Depression and suicidality in an Afghan refugee: A case report.

We report the case of a young male refugee from Afghanistan who presented after a violent suicide attempt, likely precipitated in part by discrimination and social isolation experienced after immigrating to the United States. Common psychiatric comorbidities associated with immigration from war-torn nations are reviewed with a particular emphasis on how adequate screening and additional resources for vulnerable refugees during and after immigration continues to be an unmet need. Our findings suggest that there is a critical need and additional studies should be conducted, not only to identify at risk refugee populations but also to prevent potentially violent behavior. Our findings also suggest a lack of an optimal screening tool and shed light on the struggles of refugees, particularly those from Afghanistan.

Delta Vs Gamma Auditory Steady State Synchrony in Schizophrenia.

Background: Delta band (1-4 Hz) neuronal responses support the precision and stability of auditory processing, and a deficit in delta band synchrony may be relevant to auditory domain symptoms in schizophrenia patients. Methods: Delta band synchronization elicited by a 2.5 Hz auditory steady state response (ASSR) paradigm, along with those from theta (5 Hz), alpha (10 Hz), beta (20 Hz), gamma (40 Hz), and high gamma (80 Hz) frequency ASSR, were compared in 128 patients with schizophrenia, 108 healthy controls, and 55 first-degree relatives (FDR) of patients. Results: Delta band synchronization was significantly impaired in patients compared with controls (F = 18.3, P < .001). There was a significant 2.5 Hz by 40 Hz ASSR interaction (P = .023), arising from a greater reduction of 2.5 Hz ASSR than of 40 Hz ASSR, in patients compared with controls. Greater deficit in delta ASSR was associated with auditory perceptual abnormality (P = .007) and reduced verbal working memory (P < .001). Gamma frequency ASSR impairment was also significant but more modest (F = 8.7, P = .004), and this deficit was also present in FDR (P = .022). Conclusions: The ability to sustain delta band oscillation entrainment in the auditory pathway is significantly reduced in schizophrenia patients and appears to be clinically relevant.

Frontal Glutamate and γ-Aminobutyric Acid Levels and Their Associations With Mismatch Negativity and Digit Sequencing Task Performance in Schizophrenia.

IMPORTANCE: Auditory mismatch negativity (MMN) is a biomarker for schizophrenia thought to reflect glutamatergic N-methyl-d-aspartate receptor function and excitatory-inhibitory neurotransmission balance. However, the association of glutamate level with MMN has not been directly examined in patients with schizophrenia, to our knowledge. OBJECTIVE: To investigate the contributions of glutamate and γ-aminobutyric acid (GABA) to MMN and digit sequencing task (DST) performance, an assessment of verbal working memory, in schizophrenia. DESIGN, SETTING, AND PARTICIPANTS: Fifty-three control participants from the community and 45 persons with schizophrenia from outpatient clinics completed an electroencephalographic session for MMN, magnetic resonance spectroscopy for glutamate and GABA, and a DST. The study dates were July 2011 to May 2014, and the dates of our analysis were May 2014 to August 2015. MAIN OUTCOMES AND MEASURES: Glutamate, GABA, the ratio of glutamine to glutamate, MMN amplitude, and DST. Structural equation modeling was used to test the effects of neurochemistry and MMN amplitude on DST performance. RESULTS: The 45 persons with schizophrenia were a mean (SD) of 37.7 (12.8) years and the control participants were 37.1 (13.1) years. The schizophrenia group had a mean (SD) of 14.7 (12.1) years of illness. Mismatch negativity amplitude (F = 4.39, P = .04) and glutamate (F = 9.69, P = .002) were reduced in the schizophrenia group. Smaller MMN amplitude was significantly associated with lower GABA level (P = .008), lower glutamate level (P = .05), and higher ratio of glutamine to glutamate (P = .003). Reduced MMN amplitude was linked to poor verbal working memory in schizophrenia (P = .002). Modeling revealed that a proxy of glutamatergic function, indexed by the ratio of glutamine to glutamate, influenced a path from the ratio of glutamine to glutamate to MMN to verbal working memory (P = .38 [root-mean-square error of approximation, P < .001] by χ2 test), supporting the contention that MMN serves as an intermediate biomarker linking glutamatergic function to DST performance in schizophrenia. CONCLUSIONS AND RELEVANCE: The role of glutamate and GABA in MMN and verbal working memory deficits in schizophrenia has been frequently debated. These data provide in vivo evidence that support glutamatergic and GABAergic regulation of MMN and verbal working memory function in schizophrenia.

Influence of kynurenine 3-monooxygenase (KMO) gene polymorphism on cognitive function in schizophrenia.

BACKGROUND: Cognitive deficits compromise quality of life and productivity for individuals with schizophrenia and have no effective treatments. Preclinical data point to the kynurenine pathway of tryptophan metabolism as a potential target for pro-cognitive drug development. We have previously demonstrated association of a kynurenine 3-monooxygenase (KMO) gene variant with reduced KMO gene expression in postmortem schizophrenia cortex, and neurocognitive endophenotypic deficits in a clinical sample. KMO encodes kynurenine 3-monooxygenase (KMO), the rate-limiting microglial enzyme of cortical kynurenine metabolism. Aberration of the KMO gene might be the proximal cause of impaired cortical kynurenine metabolism observed in schizophrenia. However, the relationship between KMO variation and cognitive function in schizophrenia is unknown. This study examined the effects of the KMO rs2275163C>T C (risk) allele on cognitive function in schizophrenia. METHODS: We examined the association of KMO polymorphisms with general neuropsychological performance and P50 gating in a sample of 150 schizophrenia and 95 healthy controls. RESULTS: Consistent with our original report, the KMO rs2275163C>T C (risk) allele was associated with deficits in general neuropsychological performance, and this effect was more marked in schizophrenia compared with controls. Additionally, the C (Arg452) allele of the missense rs1053230C>T variant (KMO Arg452Cys) showed a trend effect on cognitive function. Neither variant affected P50 gating. CONCLUSIONS: These data suggest that KMO variation influences a range of cognitive domains known to predict functional outcome. Extensive molecular characterization of this gene would elucidate its role in cognitive function with implications for vertical integration with basic discovery.

Long range frontal/posterior phase synchronization during remembered pursuit task is impaired in schizophrenia.

Although smooth pursuit eye movement (SPEM) is a reliable endophenotype of schizophrenia, exact underlying cognitive and neural substrates remain unknown. A simple mechanistic model of SPEM assumes an efficient interaction in integrating sensory input from the medial temporal (MT)/medial superior temporal (MST) brain regions and subsequent motor response through the frontal eye field (FEF). Poor functional connectivity between these two regions could explain impaired motion perception and SPEM maintenance in schizophrenia. In the present study, we combined an eye tracking paradigm with electroencephalography (EEG) recordings to investigate the putative functional connectivity among frontal/posterior brain regions in mediating the modulation of SPEM. Twenty four schizophrenic (SZ) and 22 healthy control (HC) participants performed remembered pursuit tasks with EEG recordings. Behaviorally, HC subjects showed significant improvement in SPEM response on repeated presentations of target compared to SZ subjects. Neurophysiologically HC subjects showed higher frontal/posterior phase synchronization in the beta to low gamma range frequency bands during all target presentations. In addition there was a significant increase in phase synchronization in the beta-2 frequency band in HC subjects during late compared to early target presentation. In contrast, higher frontal/posterior phase synchronization in the beta-2 frequency predicted better performance during late target presentation and lower enduring psychosis in SZ subjects. These data suggest a pathologically perturbed connectivity between frontal and posterior cortical regions during SPEM in SZ. The integrative eye tracking-EEG approach used in this study to dissect the endophenotype may reveal novel targets for studying schizophrenia psychopathology.

Mitochondrial DNA variations in Madras motor neuron disease.

Although the Madras motor neuron disease (MMND) was found three decades ago, its genetic basis has not been elucidated, so far. The symptom at onset was impaired hearing, upper limb weakness and atrophy. Since some clinical features of MMND overlap with mitochondrial disorders, we analyzed the complete mitochondrial genome of 45 MMND patients and found 396 variations, including 13 disease-associated, 2 mt-tRNA and 33 non-synonymous (16 MT-ND, 10 MT-CO, 3 MT-CYB and 4 MT-ATPase). A rare variant (m.8302A>G) in mt-tRNA(Leu) was found in three patients. We predict that these variation(s) may influence the disease pathogenesis along with some unknown factor(s).

Tacrolimus-induced paranoid delusions and fugue-like state.

We report the case of a 43 year old male with no prior psychiatric history with apparent tacrolimus-induced psychosis. Previous reports have identified other neurotoxic adverse effects due to tacrolimus, however, to our knowledge, there are few reports that describe psychosis induced by the immunosuppressant drug. Although psychosis may be a rare adverse effect, it can have significant impact on the long-term prognosis and treatment in transplant recipients. It is imperative to quickly identify patients who develop a mental status change while on tacrolimus and to work with the appropriate transplant team in managing these patients. Treatment usually calls for prompt discontinuation of tacrolimus, substituting with another immunosuppressant, and possible use of antipsychotics.

The role of social media networks in psychotic disorders: a case report.

We report the case of a young man diagnosed with schizophrenia who presented with stalking behaviors that may have been caused by problematic use or participation in social media networks (SMN). We review the possible role of SMN in the formation of his romantic delusion and offer suggestions for clinicians around incorporation of SMN questions into assessments. It is imperative to identify populations at risk of SMN-related stalking behaviors to stratify mental health resources and interventions. Additional studies are needed to further clarify the role of SMN in psychotic disorders.

Gender-specific association of TSNAX/DISC1 locus for schizophrenia and bipolar affective disorder in South Indian population.

Genetic association studies have implicated the TSNAX/DISC1 (disrupted in schizophrenia 1) in schizophrenia (SCZ), bipolar affective disorder (BPAD) and major depression. This study was performed to assess the possible involvement of TSNAX/DISC1 locus in the aetiology of BPAD and SCZ in the Southern Indian population. We genotyped seven single nucleotide polymorphism (SNPs) from TSNAX/DISC1 region in 1252 individuals (419 BPAD patients, 408 SCZ patients and 425 controls). Binary logistic regression revealed a nominal association for rs821616 in DISC1 for BPAD and also combined cases of BPAD or SCZ, but after correcting for multiple testing, these results were non-significant. However, significant association was observed with BPAD, as well as combined cases of BPAD or SCZ, within the female subjects for the rs766288 after applying false discovery rate corrections at the 0.05 level. Two-locus analysis showed C-C (rs766288-rs2812393) as a risk combination in BPAD, and G-T (rs2812393-rs821616) as a protective combination in SCZ and combined cases of BPAD or SCZ. Female-specific associations were observed for rs766288-rs2812393, rs766288-rs821616 and rs8212393-rs821616 in two-locus analysis. Our results provide further evidence for sex-dependent effects of the TSNAX/DISC1 locus in the aetiology of SCZ and BPAD.

Predictive pursuit association with deficits in working memory in psychosis.

BACKGROUND: Deficits in smooth pursuit eye movements are an established phenotype for schizophrenia (SZ) and are being investigated as a potential liability marker for bipolar disorder. Although the molecular determinants of this deficit are still unclear, research has verified deficits in predictive pursuit mechanisms in SZ. Because predictive pursuit might depend on the working memory system, we have hypothesized a relationship between the two in healthy control subjects (HC) and SZ and here examine whether it extends to psychotic bipolar disorder (BDP). METHODS: Volunteers with SZ (n = 38), BDP (n = 31), and HC (n = 32) performed a novel eye movement task to assess predictive pursuit as well as a standard visuospatial measure of working memory. RESULTS: Individuals with SZ and BDP both showed reduced predictive pursuit gain compared with HC (p < .05). Moreover, each patient group showed worse performance in visuospatial working memory compared with control subjects (p < .05). A strong correlation (r = .53, p = .007) was found between predictive pursuit gain and working memory in HC, a relationship that showed a trend correlation within the BDP group but not among SZ. CONCLUSIONS: Individuals with SZ and BDP showed similar deficits in predictive pursuit, suggesting that this alteration could be a characteristic trait of the psychosis domain. The correlation between predictive pursuit and working memory in HC supports the assumption that working memory is related to predictive pursuit eye movements; however, the degradation of working memory in people with psychosis disrupts its association with eye-tracking behavior.

Electrophysiological evaluation of spinocerebellar ataxias 1, 2 and 3.

INTRODUCTION: Subclinical neuropathy is an important feature of spinocerebellar ataxias (SCA) but the true prevalence and electrophysiological characteristics in genetically proven patients of SCA 1, 2 and 3 are largely unknown. METHODS: We prospectively compared the electrophysiological characteristics of neuropathy in 61 genetically confirmed cases of SCA (SCA1=28, SCA2=16 and SCA3=17). Nerve conduction studies were performed in at least one sensory and one motor nerve, in right upper and lower limb using standard methods. RESULTS: The mean age of patients and duration of illness were comparable among SCA groups (mean age (years): SCA1-34.1±12.7, SCA2-35.2±13.9 and SCA3-38.1±11.3; mean duration (years): SCA1-5.4, SCA2-6.1, and SCA3-4.4). Electrophysiological evidence of neuropathy was highest in SCA1 (96.4%), followed by SCA3 (94.1% and SCA2 (87.5%). A mixed sensorimotor neuropathy was commonly observed in all the subgroups (SCA1-78.6%, SCA2-50%, and SCA3-41.2%). Pure sensory neuropathy was most common in SCA3 (55.9%), followed by 31.3% in SCA2 and 17.9% in SCA1. Pure motor neuropathy was uncommon (6.3% in SCA2 and none in SCA1 and SCA3). CONCLUSIONS: Electrophysiological evidence of mixed sensorimotor and pure sensory neuropathy is seen in all the three subtypes of SCAs, while pure motor neuropathy is distinctly uncommon.

Gray matter volume deficits in spinocerebellar ataxia: an optimized voxel based morphometric study.

INTRODUCTION: Spinocerebellar ataxias (SCA) are a group of autosomal dominant ataxias with varied clinical phenotypes. However there are no unique distinguishing features on routine neuroimaging among the various genetically defined SCAs. Voxel-based morphometry (VBM) provides an automated unbiased analysis of structural MRI scans and gives a comprehensive assessment of anatomical differences throughout the brain. OBJECTIVES: The aims of this study were to (i) characterize the patterns of atrophy in SCA1, SCA2 and SCA3 using optimized VBM, (ii) demonstrate the characteristic anatomical differences in these genetically distinct SCA subtypes, and (iii) assess the relationship between morphometric measures and the CAG repeat lengths and other attributes of the disease. METHODS: Thirty-one genetically confirmed patients suffering from SCA (SCA1 - 12, SCA2 - 9, and SCA3 - 10) were studied. High resolution T1-weighted 3-Dimensional Magnetic Resonance Images of 31 patients were analyzed using the optimized VBM procedure. RESULTS: In all the three SCAs there was a significant loss of gray matter in both cerebellar hemispheres and vermis. Vermian atrophy was more pronounced in SCA3, while SCA1 and SCA2 had significant white matter atrophy. Pontine white matter atrophy was more pronounced in SCA2. In SCA1, the severity of ataxia strongly correlated with the degree of gray matter atrophy in cerebellar hemispheres. The duration of symptoms and lengths of CAG repeats had no correlation with the degree of atrophy. CONCLUSIONS: This study showed that the different subtypes of SCAs may have morphometric differences in the cerebellum, brainstem and the supratentorial structures.

Madras motor neuron disease (MMND): clinical description and survival pattern of 116 patients from Southern India seen over 36 years (1971-2007).

Madras motor neuron disease (MMND), MMND variant (MMNDV) and Familial MMND (FMMND) have a unique geographic distribution predominantly reported from Southern India. The characteristic features are onset in young, weakness and wasting of limbs, multiple lower cranial nerve palsies and sensorineural hearing loss. We describe the clinical features and survival pattern in 116 patients with Sporadic MMND, MMND variant and FMMND. A retrospective review of patients' medical records for clinical manifestations, electromyography, imaging, audiological and histopathology findings was performed. Over 36 years (1971 to 2007) 116 patients (men: 59; women: 57) particularly hailing from Southern India were seen. Mean age of onset was 15.8+/-7.9 years. Predominant initial manifestations were impaired hearing with wasting and weakness of distal limb muscles and pyramidal dysfunction. All patients had clinical and/or audiological evidence of hearing impairment. Patients with MMNDV in addition had optic atrophy. The overall mean survival duration was 334.9+/-27.9 months. Thus, Madras motor neuron disease is clinically a distinct entity with features of amyotrophic lateral sclerosis but with young age of onset and presence of auditory neuropathy. Studies to look for environmental and genetic basis of this intriguing disease are necessary to find the causation of this rare disorder.

SCA 1, SCA 2 & SCA 3/MJD mutations in ataxia syndromes in southern India.

BACKGROUND & OBJECTIVE: Spinocerebellar ataxias (SCAs) are often caused by expansions of CTG/ CAG trinucleotide repeat in the genome. Expansions at the SCA1, 2 and 3 loci are the most frequent, but differences in their relative proportion in regions occur across the world. We carried out this study to assess the occurrence of SCA1, 2 and 3, at a tertiary neuro-psychiatric center in Bangalore, Karnataka. METHODS: Probands (N=318) who were diagnosed to have an ataxia syndrome (progressive degenerative ataxia of unknown cause) attending the clinical services of the National Institute of Mental Health and Neuro Sciences (NIMHANS), Bangalore, were evaluated over a period of three years. Standard protocols were used for both clinical and molecular diagnosis. RESULTS: Genotyping established that SCA1, 2 and 3 accounted for more than one third of the ataxia cases seen in the clinic. In the cases with established family history and autosomal dominant inheritance SCA1 was most prevalent followed by SCA2 and SCA3. INTERPRETATION & CONCLUSION: Our findings suggested SCA1 rather than SCA2 to be the more common mutation in southern India. Large numbers of SCA3 probands were also identified. Differences in prevalence of these syndromes within India need to be explored further for founder effects, correlations with phenotype, and patterns of outcome. Family history was not apparent in almost a fifth of those tested positive, highlighting the value of testing even in the absence of family history. Molecular testing should be extended to cover the other forms of ataxia, of which a large number are now known. Combined efforts to confirm the presence of these less common forms, as well as family studies to detect novel mutations, are necessary in this context in India.