Insula and amygdala resting-state functional connectivity differentiate bipolar from unipolar depression.

OBJECTIVE: Distinguishing depressive episodes due to bipolar disorder (BD) or major depressive disorder (MDD) solely on clinical grounds is challenging. We aimed at comparing resting-state functional connectivity (rsFC) of regions subserving emotional regulation in similarly depressed BD and MDD. METHOD: We enrolled 76 in-patients (BD, n = 36; MDD, n = 40) and 40 healthy controls (HC). A seed-based approach was used to identify regions showing different rsFC with the insula and the amygdala. Insular and amygdalar parcellations were then performed along with diagnostic accuracy of the main findings. RESULTS: Lower rsFC between the left insula and the left mid-dorsolateral prefrontal cortex and between bilateral insula and right frontopolar prefrontal cortex (FPPFC) was observed in BD compared to MDD and HC. These results were driven by the dorsal anterior and posterior insula (PI). Lower rsFC between the right amygdala and the left anterior hippocampus was observed in MDD compared to BD and HC. These results were driven by the centromedial and laterobasal amygdala. Left PI/right FPPC rsFC showed 78% accuracy differentiating BD and MDD. CONCLUSION: rsFC of amygdala and insula distinguished between depressed BD and MDD. The observed differences suggest the possibility of differential pathophysiological mechanisms of emotional dysfunction in bipolar and unipolar depression.

Immune function and brain abnormalities in patients with systemic lupus erythematosus without overt neuropsychiatric manifestations.

OBJECTIVE: This study examined the relationship between immune, cognitive and neuroimaging assessments in subjects with systemic lupus erythematosus (SLE) without histories of overt neuropsychiatric (NP) disorders. METHODS: In total, 84 subjects with nonNPSLE and 37 healthy controls completed neuropsychological testing from the American College of Rheumatology SLE battery. Serum autoantibody and cytokine measures, volumetric magnetic resonance imaging, and magnetic resonance spectroscopy data were collected on a subset of subjects. RESULTS: NonNPSLE subjects had lower scores on measures of visual/complex attention, visuomotor speed and verbal memory compared with controls. No clinically significant differences between nonNPSLE patients and controls were found on serum measures of lupus anticoagulant, anticardiolipin antibodies, beta 2-glycoproteins, or pro-inflammatory cytokines (interleukin (IL)-1, IL-6, interferon alpha (IFN-alpha), and interferon gamma (IFN-gamma)). Higher scores on a global cognitive impairment index and a memory impairment index were correlated with lower IFN-alpha. Few associations between immune functions and neuroimaging parameters were found. CONCLUSIONS: Results indicated that nonNPSLE patients demonstrated cognitive impairment but not immune differences compared with controls. In these subjects, who were relatively young and with mild disease, no relationship between cognitive dysfunction, immune parameters, or previously documented neuroimaging abnormalities were noted. Immune measures acquired from cerebrospinal fluid instead of serum may yield stronger associations.

Memory impairment associated with neurometabolic abnormalities of the hippocampus in patients with non-neuropsychiatric systemic lupus erythematosus.

OBJECTIVE: Memory impairment is common in patients with systemic lupus erythematosus (SLE). This study examined hippocampal volumes and neurometabolic alterations in relation to memory function in SLE patients without a history of neuropsychiatric syndromes (nonNPSLE). METHODS: Subjects included 81 nonNPSLE patients and 34 healthy controls. Volumetric magnetic resonance imaging and magnetic resonance spectroscopy of the right and left hippocampal areas (RH, LH) were performed. Verbal and visual memory tests were administered and a memory impairment index (MII) was derived from standardized tests. RESULTS: Higher memory impairment (MII) was correlated with lower RH glutamate + glutamine/creatine (p = 0.009) and lower RH N-acetylaspartic acid/creatine (p = 0.012) in nonNPSLE patients. A trend for a negative correlation between RH and LH volumes and MII was evident for absolute hippocampal volumes. Lower RH glutamate + glutamine/creatine was also correlated with worse performance in a mean visual memory index (p = 0.017). CONCLUSIONS: An association between reduced memory and lower N-acetylaspartic acid/creatine in the RH suggests neuronal damage in nonNPSLE patients with very mild and early disease. Alterations in glutamate + glutamine/creatine further indicate early metabolic changes in nonNPSLE are related to memory impairment, a finding that might suggest that memory impairment relates to presynaptic glutamatergic dysfunction in the hippocampus.

The differential diagnosis of Axis I psychopathology presenting to a university-based multiple sclerosis clinic.

Patients carrying a presumptive diagnosis of multiple sclerosis (MS) sometimes present with non-specific clinical signs and symptoms that may be, at least in part, somatic manifestations of psychiatric conditions. This retrospective study was undertaken to identify psychiatric diagnoses among 63 patients whose initial clinical evaluations suggested a primary psychiatric, rather than a primary neurological, etiology for their symptoms. Some 92% of patients met Diagnostic and Statistical Manual of Mental Disorders Fourth Edition Text Revision (DSM-IV-TR) criteria for one or more primary psychiatric disorders, most often including somatoform, mood, and anxiety disorders. Accurate identification and diagnosis of psychiatric conditions producing pseudoneurological or non-specific somatic symptoms is necessary for both treatment and medico-economic reasons.

Effects of rivastigmine on cognitive function in patients with traumatic brain injury.

OBJECTIVE: To compare the efficacy and safety of rivastigmine (3 to 6 mg/day) vs placebo over 12 weeks in patients with traumatic brain injury and persistent cognitive impairment. METHODS: This prospective, randomized, double-blind, placebo-controlled study was conducted in 157 patients at least 12 months after injury. The primary efficacy measures were the Cambridge Neuropsychological Test Automated Battery (CANTAB) Rapid Visual Information Processing (RVIP) A' subtest and the Hopkins Verbal Learning Test (HVLT). The primary efficacy outcome was the proportion of patients who demonstrated 1.0 SD or greater improvement from baseline at week 12 on CANTAB RVIP A' or HVLT. RESULTS: The percentage of responders at week 12 on either the CANTAB RVIP A' or HVLT was 48.7% for rivastigmine and 49.3% for placebo (p = 0.940). Furthermore, for the overall study population, there were no significant differences for any of the secondary efficacy variables. In a subgroup of patients with moderate to severe memory impairment (n = 81), defined as 25% impairment or greater on HVLT at baseline, rivastigmine was significantly better than placebo for a number of measures, including the proportion of HVLT responders and CANTAB RVIP mean latency. CONCLUSIONS: Rivastigmine was safe and well tolerated in patients with traumatic brain injury with cognitive deficits. Rivastigmine shows promising results in the subgroup of patients with traumatic brain injury with moderate to severe memory deficits.

Constraint-induced therapy for moderate chronic upper extremity impairment after stroke.

PRIMARY OBJECTIVE: To explore the effectiveness of constraint-induced therapy (CIT) in the treatment of individuals with moderate chronic upper extremity paresis. RESEARCH DESIGN: Multiple case reports, pre-post-treatment comparisons as well as long-term follow-ups at 1 and 6 months after intervention. METHODS AND PROCEDURES: Seven subjects, each greater than 12 months post-stroke, participated in an intensive 3 weeks CIT programme. The Wolf Motor Function Test (WMFT), Motor Activity Log (MAL) and Fugl-Meyer Evaluation (FM) were used to measure outcomes. MAIN OUTCOMES AND RESULTS: Subjects exhibited notable improvements in mean WMFT scores (0.25 point increase post-treatment, 0.38 point increase at 1-month follow-up, 0.44 point increase at 6-month follow-up). Similarly, improvements were seen for mean MAL (1.71 points for AS, 1.77 points for HW) and FM scores (6 points FM-UE, 6 points FM-TOT) post-treatment. Additional improvements were seen at some follow-up assessments. CONCLUSIONS: Subjects demonstrated gains in objective measures, however, did not regain normal functional ability of their paretic upper extremities. Further investigation of the effects of CIT in this population, as well the functional significance of the objective measures used is warranted.

Reduced hippocampal volume in association with p50 nonsuppression following traumatic brain injury.

Traumatic brain injury (TBI) may produce persistently impaired auditory gating. This cholinergic-dependent, hippocampally mediated preattentive cognitive function that facilitates filtering of auditory stimuli may be indexed by the P50 evoked waveform to paired auditory stimuli. Abnormal P50 suppression post TBI is believed to result from injury to the hippocampus and/or its afferent cholinergic projections. This hypothesis was tested by comparing hippocampal and total brain volumes on MRI between ten P50-nonsuppressing TBI patients and ten normal control subjects matched for age, gender, and education. TBI subjects had highly significant bilateral hippocampal volume reductions, even when covaried for reductions in total brain volume. Degree of volume loss was not correlated with initial TBI severity. Findings support the hypothesis that hippocampal injury underlies P50 nonsuppression post TBI and suggest that such structural abnormalities may be observed even in "mildly" injured persons.

Fine structure of the auditory M100 in schizophrenia and schizoaffective disorder.

BACKGROUND: Several studies have demonstrated anomalous asymmetry of the 100-msec latency auditory-evoked field (M100) in schizophrenia. Recent evidence suggests this may be a compound component, however. Our study examines the localization of two M100 subcomponents in patients with schizophrenia and schizoaffective disorder. METHODS: Magnetoencephalographic recordings of auditory-evoked fields were obtained for 14 subjects with schizophrenia, 12 with schizoaffective disorder, and 23 control subjects. Two M100 subcomponents were identified and localized in each hemisphere. RESULTS: Both patient groups exhibited different lateralization compared with control subjects, with the second subcomponent tending to be less lateralized. CONCLUSIONS: The second subcomponent may be the major contributor to previously reported laterality differences. Future studies might benefit by separating M100 subcomponents so that specific functions could be addressed.

Methylphenidate treatment of neuropsychiatric symptoms of central and extrapontine myelinolysis.

OBJECTIVE: Previous reports describe the presentation and course of the neurobehavioral manifestations of central and extrapontine myelinolysis; as of yet, however, there are no specific recommendations for treatment of these problems. We offer the first report of successful treatment. METHOD: We describe a 55-year-old man with chronic alcoholism who developed central and extrapontine myelinolysis following an episode of heavy drinking and rapid correction of hyponatremia. The patient acutely developed motor, cognitive, emotional and behavioral problems best accounted for by central pontine and bilateral striatal myelinolysis. These neuropsychiatric symptoms were treated with methylphenidate over the course of 1 month in an off-on-off-on fashion. The Neuropsychiatric Inventory and other tests were used to assess treatment response. RESULTS: Marked improvements in the patient's neuropsychiatric status were noted only during treatment with methylphenidate. CONCLUSIONS: Methylphenidate effectively reversed the neuropsychiatric symptoms associated with the patient's demyelinating lesions. We discuss possible underlying mechanisms of both symptom formation and treatment effect.

Impaired auditory gating and P50 nonsuppression following traumatic brain injury.

Traumatic brain injury (TBI) can produce persistent attention and memory impairment that may in part be produced by impaired auditory sensory gating. The P50 evoked waveform response to paired auditory stimuli appears to be a useful measure of auditory gating. The first controlled measurement of the P50 ratio in TBI patients is described: when 20 patients with persistently symptomatic TBI were compared with 20 control subjects, the P50 ratio was significantly greater in the TBI group. The potential neurophysiologic and therapeutic implications of this finding in TBI patients who report symptoms consistent with impaired auditory gating are discussed.

The neuropsychiatry of pathologic affect: an approach to evaluation and treatment.

The ability to skillfully regulate the internal experience and outward expression of emotion is among the most complex and recently acquired functions of the human brain. When the capacity for emotional regulation is compromised by disease or injury the impact on individuals and their families may be considerable, both with regard to psychological well-being and social and occupational function. This article describes first a framework for the description, evaluation, and treatment of affective dysregulation. We review the literature regarding disorders of affective regulation, and in particular affective lability. Although disorders of affect as they occur in common neuropsychiatric disorders (eg, stroke, multiple sclerosis, traumatic brain injury, and so on) are the focus of this article, the review incorporates information from the study of patients with primary psychiatric disorders and hence the discussion herein may also be relevant to the understanding and treatment of affective lability in these conditions. An overview of the neurobiology that appears most relevant to understanding such problems is presented, along with several specific methods that appear to be useful in the evaluation of patients with affective lability. Finally, we review the literature regarding the treatment of disorders of affect and offer some practical suggestions for the treatment of patients with these problems.

Hippocampal to pituitary volume ratio: a specific measure of reciprocal neuroendocrine alterations in alcohol dependence.

OBJECTIVE: Studies to date provide conflicting views of the relationship between corticosteroids and decreased hippocampal volume in alcoholism. If this were mediated through the hypothalamic-pituitary-adrenal (HPA) axis, enlarged pituitary volumes relative to hippocampal volumes might be expected and be measurable using the hippocampus to pituitary volume (H:P) ratio. METHOD: Using magnetic resonance imaging (MRI), we performed volumetric analysis of the pituitary and hippocampus on 10 subjects with alcohol dependence (AD) and on 10 normal control subjects. RESULTS: Compared to normal controls, AD subjects demonstrated a trend towards decreased hippocampal volume (p < .06) and increased pituitary volume (p < .07). More importantly, H:P ratios were significantly smaller in AD subjects (p < .01). This observation persisted even when covaried for age. CONCLUSIONS: Reduced H:P ratio fits the hypothesis that ethanol stimulates pituitary corticotrophs resulting in elevated corticosteroid levels and possible injury to the hippocampus. If replicated, reduced H:P ratio may serve as a clinical measure of reciprocal neuroendocrine changes in chronic heavy ethanol use.

Bipolar disorder: anomalous brain asymmetry associated with psychosis.

OBJECTIVE: Anomalous cerebral asymmetry in schizophreniform disorders has been described, but its presence in psychotic mood disorders has not been established. Measures of cerebral asymmetry may distinguish patients with psychotic mood disorders from those with nonpsychotic mood disorders and from comparison subjects. To test this hypothesis, the authors examined functional cerebral asymmetry by using a metric based on magnetic source imaging. METHOD: A total of 33 subjects participated. Nine were patients with bipolar I disorder and a negative history of psychotic symptoms during mood disorder episodes, 12 were patients with bipolar I disorder and a positive history of psychotic symptoms during mood disorder episodes, and 12 were nonpsychiatric comparison subjects. Equivalent current dipole generators in both hemispheres were estimated for the 20-msec-latency somatosensory evoked field (M20) component produced by stimulation of the contralateral median nerve. RESULTS: The comparison subjects demonstrated asymmetry in anterior-posterior equivalent current dipole locations of the M20 (right anterior to left), and the bipolar subjects with no history of psychosis were similarly asymmetric. The bipolar subjects with a history of psychosis during mood episodes, however, demonstrated a reversal of cerebral asymmetry of the M20 (left anterior to right). CONCLUSIONS: Cerebral lateralization of the M20 distinguished bipolar subjects with psychosis from those without psychosis and comparison subjects. The M20 is generated in area 3b of the postcentral gyrus. These findings suggest anatomical displacement of the postcentral gyrus in psychotic disorders and support the hypothesis that anomalous cerebral asymmetry is a feature of psychotic disorders generally, including psychotic mood disorders.

Schizoaffective disorder: evidence for reversed cerebral asymmetry.

BACKGROUND: Schizoaffective disorder is one of the most severe of the affective psychoses, but its pathophysiology is poorly understood. Because cerebral lateralization may be disturbed in psychotic disorders generally, studies examining cerebral asymmetry may improve understanding of the neurobiology specific to schizoaffective disorder. This study examines cerebral lateralization in this patient population using magnetic source localization. METHODS: We studied 16 subjects with schizoaffective disorder and 16 controls. Magnetic source localization was used to identify the location of the 20 msec latency somatosensory evoked field component (M20). RESULTS: In control subjects, the source location was further anterior in the right hemisphere. The subjects with schizoaffective disorder were reverse lateralized. CONCLUSIONS: The findings of a reversed asymmetry of the M20 in patients with schizoaffective disorder suggest an anatomical shift in the placement of the post central gyrus in this disorder, compatible with a disorder of cerebral lateralization. Whether this finding converges or diverges with measurement of the M20 in other psychotic disorders will require further investigation.

The thalamus and the schizophrenia phenotype: failure to replicate reduced volume.

BACKGROUND: Thalamic abnormalities resulting in impaired attention and information processing may form a foundation for cognitive and perceptual disturbances in schizophrenia. Measurements of the thalamus in patients with schizophrenia have shown reductions relative to normal comparison subjects. METHODS: In the current project, magnetic resonance images of the brain were obtained in 10 male and 11 female subjects with paranoid-type schizophrenia, and 15 male and 12 female normal comparison subjects. Total brain and bilateral thalamic volumes were calculated. RESULTS: There were no significant diagnosis, hemisphere, or gender differences in thalamic volumes. CONCLUSIONS: Structural thalamic abnormalities are not likely to universally and parsimoniously explain the schizophrenia phenotype. Abnormal thalamic size in patients with schizophrenia should be understood as reflecting one of several possible structural abnormalities contributing to production of the schizophrenia phenotype, but must be regarded with caution unless paired with functional studies.

Attention and memory dysfunction after traumatic brain injury: cholinergic mechanisms, sensory gating, and a hypothesis for further investigation.

Traumatic brain injury (TBI) is a common occurrence, with a rate of nearly 400,000 new injuries per year. Cognitive and emotional disturbances may become persistent and disabling for many injured persons, and frequently involve symptomatic impairment in attention and memory. Impairments in attention and memory have been well characterized in TBI, and are likely related to disruption of cholinergic functioning in the hippocampus. Additionally, disturbances in this neurotransmitter system may also account for disturbances in sensory gating and discriminative attention in this population. The electroencephalographic P50 waveform of the evoked response to paired auditory stimuli may provide a physiologic market of impaired sensory gating among TBI survivors. The first application of this recording assessment to the TBI population is reported. Preliminary findings in three cases are presented, and the interpretation of impaired sensory gating in this population is discussed. Given the impact of TBI on cholinergic systems, the effects of cholinergic augmentation on attention and memory impairment, and the availability of an electrophysiologic marker of cholinergic dysfunction responsive to cholinergic agents, a testable cholinergic hypothesis for investigation and treatment of these patients is proposed.

Magnetoencephalography and magnetic source imaging: technology overview and applications in psychiatric neuroimaging.

Magnetoencephalography (MEG) is an electrophysiologic brain imaging technology that has been applied to the study of mental illness, particularly schizophrenia. Like electroencephalography, it provides excellent temporal resolution, and in combination with magnetic resonance imaging, can also provide good spatial resolution. Studies of the auditory system in schizophrenia using MEG have demonstrated an abnormality in functional cerebral asymmetry, in which persons with schizophrenia typically show reduced, or reversed, cerebral asymmetry compared with normal subjects. This abnormality is sex-specific; it is more pronounced in males with schizophrenia. These findings have not been demonstrated using other neuroimaging strategies. Thus, MEG appears to offer a unique and valuable contribution to psychiatric neuroimaging. Current research and clinical applications of MEG are limited, however, by the high cost of instrumentation. The cost of MEG systems should improve as more applications are developed, in schizophrenia as well as other neuropsychiatric conditions, and hospitals begin to invest in the technology.