Associations Between Findings From Myelin Water Imaging and Cognitive Performance Among Individuals With Multiple Sclerosis.

Importance: Cognitive impairment is a debilitating symptom of multiple sclerosis (MS) that affects up to 70% of patients. An improved understanding of the underlying pathology of MS-related cognitive impairment would provide considerable benefit to patients and clinicians. Objective: To determine whether there is an association between myelin damage in tissue that appears completely normal on standard clinical imaging, but can be detected by myelin water imaging (MWI), with cognitive performance in MS. Design, Setting, and Participants: In this cross-sectional study, participants with MS and controls underwent cognitive testing and magnetic resonance imaging (MRI) from August 23, 2017, to February 20, 2019. Participants were recruited through the University of British Columbia Hospital MS clinic and via online recruitment advertisements on local health authority websites. Cognitive testing was performed in the MS clinic, and MRI was performed at the adjacent academic research neuroimaging center. Seventy-three participants with clinically definite MS fulfilling the 2017 revised McDonald criteria for diagnosis and 22 age-, sex-, and education-matched healthy volunteers without neurological disease were included in the study. Data analysis was performed from March to November 2019. Exposures: MWI was performed at 3 T with a 48-echo, 3-dimensional, gradient and spin-echo (GRASE) sequence. Cognitive testing was performed with assessments drawn from cognitive batteries validated for use in MS. Main Outcomes and Measures: The association between myelin water measures, a measurement of the T2 relaxation signal from water in the myelin bilayers providing a specific marker for myelin, and cognitive test scores was assessed using Pearson correlation. Three white matter regions of interest-the cingulum, superior longitudinal fasciculus (SLF), and corpus callosum-were selected a priori according to their known involvement in MS-related cognitive impairment. Results: For the 95 total participants, the mean (SD) age was 49.33 (11.44) years. The mean (SD) age was 50.2 (10.7) years for the 73 participants with MS and 46.4 (13.5) for the 22 controls. Forty-eight participants with MS (66%) and 14 controls (64%) were women. The mean (SD) years of education were 14.7 (2.2) for patients and 15.8 (2.5) years for controls. In MS, significant associations were observed between myelin water measures and scores on the Symbol Digit Modalities Test (SLF, r = -0.490; 95% CI, -0.697 to -0.284; P < .001; corpus callosum, r = -0.471; 95% CI, -0.680 to -0.262; P < .001; and cingulum, r = -0.419; 95% CI, -0.634 to -0.205; P < .001), Selective Reminding Test (SLF, r = -0.444; 95% CI, -0.660 to -0.217; P < .001; corpus callosum, r = -0.411; 95% CI, -0.630 to -0.181; P = .001; and cingulum, r = -0.361; 95% CI, -0.602 to -0.130; P = .003), and Controlled Oral Word Association Test (SLF, r = -0.317; 95% CI, -0.549 to -0.078; P = .01; and cingulum, r = -0.335; 95% CI, -0.658 to -0.113; P = .006). No significant associations were found in controls. Conclusions and Relevance: This study used MWI to demonstrate that otherwise normal-appearing brain tissue is diffusely damaged in MS, and the findings suggest that myelin water measures are associated with cognitive performance. MWI offers an in vivo biomarker feasible for use in clinical trials investigating cognition, providing a means for monitoring changes in myelination and its association with symptom worsening or improvement.

Hypoactivity in the Paraterminal Gyrus Following Bilateral Anterior Capsulotomy.

OBJECTIVE: Bilateral anterior capsulotomy (BAC) is one of the ablative neurosurgical procedures used to treat major depressive disorder or obsessive-compulsive disorder when all other therapies fail. Tristolysis, a reduction in sadness, is the most striking clinical effect of BAC and is seen in the first 1 to 2 weeks after surgery. This retrospective study measured regional cerebral blood flow (rCBF) following surgery to identify which cortical regions were impacted and could account for this clinical effect. METHODS: All patients had their capsulotomies done in Vancouver by the same team. Pre- and postoperative single-photon emission computed tomography perfusion scans were analyzed for 10 patients with major depressive disorder and 3 with obsessive-compulsive disorder. rCBF was measured semiquantitatively by calculating the ratio between an identified region of interest and a whole brain reference area. RESULTS: Decreased rCBF was found in the paraterminal gyri. Increased rCBF was found in the dorsolateral prefrontal cortices and in the left lateral temporal lobe. CONCLUSIONS: BAC causes hypoactivity in the paraterminal gyri and is the most likely explanation for its tristolytic effect, suggesting that the paraterminal gyrus is the limbic cortical locus for the emotion of sadness. Increased activity in the dorsolateral prefrontal cortices may be occurring via connectional diaschisis, and suppression by overactive paraterminal gyri during depression may account for some of the neurocognitive deficits observed during depressive episodes.

Myelin Damage in Normal Appearing White Matter Contributes to Impaired Cognitive Processing Speed in Multiple Sclerosis.

BACKGROUND AND PURPOSE: Cognitive impairment is a core symptom in multiple sclerosis (MS). Damage to normal appearing white matter (NAWM) is likely involved. We sought to determine if greater myelin heterogeneity in NAWM is associated with decreased cognitive performance in MS. METHODS: A total of 27 participants with MS and 13 controls matched for age, sex, and education underwent myelin water imaging (MWI) from which the myelin water fraction (MWF) was calculated. Corpus callosum, superior longitudinal fasciculus, and cingulum were chosen as regions of interest (ROIs) a priori based on their involvement in MS-related cognitive impairment. Cognitive performance was assessed using the Symbol Digit Modalities Test (SDMT). Pearson ́s product moment correlations were performed to assess relationships between cognitive performance and myelin heterogeneity (variance of MWF within an ROI). RESULTS: In MS, myelin heterogeneity in all three ROIs was significantly associated with performance on the SDMT. These correlations ranged from moderate (r = -.561) to moderately strong (r = -.654) and were highly significant (P values ranged from .001 to .0002). Conversely, myelin heterogeneity was not associated with SDMT performance in controls in any ROI (P > .108). CONCLUSION: Increased myelin heterogeneity in NAWM is associated with decreased cognitive processing speed performance in MS.

Relation between prenatal maternal mood and anxiety and neonatal health.

OBJECTIVE: To examine the relation between the mood and anxiety of pregnant, psychiatrically treated women and neonatal health outcomes after birth. METHOD: We prospectively assessed 46 women treated with psychotropic medications for anxiety and depression during pregnancy. We compared measures of maternal mental health with infant outcomes, in particular, the outcomes of infants with symptoms of poor neonatal adaptation. RESULTS: The mothers of babies who demonstrated poor neonatal adaptation reported higher levels of anxiety and depression at study entry than did the mothers of healthy babies. This relation was not related to the presence or absence of treatment with clonazepam, an anxiolytic used to treat symptoms of anxiety. Further, increased psychiatric comorbidity in the mother was associated with a greater likelihood of transient symptoms in the newborn. CONCLUSIONS: Despite psychiatric treatment, the intensity and degree of comorbid symptoms appear to be related to poor transient neonatal health outcome. Our data suggest that, in addition to the impact of pharmacologic factors, maternal psychiatric status influences infant outcomes.

Antipsychotic medication during pregnancy and lactation in women with schizophrenia: evaluating the risk.

OBJECTIVE: To review studies investigating the following: whether exposing developing infants to antipsychotic medication during pregnancy and lactation is associated with increased risks of teratogenic, neonatal, and long-term neurobehavioural sequelae; whether schizophrenia itself affects pregnancy outcome; and whether the course of schizophrenia symptoms is altered by pregnancy and lactation. METHOD: We summarize the results from articles identified via a MedLine search for the period January 1, 1966, to December 1, 2001. RESULTS: Women with schizophrenia are at increased risk for poor obstetrical outcomes, including preterm delivery, low birth weight, and neonates who are small for their gestational age. A lack of information in the literature makes it difficult to comment on the relative risk of exposing developing infants to atypical antipsychotics. However, typical antipsychotics appear to carry an increased risk of congenital malformations when the fetus is exposed to phenothiazines during weeks 4 to 10 of gestation. Lack of information also precludes an understanding of whether changes associated with pregnancy and lactation significantly alter the course of schizophrenia symptoms. CONCLUSION: Research is needed so that physicians may more accurately inform women about the relative risks of using antipsychotic medications during pregnancy and lactation. Increased knowledge about the risks of medication exposure will allow clinicians to limit treatment to situations in which the risk of untreated maternal illness outweighs the risk of exposing a developing infant to medications.