Telemedicine-Based Cognitive Examinations During COVID-19 and Beyond: Perspective of the Massachusetts General Hospital Behavioral Neurology & Neuropsychiatry Group.

Telehealth and telemedicine have encountered explosive growth since the beginning of the COVID-19 pandemic, resulting in increased access to care for patients located far from medical centers and clinics. Subspecialty clinicians in behavioral neurology & neuropsychiatry (BNNP) have implemented the use of telemedicine platforms to perform cognitive examinations that were previously office based. In this perspective article, BNNP clinicians at Massachusetts General Hospital (MGH) describe their experience performing cognitive examinations via telemedicine. The article reviews the goals, prerequisites, advantages, and potential limitations of performing a video- or telephone-based telemedicine cognitive examination. The article shares the approaches used by MGH BNNP clinicians to examine cognitive and behavioral areas, such as orientation, attention and executive functions, language, verbal learning and memory, visual learning and memory, visuospatial function, praxis, and abstract abilities, as well as to survey for neuropsychiatric symptoms and assess activities of daily living. Limitations of telemedicine-based cognitive examinations include limited access to and familiarity with telecommunication technologies on the patient side, limitations of the technology itself on the clinician side, and the limited psychometric validation of virtual assessments. Therefore, an in-person examination with a BNNP clinician or a formal in-person neuropsychological examination with a neuropsychologist may be recommended. Overall, this article emphasizes the use of standardized cognitive and behavioral assessment instruments that are either in the public domain or, if copyrighted, are nonproprietary and do not require a fee to be used by the practicing BNNP clinician.

The Impact of Sex Hormones on Transcranial Magnetic Stimulation Measures of Cortical Excitability: A Systematic Review and Considerations for Clinical Practice.

ABSTRACT: Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising alternative for the treatment of major depressive disorder (MDD), although its clinical effectiveness varies substantially. The effects of sex hormone fluctuations on cortical excitability have been identified as potential factors that can explain this variability. However, data on how sex hormone changes affect clinical response to rTMS is limited. To address this gap, we reviewed the literature examining the effects of sex hormones and hormonal treatments on transcranial magnetic stimulation (TMS) measures of cortical excitability. Results show that variations of endogenous estrogen, testosterone, and progesterone have modulatory effects on TMS-derived measures of cortical excitability. Specifically, higher levels of estrogen and testosterone were associated with greater cortical excitability, while higher progesterone was associated with lower cortical excitability. This highlights the importance of additional investigation into the effects of hormonal changes on rTMS outcomes and circuit-specific physiological variables. These results call for TMS clinicians to consider performing more frequent motor threshold (MT) assessments in patients receiving high doses of estrogen, testosterone, and progesterone in cases such as in vitro fertilization, hormone replacement therapy, and gender-affirming hormonal treatments. It may also be important to consider physiological hormonal fluctuations and their impact on depressive symptoms and the MT when treating female patients with rTMS.

Biomarkers in Psychiatric Drug Development: From Precision Medicine to Novel Therapeutics.

Burden of psychiatric disorders is compounded by their wide prevalence as well as the limited efficacy of currently available treatments and the current approaches for prescribing these treatments. The selection of treatments continues to be subjective and often results in a trial-and-error approach. Emerging research suggests that biological markers (or biomarkers) can be used to develop precision medicine approaches for psychiatric disorders. Furthermore, the biomarkers also promise to elucidate the underlying pathophysiological mechanisms which in turn can be used to develop novel therapeutic treatments. In this chapter we have focused on mood disorders and reviewed studies on electroencephalography (EEG), magnetic resonance imaging (MRI), and blood-based biomarkers that can guide selection of one treatment versus another (treatment-selection biomarker) as well as biomarkers that can guide the development of novel therapeutics. These studies suggest that the use of objective physiological data is poised to alter the landscape of psychiatric diagnosis and treatment. However, practical and economic barriers remain as major hurdles. The key to finding such translational diagnostic and therapeutic biomarkers is a better understanding of the underlying pathophysiology, and despite the tremendous advances in neuroscience, it is clear there remains much left to be elucidated.

Habenula Connectivity and Intravenous Ketamine in Treatment-Resistant Depression.

BACKGROUND: Ketamine's potent and rapid antidepressant properties have shown great promise to treat severe forms of major depressive disorder (MDD). A recently hypothesized antidepressant mechanism of action of ketamine is the inhibition of N-methyl-D-aspartate receptor-dependent bursting activity of the habenula (Hb), a small brain structure that modulates reward and affective states. METHODS: Resting-state functional magnetic resonance imaging was conducted in 35 patients with MDD at baseline and 24 hours following treatment with i.v. ketamine. A seed-to-voxel functional connectivity (FC) analysis was performed with the Hb as a seed-of-interest. Pre-post changes in FC and the associations between changes in FC of the Hb and depressive symptom severity were examined. RESULTS: A reduction in Montgomery-Åsberg Depression Rating Scale scores from baseline to 24 hours after ketamine infusion was associated with increased FC between the right Hb and a cluster in the right frontal pole (t = 4.65, P = .03, false discovery rate [FDR]-corrected). A reduction in Quick Inventory of Depressive Symptomatology-Self Report score following ketamine was associated with increased FC between the right Hb and clusters in the right occipital pole (t = 5.18, P < .0001, FDR-corrected), right temporal pole (t = 4.97, P < .0001, FDR-corrected), right parahippocampal gyrus (t = 5.80, P = .001, FDR-corrected), and left lateral occipital cortex (t = 4.73, P = .03, FDR-corrected). Given the small size of the Hb, it is possible that peri-habenular regions contributed to the results. CONCLUSIONS: These preliminary results suggest that the Hb might be involved in ketamine's antidepressant action in patients with MDD, although these findings are limited by the lack of a control group.

Novel investigational therapeutics for generalized anxiety disorder (GAD).

Introduction: Generalized anxiety disorder (GAD) is a common and disabling psychiatric condition that affects 3% of the population and exacts significant costs to society if untreated. There are numerous treatment options available, but all have side effects, and none are reliably effective; hence, there is a significant need for new medications.Areas covered: The authors reviewed clinical Phase II and III studies listed on the clinicaltrials.gov and clinicaltrialsregister.eu websites, 2007-present. Additional information was gathered from the study sponsor websites and Pubmed. The categories of mechanisms investigated include: modulators of GABAergic or glutamatergic activity; modulators of monoaminergic systems including serotonin, norepinephrine, and dopamine; and modulators of neuropeptide corticotropin release factor.Expert opinion: There are few investigational drugs in the later stages of clinical development. Challenges include high placebo response rates, enrollment of symptomatic volunteers with minimal depressive and anxiety comorbidity, and the lack of a unifying pathophysiological model. Drug developers should consider implementing trial designs such as sequential parallel comparison design to enhance signal detection. Inclusion of depressive comorbidity may also enhance signal detection by reducing placebo-responsivity. More studies examining glutamate-mediated neuroplasticity in GAD are needed.

Striato-nigro-striatal tract dispersion abnormalities in patients with chronic schizophrenia.

The white matter connections between the midbrain dopamine neurons and the striatum are part of a neural system involved in reward-based learning, a process that is impaired in patients with schizophrenia. The striato-nigro-striatal (SNS) tract, which participates in this process, has not as yet been explored. The present study aimed to use diffusion MRI (dMRI) to delineate the SNS tract, and to compare the application of two dMRI measures, Tract Dispersion (TD), an index of white matter morphology, and Fractional Anisotropy (FA), an index of white matter integrity, to detect group differences between patients with chronic schizophrenia (CSZ) and healthy controls (HC). dMRI scans were acquired in 22 male patients with CSZ and 23 age-matched HC. Two-tensor tractography was used in addition to manually-delineated regions of interest to extract the SNS tract. A mixed-model analysis of variance was used to investigate differences in TD and FA between CSZ patients and HC. The associations between TD and behavioral measures were also explored. Patients and controls differed significantly in TD (P = 0.04), but not in FA (P = 0.69). The group differences in TD were driven by a higher TD in the right hemisphere in the CSZ group. Higher TD correlated significantly with poorer performance in the Iowa Gambling Task (IGT) when combining the scores of both groups. The findings suggest that dysconnectiviy of the SNS tract which is associated with schizophrenia, could arise from abnormalities in white matter morphology. These abnormalities may potentially reflect irregularities in brain development.

Sexually dimorphic structural abnormalities in major connections of the medial forebrain bundle in alcoholism.

Background: The mesocorticolimbic system is particularly susceptible to the effects of chronic alcoholism. Disruption of this system has been linked to drug seeking and the development of Reward Deficiency Syndrome, a neurobiological framework for describing the development and relapsing patterns of addictions. In this study, we evaluated the association of alcoholism and sex with major connections of the medial forebrain bundle (MFB), a prominent mesocorticolimbic fiber pathway connecting the ventral tegmental area with the basal forebrain. Given sex differences in clinical consequences of alcohol consumption, we hypothesized that alcoholic men and women would differ in structural abnormalities of the MFB. Methods: Diffusion magnetic resonance imaging (dMRI) data were acquired from 30 abstinent long-term alcoholic individuals (ALC; 9 men) and 25 non-alcoholic controls (NC; 8 men). Major connections of the MFB were extracted using multi-tensor tractography. We compared groups on MFB volume, fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD), with hemisphere and sex as independent variables. We also evaluated associations between abnormal structural measures and drinking measures. Results: Analyses revealed significant group-by-sex interactions for FA and RD: while ALC men had lower FA and higher RD compared to NC men, ALC women had higher FA and lower RD compared to NC women. We also detected a significant negative association between FA and number of daily drinks in ALC women. Conclusion: Alcoholism is associated with sexually dimorphic structural abnormalities in the MFB. The results expand upon other findings of differences in brain reward circuitry of alcoholic men and women.

A comparison of three fiber tract delineation methods and their impact on white matter analysis.

Diffusion magnetic resonance imaging (dMRI) is an important method for studying white matter connectivity in the brain in vivo in both healthy and clinical populations. Improvements in dMRI tractography algorithms, which reconstruct macroscopic three-dimensional white matter fiber pathways, have allowed for methodological advances in the study of white matter; however, insufficient attention has been paid to comparing post-tractography methods that extract white matter fiber tracts of interest from whole-brain tractography. Here we conduct a comparison of three representative and conceptually distinct approaches to fiber tract delineation: 1) a manual multiple region of interest-based approach, 2) an atlas-based approach, and 3) a groupwise fiber clustering approach, by employing methods that exemplify these approaches to delineate the arcuate fasciculus, the middle longitudinal fasciculus, and the uncinate fasciculus in 10 healthy male subjects. We enable qualitative comparisons across methods, conduct quantitative evaluations of tract volume, tract length, mean fractional anisotropy, and true positive and true negative rates, and report measures of intra-method and inter-method agreement. We discuss methodological similarities and differences between the three approaches and the major advantages and drawbacks of each, and review research and clinical contexts for which each method may be most apposite. Emphasis is given to the means by which different white matter fiber tract delineation approaches may systematically produce variable results, despite utilizing the same input tractography and reliance on similar anatomical knowledge.

Psychosis of epilepsy: a multifaceted neuropsychiatric disorder.

Psychosis of epilepsy (POE) is a term applied to a group of psychotic disorders with a distinct phenomenology in which potential etiopathogenic mechanisms are believed to be closely related to a seizure disorder. POE can present as interictal psychotic episodes, which may often differ semiologically from primary schizophrenic disorder. They may present as ictal or postictal psychotic episodes and may be the expression of an iatrogenic process to pharmacologic and/or surgical interventions.Epilepsy and POE have a complex and bidirectional relation, as not only are patients with epilepsy at greater risk of developing a psychotic disorder, but patients with a primary psychotic disorder are also at greater risk of developing epilepsy. The prevalence of POE is more than 7 times higher than the frequency of primary schizophreniform disorders in the general population. While POE has been associated with focal epilepsy of temporal and frontal lobe origin, its etiology and pathophysiology of POE have yet to be established.The treatment of all forms of POE, with the exception of ictal psychotic episodes, requires the use of antipsychotic drugs, preferably the atypical antipsychotic agents with a very low or negligible potential to lower the seizure threshold (eg, risperidone, apiprazole), starting at a low dose with stepwise increments.

Frecuencia de depresión en pacientes con epilepsia que consultan dos instituciones de tercer nivel en Cali, Colombia / Frequency of depression in patients with epilepsy treated at two health institutions in Cali, Colombia

Objetivos: Determinar la frecuencia de depresión en pacientes con epilepsia que consultaron dos instituciones de tercer nivel de Cali, Colombia, durante los meses de mayo y junio del 2009, usando el Inventario de Depresión de Beck (BDI) y el Inventario de Depresión en Pacientes con Trastornos Neurológicos para Epilepsia (NDDI-E). Así mismo, identificar las características sociodemográficas y clínicas de la población bajo estudio, determinar factores clínicos asociados al cuadro depresivo y describir el tratamiento farmacológico suministrado a los pacientes. Método: Estudio descriptivo transversal que involucró a 124 pacientes con epilepsia mayores de edad. A estos pacientes se les aplicó el BDI y el NDDI-E, además de un formato en el que se registraron los datos demográficos. Para el análisis de los datos se utilizó el paquete estadístico Epi Info versión 3.4.1. Resultados: Se encontró que, de acuerdo con el BDI, 57,3% (IC: 48,1%-66,1%) de los pacientes estaban deprimidos y, según la NDDI-E, 34,7% (IC: 26,4%-46,7%). Esta discrepancia se explica porque las dos escalas miden severidades diferentes de los síntomas depresivos. La mayor parte de los pacientes con depresión estaban en tratamiento farmacológico. Conclusiones: Se encontró una frecuencia de depresión del 57,3% con una intensidad variable, dependiendo del instrumento que se use para medirla...

Objective: To find the prevalence of depressive symptoms in outpatients with epilepsy treated at the Hospital Psiquiátrico Universitario del Valle (HDPUV) and the Liga Colombiana Contra la Epilepsia (LCCE) between May and June, 2009. Method: It is a descriptive crosssectional study which included 124 subjects over 18 years. Patients underwent Beck´s Depression Inventory (BDI) and the Neurological Disorders and Depression Inventory in Epilepsy (NDDI-E), as well as a format for demographic variables. Data analysis was made with Epi Info version 3.4.1. Results: It was found that according to the BDI, 57.3% (IC:48.1%-66.1%) of the patients were diagnosed with depression, whereas 34.7% of the patients had a diagnosis of severe depressive disorder when the NDDI-E was applied. The explanation to this discrepancy is based on the fact that the inventories measure the severity of depressive symptoms differently. Most of the patients were under pharmacologic treatment. Conclusions: Depressive symptoms have a high prevalence in patients with epilepsy (57.3%), with a varying severity of the symptoms depending on the instrument used for the diagnosis...