Specific Substantial Dysconnectivity in Schizophrenia: A Transdiagnostic Multimodal Meta-analysis of Resting-State Functional and Structural Magnetic Resonance Imaging Studies.

BACKGROUND: This study investigated characteristic large-scale brain changes in schizophrenia. Numerous imaging studies have demonstrated brain changes in schizophrenia, particularly aberrant intrinsic functional connectivity (iFC) of ongoing brain activity, measured by resting-state functional magnetic resonance imaging, and aberrant gray matter volume (GMV) of distributed brain regions, measured by structural magnetic resonance imaging. It is unclear, however, which iFC changes are specific to schizophrenia compared with those of other disorders and whether such specific iFC changes converge with GMV changes. To address this question of specific substantial dysconnectivity in schizophrenia, we performed a transdiagnostic multimodal meta-analysis of resting-state functional and structural magnetic resonance imaging studies in schizophrenia and other psychiatric disorders. METHODS: Multiple databases were searched up to June 2017 for whole-brain seed-based iFC studies and voxel-based morphometry studies in schizophrenia, major depressive disorder, bipolar disorder, addiction, and anxiety. Coordinate-based meta-analyses were performed to detect 1) schizophrenia-specific hyperconnectivity or hypoconnectivity of intrinsic brain networks (compared with hyperconnectivity or hypoconnectivity of each other disorder both separately and combined across comparisons) and 2) the overlap between dysconnectivity and GMV changes (via multimodal conjunction analysis). RESULTS: For iFC meta-analysis, 173 publications comprising 4962 patients and 4575 control subjects were included, and for GMV meta-analysis, 127 publications comprising 6311 patients and 6745 control subjects were included. Disorder-specific iFC dysconnectivity in schizophrenia (consistent across comparisons with other disorders) was found for limbic, frontoparietal executive, default mode, and salience networks. Disorder-specific dysconnectivity and GMV reductions converged in insula, lateral postcentral cortex, striatum, and thalamus. CONCLUSIONS: Results demonstrated specific substantial dysconnectivity in schizophrenia in insula, lateral postcentral cortex, striatum, and thalamus. Data suggest that these regions are characteristic targets of schizophrenia.

Elevated striatal dopamine attenuates nigrothalamic inputs and impairs transthalamic cortico-cortical communication in schizophrenia: a hypothesis.

Schizophrenia has been found to involve source-monitoring deficits, whereby perceptions that result from self-initiated motor output become attributed to outside sources. One example of this phenomenon are the so called passivity experiences, such as delusions of control, during which the individual feels that own actions are controlled remotely by someone else. To explain these phenomena, it has been proposed that this illness involves efference copy failure. In other words, brain mechanism that prepare perceptual processes for the sensory consequences of self-initiated actions are impaired leading to their misattribution and to psychosis. In earlier work, it was argued that efference copy failure in schizophrenia is related to thalamic abnormalities. Namely, the thalamus can be thought of as a hub for cortico-cortical interactions, and these transthalamic cortico-cortical interactions were found to play a part in internal motor monitoring. Cortico-cortical communication via the thalamus can be impaired in a number of ways. For example, one way to impair these interactions is by interfering with the ability of the thalamus to display bursts of firing. As the burst firing mode in the thalamus requires a preceding period of prolonged hyperpolarization (100ms), one way to reduce the burst propensity of thalamic neurons is to interfere with the ability to display prolonged hyperpolarizations. In this paper, we argue that elevated striatal dopaminergic activity in schizophrenia attenuates nigrothalamic GABAergic inputs, and thereby reduces burst propensity of the mediodorsal (MD) thalamic nucleus in schizophrenia, with the ultimate result of reduced transthalamic cortico-cortical communication, relative disconnection between functionally associated cortical areas and to psychosis. Conversely, dopamine D2 receptor blockers (antipsychotics) may help restore nigrothalamic GABAergic inputs, thereby increasing the burst propensity in the thalamus.

NMDA receptor hypofunction and the thalamus in schizophrenia.

The thalamus can be subdivided into two kinds of nuclei, the higher order (HO) and the first order (FO) relays, which are distinguished based on the origin of their main or driver inputs. The driver inputs to the HO nuclei arrive from the cortex, and the messages they deliver are then relayed to other cortical areas. As the origin of these inputs is the cortical layer V, whose axons branch and innervate lower motor centers in the CNS, the messages are copies of motor instructions issued to those lower motor centers. These copies are thus an integral part of perceptual processes. In schizophrenia, the HO nuclei are shrunken suggesting that a reduced ability to integrate copies of ongoing motor commands in perceptual processes may be one part of the underlying pathophysiology. The driver inputs in the thalamus utilize ionotropic glutamate receptors such as the NMDAR. NMDAR antagonists may exert their pro-psychotic effects by impairing the function of the HO nuclei. Here, we argue that such agents (or the proposed NMDAR hypofunction in schizophrenia) weaken the driver inputs in the HO nuclei, thereby producing a cortico-thalamo-cortical disconnection and impairing sensorimotor integration.

Cannabis, psychosis and the thalamus: a theoretical review.

The role of cannabis in the etiology of schizophrenia has been documented as possibly the strongest environmental risk factor. However, the pathomechanism whereby cannabis use increases this risk has not yet been identified. We argue that this pathomechanism may involve direct effects of exogenous cannabinoids on T-type calcium channels in the thalamus. These channels are crucial for amplification of corticothalamic inputs, as well as for the ability of the thalamus to generate neuronal burst firing. Cortically induced thalamic burst firing has been found to be important in trans-thalamic cortico-cortical interactions. Therefore, any potential interference with the burst firing mode in the thalamus could lead to an impairment in these interactions, which in turn causes a relative disconnection between cortical areas. This in turn could result in reduced ability to recognize re-afferent sensory inputs and psychosis. We also argue that the effects of Δ(9)THC are more detrimental compared with the effects of cannabidiol, as the former may increase the excitability of thalamic neurons by its direct effect on T-type calcium channels.

Neuroconnectivity and valproic acid: the myelin hypothesis.

Neuropsychiatric medications that directly alter the epigenome, such as valproic acid, can under certain conditions reactivate critical developmental periods and thus impact adult neuroconnectivity. In animal models valproic acid was shown to inhibit the process of postnatal myelination and to replicate age-dependent decline in remyelination efficiency. The human central nervous system's myelination process, unlike that of non-human primates commonly used in the experimental models, is an intricate heterochronous process that continues well into adult life and which probably underlies later life neurocognitive changes and plasticity. Chronic exposure to valproic acid, especially in patients with epilepsy and neuropsychiatric disorders, may profoundly affect this process and its developmental trajectory. Further studies using novel MRI methods that allow in vivo mapping of myelination trajectories across the lifespan are urgently required to address the potential effects of valproic acid on brain development.

Abnormalities in thalamic neurophysiology in schizophrenia: could psychosis be a result of potassium channel dysfunction?

Psychosis in schizophrenia is associated with source-monitoring deficits whereby self-initiated behaviors become attributed to outside sources. One of the proposed functions of the thalamus is to adjust sensory responsiveness in accordance with the behavioral contextual cues. The thalamus is markedly affected in schizophrenia, and thalamic dysfunction may here result in reduced ability to adjust sensory responsiveness to ongoing behavior. One of the ways in which the thalamus accomplishes the adjustment of sensory processing is by a neurophysiological shift to post-inhibitory burst firing mode prior to and during certain exploratory actions. Reduced amount of thalamic burst firing may result from increased neuronal excitability secondary to a reported potassium channel dysfunction in schizophrenia. Pharmacological agents that reduce the excitability of thalamic cells and thereby promote burst firing by and large tend to have antipsychotic effects.

Sleep abnormalities in schizophrenia may suggest impaired trans-thalamic cortico-cortical communication: towards a dynamic model of the illness.

Schizophrenia is associated with a wide range of symptoms. These include auditory hallucinations, delusions, and experiences that one is not in control of one's own thoughts and actions, but that they are inserted by an outside agency. It has been proposed that a disturbance in the sense of self may account for many of these symptoms. This disturbance in turn may be associated with source monitoring deficits. In other words, individuals with schizophrenia may misattribute the source of their own thoughts and actions to an outside agency, which then results in the experience of psychosis such as that of hearing voices. To explain the source monitoring deficits, it has been proposed that this illness involves impairment in corollary discharge mechanisms. Corollary discharge refers to preparation of sensory systems that will be affected by an action in advance of that action, which then allows this action to be recognized as one's own. Current research on corollary discharges suggests that they may involve the thalamus, which is notably affected in schizophrenia in terms of volume loss. Sleep abnormalities in this illness also suggest thalamic dysfunction as sleep spindles, which are markedly reduced in schizophrenia, require intact thalamocortical interactions. In this review, evidence is presented that suggests that propagation of corollary discharges and sleep spindles may be two mechanistically related processes as both involve trans-thalamic cortico-cortical interactions. These interactions may be impaired in schizophrenia and characterization of their mechanism may constitute a step towards developing a dynamic model of schizophrenia.

Lingual epilepsia partialis continua in a girl.

Epilepsia partialis continua (EPC) is characterized by focal seizures that cannot be stopped. The most common cause of EPC in children is Rasmussen's encephalitis. In this video case report, we describe an 11-year old female with continuous lingual EPC for two years. She has shown no signs of Rasmussen's Encephalitis or other neurodegenerative process and structural MRI is normal. [Published with video sequences].

Sexual addiction, sexual compulsivity, sexual impulsivity, or what? Toward a theoretical model.

We critically review the concepts of sexual addiction, sexual compulsivity, and sexual impulsivity and discuss their theoretical bases. A sample of 31 self-defined sex addicts were assessed by means of interview and questionnaires and compared with a large age-matched control group. A tendency to experience increased sexual interest in states of depression or anxiety was strongly characteristic of the sex addict group. Dissociative experiences were described by 45% of sex addicts and may have some explanatory relevance. Obsessive-compulsive mechanisms may be relevant in some cases, and the addiction concept may prove to be relevant with further research. Overall, results suggested that out of control sexual behavior results from a variety of mechanisms. We propose an alternative theoretical approach to investigating these mechanisms based on the dual control model and recent research on the relation between mood and sexuality.

Sexual risk-taking in gay men: the relevance of sexual arousability, mood, and sensation seeking.

This paper examined the relationship of three aspects of personality to sexual risk-taking in gay men: (1). sexual arousability, as propensity for sexual excitation, and propensity for inhibition of sexual arousal in the face of threat (measured by the Sexual Excitation, SES, and Sexual Inhibition, SIS1, SIS2, scales); (2). the relation between negative mood and sexuality; and (3). sensation seeking. Risk-taking was assessed for the past 6 months in relation to unprotected anal intercourse (UAI), oral sex, number of casual partners, and patterns of cruising behavior. A combination of number of partners and use of condoms was used to derive a "longer-term risk" grouping. Two patterns of association were identified. UAI and high risk oral sex were more likely in those with low inhibition of sexual response due to "threat of performance consequences" (i.e., low SIS2) and low trait anxiety (low STAI). High numbers of casual partners and frequent cruising were associated with increased sexual interest in states of depression and high propensity for sexual excitation (SES). Higher "long-term risk" was also associated with low SIS2. Unexpectedly, high SIS1, which is strongly related to vulnerability to erectile failure, was also predictive of higher long-term risk. Possible reasons for this are discussed. Disinhibition from the Sensation Seeking Scales was a positive predictor of all types of sexual risk assessed. All three aspects of personality are of potential relevance to designing better interventions to reduce high risk sexual behavior and in evaluating their effectiveness.

The relation between mood and sexuality in heterosexual men.

This paper reports on a study of individual variability in the relationship between negative mood and sexuality in men. Part 1 involves a questionnaire survey of 919 white heterosexual men, asking what typically happens to sexual interest and response when (a) depressed and (b) anxious/stressed, using the Mood and Sexuality Questionnaire (MSQ). Trait measures of sexual inhibition and excitation, depression, anxiety, and sensation seeking were also used. Relationships between trait measures and MSQ scores were tested using multiple linear and ordinal logistic regression. Of those reporting the experience of depression, 9.4% indicated increased and 42% decreased sexual interest when depressed; for anxiety/stress, the percentages were 20.6 and 28.3%, respectively. Increase in sexual interest during negative mood states was negatively related to age and trait measures of sexual inhibition and positively related to depression proneness and sexual excitation. In Part 2, the relationship between mood and sexuality was explored qualitatively, using in-depth interviews with 43 participants from Part 1. This supported the findings in Part 1, while finding more complex relations with depression than anxiety. Sex when depressed can serve needs for intimacy and self-validation as well as sexual pleasure. Sex when anxious appears to be more simply related to the calming effect of sexual release, plus a possible "excitation transfer" effect of anxious arousal. Further research is needed to explore these relationships in clinical mood disorders. Paradoxical increases of sexual interest with negative mood may help explain high risk as well as "out of control" patterns of sexual behavior.

The relation between mood and sexuality in gay men.

Negative mood, such as depression and anxiety, is usually associated with a decrease in sexual interest and responsiveness. In a minority of individuals, the reverse applies, often with an associated tendency to use sex as a mood regulator. In homosexual men, the prevalence of depression and anxiety states is increased, and the relationship between negative mood and sexuality is, therefore, of particular interest. A new brief instrument, The Mood and Sexuality Questionnaire, was administered to a sample of 662 gay men, with other trait measures of depression and anxiety, propensity for sexual inhibition and sexual excitation, sensation seeking, and questions about sexual activity and response. Sixteen percent reported that, when depressed, they typically experienced increased sexual interest with 7% reporting increased capacity for erectile response; 47% and 37% reported a decrease, respectively; the remainder reported no change. When experiencing anxiety, 24% reported that they typically experienced increased sexual interest, with 14% reporting increased responsiveness, and 39% and 31% reporting a decrease. Forty-three men were interviewed in depth. The resulting qualitative data showed depression to have a more complex relationship to sexual interest than anxiety; other mediating mechanisms, such as need for intimacy and self-validation, were sometimes involved. Fourteen percent of those interviewed reported reduced concern about sexual risk when depressed. Paradoxical increases in sexual interest or activity during negative mood states are relevant to high risk sexual behavior among gay men, and deserve closer study.