification of cocaine-related changes in brain chemistry that can be used to guide the development of future treatments for cocaine-dependent persons. This study assessed whether brain GABA levels in cocaine-dependent subjects with and without an alcohol disorder differ from GABA levels in healthy comparison subjects. Two-dimensional, proton magnetic resonance spectroscopy was used to determine GABA levels in the left prefrontal lobe of cocaine-dependent subjects (N=35) recruited from a National Institute on Drug Abuse (NIDA)-sponsored treatment trial of cocaine dependence and a comparison group (N=20). At treatment baseline, mean GABA concentrations were 0.93+/-0.27 mM/kg in cocaine-dependent subjects and 1.32+/-0.44 mM/kg in the comparison sample (t [d.f.=53]=3.65, P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001). Cocaine-dependent subjects with a history of a co-morbid alcohol disorder (N=23) had significantly lower baseline GABA levels (0.87 mM/kg) (t [d.f.=41]=4.31, P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001) than the comparison group. However, cocaine-dependent subjects without an alcohol disorder (N=12) also had lower GABA levels (1.04 mM/kg) than the comparison subjects (t [d.f.=30]=2.09, P=0.045), suggesting that cocaine dependence alone can decrease GABA levels.
Magnetic resonance spectroscopy (MRS) provides a noninvasive means to monitor the concentration o... more Magnetic resonance spectroscopy (MRS) provides a noninvasive means to monitor the concentration of several important brain metabolites. In previous work (Charles et al.,1992; Renshaw et al.,1993) we have'reported a markedly elevated choline resonance in ! H MR spectra obtained from the basal ganglia, in the present study, we are evaluating a series of patients before and after eight weeks of treatment with fluoxetine. Patients with unipolar depression (N ,=25) were recruited from those participating in standardized treatment trials at McLean Hospital and the Massachusetts General Hospital. patients underwent MRS prior to the initiation of treatment with fluoxetine, 20 rag/day, and again after eight weeks of treatment (N = 13). Normal control subjects were recruited from the hospital staff (N=I5). Proton MRS was performed using a i.5 T magnetic resonance whole body imaging device and a modified STEAM pulse sequence. The intensity of the basal ganglia IH MRS choline resonance, expressed as the area ratio of the choline peak to the creatine peak (Cho/ Or), was significantly higher in untreated, depressed subjects (0.80 +/-0.34) than in normal controls (0.47 +/-0.21) (p -.0009). With treatment, mean Hamilton Depression scores (HAM-D) decreased significantly (20 +/-4 vs. 9 +/-6; p-.002) as did Cho/Cr ratios (0.62 +/-0.35; p-.008). There was a trend for the decrease in HAM-D scores with treatment to con'elate with the decrease in Cho/Cr ratios (p-.08). This study replicates our previous finding of an increased basal ganglia ! H MRS choline resonance in depressed subjects and suggests that clinical improvement is associated with a relative normalization of this biochemical alteration.
Recent studies suggest that childhood sexual abuse (CSA) elicits a cascade of neurohumoral events... more 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. ∅⊃
Ž . This study sought to identify whether subjects with a family history FHq of alcoholism had ch... more Ž . This study sought to identify whether subjects with a family history FHq of alcoholism had changes in regional Ž . cerebral blood volume rCBV after an alprazolam challenge which distinguished them from subjects without a Ž . Ž . family history FHy of alcoholism using functional MRI fMRI . Twelve FHq and eight FHy subjects were challenged with 1 mg of alprazolam or placebo in a double-blind crossover design. FMRI scans were obtained at baseline, 1 and 2 h after the challenge using the dynamic susceptibility contrast method with gadolinium. Mood scales, the Tufts Addiction Research Center Inventory-Morphine Benzedrine Group Scale and the drug liking scale, were administered every 30 min to assess drug effects. Global analysis of CBV showed a treatment by time decrease on alprazolam relative to placebo, but no effect by family history. The FHq group showed rCBV decreases at 1 h in the left caudate and left inferior prefrontal region, while the FHy group showed rCBV decreases at 2 h in the right inferior prefrontal region and anterior cingulate in response to alprazolam relative to placebo. FHq subjects reported more mood enhancement with alprazolam. This fMRI technique detected global and regional CBV changes induced by alprazolam. The location and rate of alprazolam-induced rCBV changes differed between FHq and FHy subjects. These changes may be related to the increased mood enhancement found in subjects genetically predisposed to alcoholism. ᮊ
Attempts to identify biological response predictors generally have met with limited success, part... more Attempts to identify biological response predictors generally have met with limited success, particularly where the goal is to develop clinically useful indices. This article reviews the biological approaches to predicting treatment response, beginning with neuroendocrine studies and electroencephalogram analysis and concluding with structural and functional neuroimaging. The article describes the designs of typical studies to aid in interpreting their results and concludes by addressing some of the problems and limitations associated with these approaches and suggesting future directions for this research.
The methionine variant of Val66Met brain-derived neurotrophic factor BDNF met and catecholamine-O... more The methionine variant of Val66Met brain-derived neurotrophic factor BDNF met and catecholamine-O-methyltransferase (COMT L) is associated with a deficit in attention and aggravation of delusions in schizophrenia. We hypothesized that the BDNF-COMT gene interaction would affect the symptoms and cognition in schizophrenia. Ninety-six schizophrenic patients and 79 control participants were recruited. The patients who were BDNF met/met x COMT L carriers had the highest scores of delusion of Positive Symptoms and the Scale for Assessment of Negative Symptoms, word reading of the color word test, and trail-making test B time, compared with the other three genotype interactions. The current results suggest that patients with the BDNF met/met x COMT L allele had more delusional symptoms and poorer cognitive flexibility, compared with the other three genotype interactions.
Magnetic Resonance Materials in Physics, Biology and Medicine, 2005
We previously reported cerebellar and putaminal transverse relaxation time (T2) differences in ch... more 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.
A proton magnetic resonance spectral editing technique is presented that uses PRESS excitation to... more A proton magnetic resonance spectral editing technique is presented that uses PRESS excitation to achieve spatially localized measurements of brain gamma-aminobutyric acid (GABA). The homonuclear difference spectroscopy technique employs a frequency selective inversion pulse to suppress the creatine resonance at 3.0 ppm. The timing of this pulse is optimized to maximize the suppression of creatine by minimizing the effect of the editing pulse on the 3.0 ppm resonances. The PRESS excitation achieves three dimensional spatial localization in a single acquisition making it less sensitive to patient motion than multiple acquisition techniques. The performance and utility of this technique were evaluated by phantom experiments and by in vivo measurements of brain GABA concentration in 10 normal subjects.
Journal of the American Academy of Child & Adolescent Psychiatry, 1999
Objective: To examine further the role of the amygdala in the recognition of facial expression in... more Objective: To examine further the role of the amygdala in the recognition of facial expression in adolescents. Method:
To investigate the feasibility of using 1 H and 23 Na MRI to detect fluid levels in the lower leg... more To investigate the feasibility of using 1 H and 23 Na MRI to detect fluid levels in the lower leg muscle.
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Papers by Perry Renshaw