Mechanisms and Therapeutic Implications of Neuroleptic Atypicality

Neuroleptics have proven effective for the overall treatment of schizophrenia. The neuroleptic therapy of schizophrenia, however, has been limited by tardive dyskinesia and by the relative inability of neuroleptics to ameliorate the negative symptoms of schizophrenia. Intensive research has been conducted to identify atypical neuroleptics which would not cause TD and which would have relatively greater efficacy in treating negative symptoms. Based upon animal models of TD and negative symptoms, four neuroleptics have been identified which may have these properties: clozapine, thioridazine, sulpiride, and molindone. Clinical studies of TD suggest that these four potentially atypical agents may have lower dyskinetic potential than typical neuroleptics. Additionally, clinical studies of negative symptoms suggest that molindone and sulpiride, but not clozapine or thioridazine may preferentially treat depressive-like negative schizophrenic symptomatology. The atypical effects of clozapine, thioridazine, sulpiride and molindone, suggest that they may have a distinct place in the pharmacotherapy of schizophrenia

Preliminary Evidence of Pre-Attentive Distinctions of Frequency-Modulated Tones that Convey Affect

Recognizing emotion is an evolutionary imperative. An early stage of auditory scene analysis involves the perceptual grouping of acoustic features, which can be based on both temporal coincidence and spectral features such as perceived pitch. Perceived pitch, or fundamental frequency (F0), is an especially salient cue for differentiating affective intent through speech intonation (prosody). We hypothesized that: (1) simple frequency-modulated tone abstractions, based on the parameters of actual prosodic stimuli, would be reliably classified as representing differing emotional categories; and (2) that such differences would yield significant mismatch negativities (MMNs) – an index of pre-attentive deviance detection within the auditory environment. We constructed a set of FM tones that approximated the F0 mean and variation of reliably recognized happy and neutral prosodic stimuli. These stimuli were presented to 13 subjects using a passive listening oddball paradigm. We additionally included stimuli with no frequency modulation (FM) and FM tones with identical carrier frequencies but differing modulation depths as control conditions. Following electrophysiological recording, subjects were asked to identify the sounds they heard as happy, sad, angry, or neutral. We observed that FM tones abstracted from happy and no-expression speech stimuli elicited MMNs. Post hoc behavioral testing revealed that subjects reliably identified the FM tones in a consistent manner. Finally, we also observed that FM tones and no-FM tones elicited equivalent MMNs. MMNs to FM tones that differentiate affect suggests that these abstractions may be sufficient to characterize prosodic distinctions, and that these distinctions can be represented in pre-attentive auditory sensory memory

The Spectrotemporal Filter Mechanism of Auditory Selective Attention

SummaryAlthough we have convincing evidence that attention to auditory stimuli modulates neuronal responses at or before the level of primary auditory cortex (A1), the underlying physiological mechanisms are unknown. We found that attending to rhythmic auditory streams resulted in the entrainment of ongoing oscillatory activity reflecting rhythmic excitability fluctuations in A1. Strikingly, although the rhythm of the entrained oscillations in A1 neuronal ensembles reflected the temporal structure of the attended stream, the phase depended on the attended frequency content. Counter-phase entrainment across differently tuned A1 regions resulted in both the amplification and sharpening of responses at attended time points, in essence acting as a spectrotemporal filter mechanism. Our data suggest that selective attention generates a dynamically evolving model of attended auditory stimulus streams in the form of modulatory subthreshold oscillations across tonotopically organized neuronal ensembles in A1 that enhances the representation of attended stimuli

Impaired Motion Processing in Schizophrenia and the Attenuated Psychosis Syndrome : Etiological and Clinical Implications

The authors thank Gail Silipo, M.A. for assistance in subject recruitment, Raj Sangoi (RT)(R)(MR) and Caxia Hu, M.S., for assistance in MRI scanning and Isabel and Herb Stusser for their generous support. This research was supported by NIMH grant MH084031 (MJH) DA03383 (DCJ).Peer reviewedPostprin

Predicting success: patterns of cortical activation and deactivation prior to response inhibition

The present study investigated the relationships between attention and other preparatory processes prior to a response inhibition task and the processes involved in the inhibition itself. To achieve this, a mixed fMRI design was employed to identify the functional areas activated during both inhibition decision events and the block of trials following a visual cue introduced 2 to 7 sec prior (cue period). Preparing for successful performance produced increases in activation for both the cue period and the inhibition itself in the frontoparietal cortical network. Furthermore, preparation produced activation decreases in midline areas (insula and medial prefrontal) argued to be responsible for monitoring internal emotional states, and these cue period deactivations alone predicted subsequent success or failure. The results suggest that when cues are provided to signify the imminent requirement for behavioral control, successful performance results from a coordinated pattern of preparatory activation in task-relevant areas and deactivation of task-irrelevant ones

Grabbing Your Ear: Rapid Auditory-Somatosensory Multisensory Interactions in Low-level Sensory Cortices Are Not Constrained by Stimulus Alignment

Multisensory interactions are observed in species from single-cell organisms to humans. Important early work was primarily carried out in the cat superior colliculus and a set of critical parameters for their occurrence were defined. Primary among these were temporal synchrony and spatial alignment of bisensory inputs. Here, we assessed whether spatial alignment was also a critical parameter for the temporally earliest multisensory interactions that are observed in lower-level sensory cortices of the human. While multisensory interactions in humans have been shown behaviorally for spatially disparate stimuli (e.g. the ventriloquist effect), it is not clear if such effects are due to early sensory level integration or later perceptual level processing. In the present study, we used psychophysical and electrophysiological indices to show that auditory-somatosensory interactions in humans occur via the same early sensory mechanism both when stimuli are in and out of spatial register. Subjects more rapidly detected multisensory than unisensory events. At just 50 ms post-stimulus, neural responses to the multisensory ‘whole' were greater than the summed responses from the constituent unisensory ‘parts'. For all spatial configurations, this effect followed from a modulation of the strength of brain responses, rather than the activation of regions specifically responsive to multisensory pairs. Using the local auto-regressive average source estimation, we localized the initial auditory-somatosensory interactions to auditory association areas contralateral to the side of somatosensory stimulation. Thus, multisensory interactions can occur across wide peripersonal spatial separations remarkably early in sensory processing and in cortical regions traditionally considered unisensor

The characteristics of cognitive neuroscience tests in a schizophrenia cognition clinical trial: Psychometric properties and correlations with standard measures.

In comparison to batteries of standard neuropsychological tests, cognitive neuroscience tests may offer a more specific assessment of discrete neurobiological processes that may be aberrant in schizophrenia. However, more information regarding psychometric properties and correlations with standard neuropsychological tests and functional measures is warranted to establish their validity as treatment outcome measures. The N-back and AX-Continuous Performance Task (AX-CPT) are two promising cognitive neuroscience tests designed to measure specific components of working memory and contextual processing respectively. In the current study, we report the psychometric properties of multiple outcome measures from these two tests as well as their correlations with standard neuropsychological measures and functional capacity measures. The results suggest that while the AX-CPT and N-back display favorable psychometric properties, they do not exhibit greater sensitivity or specificity with functional measures than standard neurocognitive tests

Multimodal Computational Modeling of Visual Object Recognition Deficits but Intact Repetition Priming in Schizophrenia

The term perceptual closure refers to the neural processes responsible for “filling-in” missing information in the visual image under highly adverse viewing conditions such as fog or camouflage. Here we used a closure task that required the participants to identify barely recognizable fragmented line-drawings of common objects. Patients with schizophrenia have been shown to perform poorly on this task. Following priming, controls and importantly patients can complete the line-drawings at greater levels of fragmentation behaviorally, suggesting an improvement in their ability to performthe task. Closure phenomena have been shown to involve a distributed network of cortical regions, notably the lateral occipital complex (LOC) of the ventral visual stream, dorsal visual stream (DS), hippocampal formation (HIPP) and the prefrontal cortex (PFC). We have previously demonstrated the failure of closure processes in schizophrenia and shown that the dysregulation in the sensory information transmitted to the prefrontal cortex plays a critical role in this failure. Here, using a multimodal imaging approach in patients, combining event related electrophysiological recordings (ERP) and functional magnetic resonance imaging (fMRI), we characterize the spatiotemporal dynamics of priming in perceptual closure. Using directed functional connectivitymeasures we demonstrate that priming modifies the network-level interactions between the nodes of closure processing in a manner that is functionally advantageous to patients resulting in the mitigation of their deficit in perceptual closure

Disruption of early visual processing in amyloid-positive healthy individuals and mild cognitive impairment

Background Amyloid deposition is a primary predictor of Alzheimer’s disease (AD) and related neurodegenerative disorders. Retinal changes involving the structure and function of the ganglion cell layer are increasingly documented in both established and prodromal AD. Visual event-related potentials (vERP) are sensitive to dysfunction in the magno- and parvocellular visual systems, which originate within the retinal ganglion cell layer. The present study evaluates vERP as a function of amyloid deposition in aging, and in mild cognitive impairment (MCI). Methods vERP to stimulus-onset, motion-onset, and alpha-frequency steady-state (ssVEP) stimuli were obtained from 16 amyloid-positive and 41 amyloid-negative healthy elders and 15 MCI individuals and analyzed using time–frequency approaches. Social cognition was assessed in a subset of individuals using The Awareness of Social Inference Test (TASIT). Results Neurocognitively intact but amyloid-positive participants and MCI individuals showed significant deficits in stimulus-onset (theta) and motion-onset (delta) vERP generation relative to amyloid-negative participants (all p  70%. Discussion vERP may assist in the early detection of amyloid deposition among older individuals without observable neurocognitive impairments and in linking previously documented retinal deficits in both prodromal AD and MCI to behavioral impairments in social cognition

Network-level mechanisms underlying effects of transcranial direct current stimulation (tDCS) on visuomotor learning

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation approach in which low level currents are administered over the scalp to influence underlying brain function. Prevailing theories of tDCS focus on modulation of excitation-inhibition balance at the local stimulation location. However, network level effects are reported as well, and appear to depend upon differential underlying mechanisms. Here, we evaluated potential network-level effects of tDCS during the Serial Reaction Time Task (SRTT) using convergent EEG- and fMRI-based connectivity approaches. Motor learning manifested as a significant (p \u3c.0001) shift from slow to fast responses and corresponded to a significant increase in beta-coherence (p \u3c.0001) and fMRI connectivity (p \u3c.01) particularly within the visual-motor pathway. Differential patterns of tDCS effect were observed within different parametric task versions, consistent with network models. Overall, these findings demonstrate objective physiological effects of tDCS at the network level that result in effective behavioral modulation when tDCS parameters are matched to network-level requirements of the underlying task