Treating Working Memory Deficits in Schizophrenia: A Review of the Neurobiology

REVIEW

Treating Working Memory Deficits in Schizophrenia: A Review of the Neurobiology Tristram A. Lett, Aristotle N. Voineskos, James L. Kennedy, Brian Levine, and Zafiris J. Daskalakis Cognitive deficits are a core feature of schizophrenia. Among these deficits, working memory impairment is considered a central cognitive impairment in schizophrenia. The prefrontal cortex, a region critical for working memory performance, has been demonstrated as a critical liability region in schizophrenia. As yet, there are no standardized treatment options for working memory deficits in schizophrenia. In this review, we summarize the neuronal basis for working memory impairment in schizophrenia, including dysfunction in prefrontal signaling pathways (e.g., γ-aminobutyric acid transmission) and neural network synchrony (e.g., gamma/theta oscillations). We discuss therapeutic strategies for working memory dysfunction such as pharmacological agents, cognitive remediation therapy, and repetitive transcranial magnetic stimulation. Despite the drawbacks of current approaches, the advances in neurobiological and translational treatment strategies suggest that clinical application of these methods will occur in the near future. Key Words: Cognition, EEG, neurophysiology, schizophrenia, TMS, working memory

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chizophrenia is a common and chronic psychiatric disorder characterized by delusions, hallucinations with concomitant cognitive, organizational, and motivational impairments. Currently approved pharmaceutical treatments for schizophrenia are typically effective for positive symptoms but have little or no effect on cognitive impairment (1). This is of particular concern, because cognitive performance is a key determinant of long-term outcome and mortality in schizophrenia (2). Cognitive dysfunction in schizophrenia shows high prevalence, is relatively stable over time, and is independent of psychotic symptoms (3). Moreover, cognitive dysfunction is present in healthy relatives of schizophrenia patients, and it has been suggested as a biomarker of schizophrenia (4). As a consequence, disturbances in critical cognitive process, such as working memory, are regarded as a core feature of schizophrenia. Of the demonstrated neurocognitive deficits in schizophrenia, research has focused on working memory, which has been defined as the ability to transiently hold and manipulate information to guide goal-directed behavior (5). The contents of working memory are constitutively updated, monitored, and manipulated in response to immediate processing demands (5). Working memory prolongs the impact of experience beyond immediately accessible information to enable the incorporation of information from long-term memory, lexical labels, and other events into goal-oriented behavior (6). The dorsolateral prefrontal cortex (DLPFC) is crucial to working memory function in healthy adults (7). In schizophrenia patients, working memory deficits are associated with dysfunction of DLPFC as well as DLPFC From the Centre for Addiction and Mental Health (TAL, ANV, JLK, ZJD); Institute of Medical Science (TAL, ANV, JLK, ZJD); Department of Psychiatry (ANV, JLK, ZJD); Department of Psychology (BL), University of Toronto; and the Rotman Research Institute (BL), Baycrest Centre Toronto, Toronto, Ontario, Canada. Address correspondence to Zafiris J. Daskalakis, M.D., Ph.D., Temerty Chair in Therapeutic Brain Intervention, Professor of Psychiatry, University of Toronto, Centre for Addiction and Mental Health (CAMH), 1001 Queen Street West, Toronto, Ontario, M6J 1H4 Canada; E-mail: [email protected]. Received Jan 3, 2013; revised and accepted Jul 22, 2013.

0006-3223/$36.00 http://dx.doi.org/10.1016/j.biopsych.2013.07.026

connectivity with other regions and disruption of neurotransmitter input (e.g., γ-aminobutyric acid [GABA], glutamate, and dopamine) (8–10). Working memory in schizophrenia might also have a genetic basis. Schizophrenia patients and their unaffected co-twins perform significantly worse than control subjects on spatial working memory tasks (11). The letter-number-sequencing task (a measure of working memory) has been identified as an endophenotype of schizophrenia with a heritability of .39 (.25–.52) (12). Thus, improved identification of circuit disruption (from DLPFC to other regions) can help provide insights into the pathophysiology of working memory impairment in schizophrenia and the development of novel therapeutic interventions. In this article, we review the neuropsychological and neuroanatomical basis of working memory and its relationship to schizophrenia. Next, the therapeutic approaches for treatment of working memory deficits in schizophrenia are discussed, including pharmacological interventions and cognitive remediation therapy (CRT). Finally, we establish the neurophysiological basis for working memory deficits and present repetitive transcranial magnetic stimulation (rTMS) as a potential novel therapeutic strategy.

Working Memory A key benefit of studying working memory is that psychology and cognitive neuroscience have built a comprehensive framework for understanding the cognitive architecture of working memory and its neural correlates. For instance, studies in nonhuman primates suggest that lesions to the prefrontal cortex (PFC) cause marked reduction in working memory function and that subdivisions of the PFC might represent multiple working memory domains, each having its own specialized processing or content-specific storage (13,14). According to the seminal theoretical model by Baddeley (5), working memory functions can be fractionalized into specialized systems that serve as buffers for the storage and manipulation of information. The model is complemented by empirical evidence that most primate electrophysiology and neuroimaging studies, regardless of experimental procedure, report delay-period activity in the PFC [for examples, see (15,16)]. The PFC is an integral component of executive functioning (e.g., complex attention, planning, and mental flexibility) (17). The PFC contributes to working memory by exerting topdown control through filtering and strategic reorganization of BIOL PSYCHIATRY 2013;]:]]]–]]] & 2013 Society of Biological Psychiatry

2 BIOL PSYCHIATRY 2013;]:]]]–]]] information (18). Therefore, working memory performance would depend on efficient communication to the PFC and its capacity to inhibit extraneous information. Top-down attention relies on parietal and prefrontal regions that largely overlap with activation during working memory tasks in both these regions (19). Moreover, high global brain connectivity to the DLPFC predicts better working memory performance as well as general fluid intelligence (20). The PFC thus acts as a flexible hub by which frontal connectivity is adjusted according to task demands (21). More recently, research has emphasized recruitment of extrafrontal regions involved in perceptual or long-term representations in orchestration with DLPFC (22). Electroencephalagram (EEG) studies show theta coupling between prefrontal and parietal cortices is increased with more complex manipulation (23), memory load (24), and predict individual working memory capacity (25). Theta phase synchrony between the prefrontal and temporal cortices occurs during the maintenance phase of working memory (26) in addition to encoding and retrieval (27). Further evidence for medial temporal lobe involvement comes from intracranial EEG recording in human epilepsy patients that shows crossfrequency coupling of oscillatory activity in the hippocampus between beta/gamma range and the theta band, and the precision of coupling predicts working memory performance (28). This sustained phase synchronization between higher-order sensory, frontal, and temporal cortices and the hippocampus provides a mechanism for working memory maintenance by which activity in different brain regions is sustained in the absence of direct sensory output (26). An important consequence of these findings is that working memory depends on network-level activation and coordination.

Working Memory and Schizophrenia Schizophrenia patients are cognitively compromised on the order of magnitude 1.0–1.8 SDs below the normal mean (29). Patients with an earlier onset have more severe cognitive deficits that persist throughout the course of the disorder (30). Cognitive impairments are present in the prodromal period and might contribute to heterogeneity in patterns of cognitive changes across illness phases and among individuals (31). Meta-analyses in schizophrenia demonstrate large deficits in all 3 domains of working memory (phonological, visuospatial, and central executive) with no clear differences across domains or tasks (32,33). There was also no consistent association between duration of illness, antipsychotic medication, or symptom profile and working memory in schizophrenia (33). The DLPFC has been identified as a key liability region for working memory dysfunction in schizophrenia (34). In an early study, healthy individuals demonstrated increased blood flow to the DLPFC during the Wisconsin Card Sorting Task that was not observed in medication-free schizophrenia patients (35). However, recent neuroimaging studies generated conflicting findings with regard to DLPFC activation during working memory tasks. Both “task-related hypofrontality” and “task-related hyperfrontality” have been reported in patients with schizophrenia relative to healthy subjects (34). These discrepancies are potentially driven by study differences in task performance or difficulty, although it is possible that the findings are confounded by coupling and activation in other cortical regions. For example, stronger activation of deep brain structures [e.g., thalamus (36)] and the anterior cingulate cortex (37) in schizophrenia patients might be a product www.sobp.org/journal

T.A. Lett et al. of compensatory mechanism for working memory deficits. Therefore, working memory dysfunction could be a result of reduced function of specific regions but also an impairment to engage functional networks synchronized to a given cognitive task. The disruption of working memory networks in schizophrenia is still poorly understood. As reviewed in the preceding text, dynamic network connectivity is necessary for proper working memory functioning. Given the functional and anatomical “dysconnectivity” observed in schizophrenia (38), especially to the DLPFC (39), working memory deficits in schizophrenia could be due to dysfunction of establishing or changing brain networks. Thus, establishing a link between functional integration and working memory deficits is crucial to developing novel, neurobiologicalbased interventions to enhance working memory performance.

Current Treatments of Working Memory Deficits Therapeutic strategies for working memory deficits in schizophrenia are of great interest, considering their predictive value for functional outcome. Nonpharmacological and pharmacological treatment strategies have been investigated but demonstrate mixed results. Antipsychotic Treatment Pharmacological studies have examined differences in effects of antipsychotic medications on cognitive functioning. Although showing small effects toward improved cognitive performance with treatment, some studies show therapeutic advantages of atypical antipsychotics compared with typical antipsychotics (40); however, the large, multisite CATIE trial (Clinical Antipsychotic Trials of Intervention Effectiveness) failed to find any advantage of atypical antipsychotics in treating cognition (1). Clozapine, the atypical antipsychotic agent for treatment resistant-schizophrenia (41), is no longer considered superior to other atypical antipsychotic agents for cognitive deficits (42). These results were driven by multiple pharmacological initiatives, such as the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) (43), TURNS (Treatment Units for Research on Neurocognition and Schizophrenia) (44), and CNTRICS (Cognitive Neuroscience Treatment Research to Improve Cognition Schizophrenia) (45). These initiatives highlight continuing interest and committed resources currently dedicated for novel therapies for cognitive deficits in schizophrenia and, in particular, working memory deficits. It should be noted that the long-term consequences of antipsychotic treatment might be detrimental to cognition. Progressive declines in working memory performance are observed in nonhuman primates undergoing chronic treatment of haloperidol over a 6-month period (46). Additionally, gray matter loss, higher neuronal density, and reduced glial cell number similar to that histologically observed in schizophrenia was reported in nonhuman primates exposed to olanzapine or haloperidol over a 2-year period (47,48). A longitudinal firstepisode schizophrenia study showed progressive decline of white and gray matter volume correlating with antipsychotic medication dose (49). Thus, the evidence does not support a benefit from antipsychotic medication with regard to cognitive deficits but rather indicates a potential negative effect on working memory in schizophrenia during long-term treatment. Pharmacological Targets The pharmacology of working memory dysfunction might provide critical understanding for the development of new

T.A. Lett et al. treatments (Figure 1) (50). Blockade of the glutamate-mediated excitatory neurotransmission by N-methyl-D-aspartate receptor (NMDAR) antagonists mimics positive and negative symptoms as well as cognitive deficits in schizophrenia. These findings suggest that enhancing NMDAR neurotransmission might reverse cognitive deficits (51,52). Furthermore, NMDAR ablation on GABA interneurons impairs hippocampal theta rhythm leading to impaired working memory (53). The NMDAR activation also subserves persistent DLPFC neuronal firing during working memory (54), suggesting that glutamate function and connectivity is integral to working memory performance. Results from the CONSIST (Cognitive and Negative Symptoms in Schizophrenia Trial), however, suggest that either glycine (binds to allosteric site of the NMDAR) or D-cycloserine (partial NMDA agonist) were not effective in treating cognitive impairments (55). Vis-à-vis dopamine, early preclinical work shows that dopamine neurotransmission might be augmented to treat working memory deficits in schizophrenia. Increased availability of PFC dopamine D1 receptors has been reported in schizophrenia and might reflect a compensatory upregulation, due to reduced PFC dopamine release; furthermore, the increased expression has been directly associated with poor working memory performance (56,57). In nonhuman primates, intermittent long-term D1 receptor agonist treatment yielded persistent improvements in haloperidol-induced working memory deficits (46). The selective D1 receptor agonist, dihydrexidine, was reported to be welltolerated in schizophrenia subjects (58). Single-dose administration of dihydrexidine was reported to have no effect on neurocognition (59). Nevertheless, intermittent D1 receptor agonist treatment remains a promising strategy. Catecholamine-O-methyltransferase has been directly associated with PFC dopamine turnover and working memory performance (60). CatecholamineO-methyltransferase inhibitors, such as tolcapone, are a promising target, although they have unfortunately also been associated with hepatotoxicity (61). Finally, GABAergic inhibitory neurotransmission in the DLPFC is altered in schizophrenia (62) and is integral to organizing gamma oscillations associated with working memory load (63). The major determinant of GABA in the neocortex, glutamic acid decarboxylase, is consistently downregulated in postmortem studies of patients with schizophrenia (64). The selective agonist of the GABAA receptor, MK-0777, was shown to be effective in treating working memory deficits and could potentially modulate frontal gamma activity in a study with limited sample size (65). A subsequent study failed to replicate the enhancement of working memory by MK-0777 in schizophrenia (66); however, modulating GABA neurotransmission remains a promising target. Other pharmacological strategies including galantamine, a combined acetylcholinesterase inhibitor and allosteric potentiator of the nicotinic receptor, show modest effect across several cognitive domains (67) with no improvement in working memory as confirmed by a recent Cochrane review (68). Furthermore, other pharmacological treatment attempts have failed, including: the novel neuropeptide davunetide; the nicotinic agonist varenicline; and pregnenolone (69–71). Although some improvement in working memory performance was shown with pergolide, minocycline, amphetamine, and recombinant human erythropoietin, none of these findings have been replicated in a controlled study (72–75). In summary, pharmacological investigations for working memory deficits in schizophrenia could benefit from the use of novel agents, because existing studies have demonstrated limited treatment effects (61).

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Figure 1. Hypothesized prefrontal cortical circuit highlighting synapses that are implicated in working memory dysfunction and targets of pharmacological cognitive enhancers. Direct and indirect disruptions of dopamine, glutamate, and γ-aminobutyric acid (GABA) neurotransmitter signaling are reported in schizophrenia, and these synapses are integral to working memory function. In the prefrontal cortex, chandelier cells (parvalbumin-containing, fast-spiking GABA interneurons) mediate GABA neurotransmission at the axon initial segment of pyramidal cells (excitatory neurons) to GABAA receptors, including the α2 subunit. Pyramidal cells release glutamate to N-methyl-D-aspartate receptors (NMDARs) on chandelier cell forming a feedback mechanism responsible for gamma oscillation activity in the prefrontal cortex. Pyramidal cells synapse on basket cells (parvalbumin-containing, fast-spiking GABA interneurons) with reciprocal GABAergic synapses of basket cells on the soma of pyramidal interneurons. Pyramidal cells also release glutamate on striatal dopamine neurons (and other regions, such as the hippocampus and ventral tegmental area) leading to activation of dopamine D1 receptors (D1R) on prefrontal chandelier and pyramidal cells, thereby augmenting the activation timing of these neurons. Examples of pharmacological targets to improve working performance include: 1) restoring glutamate signaling with glycine (binding to the allosteric site of the NMDAR) or D-cycloserine (partial NMDA agonist); 2) selectively increasing dopamine signaling to the D1R with dihydrexidine (D1R agonist); and 3) increasing GABAergic tone through agonism of the GABAA α2 subunit by MK-0777. For further review, please see Lewis and Gonzalez-Burgos (50) and Lisman et al. (149). GABA(A)α1, GABAA receptor including the α1 subunit; GABA(A)α2, GABAA receptor including the α2 subunit.

Cognitive Training Perhaps the best-supported strategy targeting working memory deficits (and cognitive dysfunction in general) in schizophrenia is CRT. Cognitive remediation therapy employs drill or practice exercises, teaching strategies to improve cognitive functioning, as well as compensatory strategies and group discussions (76). A number of studies have investigated effects of CRT on different cognitive domains (e.g., attention/vigilance, processing speed, verbal working memory, or social cognition) (77). Computerized and noncomputerized training methods for these different domains of cognitive function have been described. Although the neural mechanisms of action remain poorly understood, CRT might influence cortical connectivity and brain structure relevant to the specific training involved. Wykes et al. (78) found that www.sobp.org/journal

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4 BIOL PSYCHIATRY 2013;]:]]]–]]] schizophrenia patients undergoing CRT for executive functioning (n ¼ 6) over 3 months showed increased brain activation in frontocortical regions associated with working memory compared with control therapy patients. Increased activation of the inferior frontal cortex after 10 weeks of verbal memory training in eight patients with schizophrenia was associated with verbal working memory improvement (79). A 2-year randomized control trial of cognitive enhancement therapy (combined neurocognitive and social cognitive remediation) in 121 patients reported strong, lasting effect on cognition and global functioning (Cohen’s d ⬎ 1.00), although there was no association with working memory (80). Subsequently, it was reported that the cognitive enhancement therapy group had preservation of left hippocampal, parahippocampal, and fusiform gyrus gray matter volume and increased amygdala volume (81). Furthermore, less gray matter loss in the parahippocampus and fusiform gyrus as well as greater amygdala gray matter volume was related to improved cognition (81). In poor-reading children, 100 hours of remedial reading training normalized left frontal fractional anisotropy to that of normal reading children (82). More recently, strategy-learning-based CRT in 30 schizophrenia subjects normalized activation toward the pattern of healthy control subjects during an N-back working memory functional magnetic resonance imaging paradigm (83). Moreover, after CRT these subjects had increased fractional anisotropy in the genu of the corpus callosum that was correlated with total cognition and executive function, although CRT was not associated with working memory improvement (83). Taken together, these results suggest that CRT initiates learning-induced plasticity in cognitively compromised populations. The most recent meta-analyses indicate that CRT can provide a moderate improvement in global cognition (effect size is approximately .4–.5) (77,84). Despite the difference between CRT approaches in terms of methods used and targeted cognitive domains, studies have shown consistent effect sizes (85); moreover, no single method (e.g., remediation approach, CRT duration) was superior in terms of cognitive outcome (77,84). Although some CRT studies have shown no effect on working memory (77,86), computer-based programs that focused on the remediation of verbal working memory in schizophrenia through auditory training exercises have shown promise (87–89). For instance, Fisher et al. (88) demonstrated significant improvements on the letter–number span working memory task in patients with schizophrenia after 50 hours of auditory training exercises, compared with a control group. This training also improved auditory psychophysical performance that was related to improved verbal working memory and global cognition. Moreover, the active group had significantly elevated peripheral levels of the brain-derived neurotrophic factor (BDNF), indicating CRT might induce neuroplasticity. Six-month follow-up revealed a clear improvement of global cognition with lasting effects on auditory function, visual processing, and cognitive control (89). Although a recent study failed to replicate these results (90), CRT might have enduring therapeutic value. Particularly when CRT is provided with adjunctive psychiatric rehabilitation, such as social group exercises (80), it is shown to be more effective (77). The observed effects on neuroplasticity together with moderate effect sizes of the training suggest that CRT might best serve in combination with neurophysiological-based interventions inducing neuroplasticity, such as rTMS or with pharmacological approaches. For example, CRT might act in concert with other methods of inducing neuroplasticity to reinforce working memory pathways. However, to the best of our knowledge, there are no published studies examining CRT in combination with other cognitive neuroenhancement techniques. www.sobp.org/journal

TMS and Cognition Transcranial magnetic stimulation is an investigational tool to examine physiological brain processes in relation to cognition and psychiatric illness (91). For example, rTMS intervention to the DLPFC transiently impairs encoding and retrieval mechanisms with visuospatial (92) and verbal stimuli (93); however, the same stimulation can facilitate cognition in picture naming, object naming, speed during reasoning puzzle, and cognitive reaction tasks (94–97). In this regard, rTMS modulates cortical excitability through local inhibitory circuits that could facilitate or inhibit brain networks relevant to the cognitive task (98). Combining TMS with EEG (TMS-EEG) allows measurement of both temporal and spatial activations at the targeted brain region (99). A link between regional neurophysiology and cognitive function can be examined, by assessing how TMS-induced modulation of cortical activation of the DLPFC relates to working memory function. For instance, long interval cortical inhibition (a measure closely associated with GABAB receptor neurotransmission) has been strongly correlated with performance on the N-back (r ¼ .63, p ¼ .04) and letter–number-sequencing (r ¼ .68, p ¼ .005) working memory tasks in healthy control subjects (100–102). Furthermore, this suggests that long interval cortical inhibition might be important in modulating high-frequency oscillations in the DLPFC that influences working memory (102). Therefore, TMSEEG measures of cortical inhibition and DLPFC synchrony might provide key insights into working memory function. The connection between targeted area and brain functioning is of great importance, because psychiatric disorders, such as schizophrenia, have abnormal neural oscillations and synchrony. This has been demonstrated in rhythm-generating networks of GABA interneurons and in cortico–cortical connections (103).

Brain Networks Synchrony Theories of schizophrenia emphasize deficits in the coordination of distributed neuronal oscillatory activity that lead to working memory dysfunction (104). Patients with schizophrenia have abnormal gamma oscillations and gamma–theta coupling that might underlie independent cognitive and functional impairments (104–106). Gamma frequency oscillations are particularly interesting, because of their integral relationship with higher brain processes (107). They provide a temporal structure for information processing in the brain, mediating storage and recall of information (108). One GABA interneuron typically connects extensively with several pyramidal neurons forming neuronal networks that fire contemporaneously, a process that can been recorded over the surface of the cortex as gamma oscillatory activity (Figure 1) (109). The kinetics of inhibitory interneurons in the cortex are such that their firing rate is much higher than that of pyramidal cells, permitting higher rates of pyramidal cell firing compared with baseline (110). Finally, inhibitory interneurons form synaptic connections with pyramidal neurons at the cell body, a synaptic relationship that allows greater control of pyramidal neuron firing compared with synaptic terminations at more distal regions of the neuron (111). As a result of this pattern of connectivity, inhibitory interneurons exert fine control over the firing of pyramidal neuron networks, which translates into highfrequency gamma oscillatory activity on EEG (112). Gamma oscillations are also coupled to theta rhythms (110), and this coupling has been found to be essential for working memory (27). This suggests that specific interplay between large ensembles of neurons has clinical significance.

T.A. Lett et al. In patients with schizophrenia, aberrant gamma oscillatory activity has been reported during a cognitive control task, compared with healthy subjects (107). Furthermore, inability to support stimulus-driven gamma oscillations in schizophrenia patients has been associated with working memory dysfunction (104). Excessive frontal activation of gamma oscillations were reported in schizophrenia and correlated with working memory task difficulty (113). Finally, the increase in gamma oscillations was associated with a later maintenance phase of working memory and induced gamma and theta activity during retrieval (114). Taken together, these results suggest that schizophrenia patients are not properly able to coordinate cortical activity that is appropriate cognitive demand.

Modulating Network Plasticity There are several mechanisms for TMS to induce and measure cortical plasticity. The TMS activation of a population of neurons in the same synaptic pathway (homosynaptic) or in different pathways (heterosynaptic) is modulating synaptic efficacy either by: increased synaptic strength (long-term potentiation [LTP]); or decreased synaptic strength (long-term depression) (115). Through these mechanisms, low-frequency rTMS will cause a decrease in brain excitability (116); in contrast, high-frequency rTMS causes increased brain excitability (117). Similarly, other magnetic brain stimulation protocols can produce changes in excitation or inhibition (Table S1 in Supplement 1). Furthermore, studies of the motor cortex have shown that TMS protocols potentiate lasting effects on this excitability for 30 min to several hours (118). A recent study suggests that one paradigm, known as pairedassociated stimulation (PAS), might enhance motor learning at 1 week post-PAS (119). The PAS-25, peripheral nerve stimulation 25 msec before rTMS, induced LTP, leading to enduring enhancement of evoked motor potential. These lasting effects are particularly exciting, because rTMS can modulate brain network oscillatory activity, thus providing evidence that PAS could trigger structural and functional changes necessary for long-term improvement of motor performance. Similar findings have been reported in animal studies. A recent study by Benali et al. (120) found that the intermittent theta-burst stimulation (a type of rTMS) (121) to the rat neocortex differently modulates gamma oscillations and protein expression. Intermittent theta-burst stimulation (excitatory) enhanced neural firing and EEG gamma power by reducing parvalbumin expression in fast spiking GABA interneurons; in contrast, continuous theta-burst stimulation (inhibitory) rather affected pyramidal neurons calbindin D-28k expression. Taken together, the lasting cortical plasticity induced by TMS is promising, especially because it can alleviate difficult-to-treat facets of complex psychiatric disorders, such as cognitive deficits in schizophrenia.

Remodeling of Connectivity in Schizophrenia by rTMS There is overwhelming evidence that schizophrenia is, at least in part, a disorder of dysconnectivity of the brain (122). This abnormal functional integration of processes might be due to aberrant wiring during development or aberrant synaptic plasticity or both. This includes abnormal functional connectivity [e.g., frontotemporal connectivity, gamma synchrony (123,124)], abnormal structural connectivity [e.g., white matter integrity, reduced brain asymmetry (125–127)], and synaptic plasticity [e.g., pharmacological-induced schizophrenia symptomology, reduced dendritic field size and

BIOL PSYCHIATRY 2013;]:]]]–]]] 5 density (128,129)]. Genetic factors common to all of these points of dysfunction [e.g., disrupted-in-schizophrenia 1 (DISC1), glutamate decarboxylase 1 (GAD1), neuregulin 1 (NRG1), microRNA 137 (MIR137), and zinc finger protein 804A (ZNF804A) genes (130,131)] all point to the possibility that schizophrenia patients are predisposed to dysconnectivity. Moreover, neural dysconnectivity might be a causative factor in the more intractable deficits of schizophrenia, such as working memory functioning (132). Importantly, rTMS as an external intervention might be used to activate neural developmental pathways sidestepping the normal modes of synaptic plasticity. In this regard, rTMS might galvanize plasticity in brain networks that are compromised in schizophrenia. For instance, intermittent theta-burst stimulation could remediate abnormalities of gamma oscillations of cognitive processing in schizophrenia patients (105). Indeed, high-frequency rTMS to the DLFPC results in reduced frontal gamma oscillation in schizophrenia patients during the N-back working memory task (Figure 2A) (133).

Activity-Dependent Regulation of Molecular Factors by rTMS In most cases, molecular factors that regulate plasticity relate neuronal activation to expression of activity-dependent genes (134). Knowledge of the molecular factors involved in rTMS induction of neural plasticity is necessary to understand how rTMS might be used to shape lasting effects on neural circuitry. Activity-dependent gene expression is integral in the refinement of neuronal network in development as well as in the adaptive, long-lasting modifications necessary for mature brain function, such as learning and memory. It has been well-established that the cyclic adenosine monophosphate-response element binding-protein (CREB) plays a central role, at least in part, in mediating activity-dependent neuroplasticity (Figure 2B) (135). Ji et al. (136) reported that rTMS stimulation to the rat brain activated CREB, leading to increased expression in paraventricular nucleus of the thalamus, cingulate cortex, and frontal cortex. Furthermore, CREB functionally regulates the BDNF gene (137), and theta-burst induction of LTP causes upregulation of BDNF (138). Most recently, it was shown that rTMS treatment to human neuroblastoma cell lines (SH-SY5Y) resulted in activation of CREB (139). Interestingly, CREB regulates cellular fate by inducing expression of the small, noncoding microRNA, miR-132, that controls the messenger RNA stability or translation of many genes involved in epigenetic regulation and neuronal morphogenesis including: dihydropyrimidinase-like 3 (DPYSL3), Rho GTPase activating protein 32 (ARHGAP32), GATA binding protein 2 (GATA2), DNA(cytosine-5)-methyltransferase-3-alpha (DNMT3A), and methyl CpG binding protein 2 (MECP2) (140–142). Taken together, CREB and downstream factors might play a critical role in rTMS-induced plasticity. It should be noted that many of the molecular factors potentially modulated by rTMS (e.g., MECP2, BDNF, and miR-132) are also schizophrenia risk factors related to neuroplasticity. This relationship suggests that rTMS could rescue normal function of neuroplasticity networks in schizophrenia; however, further research is imperative to establish causal relationships between rTMS gene networks involved in plasticity.

Treatment of Working Memory Deficits in Schizophrenia with rTMS To date, there are only two published clinical trials examining the efficacy of rTMS for treatment of working memory dysfunction in schizophrenia. In a 4-week sham-controlled rTMS trial, patients www.sobp.org/journal

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Figure 2. Neuroplasticity induction by repetitive transcranial magnetic stimulation (rTMS). (A) Topographical illustration of change in gamma power (30–50 Hz) during the 3-back working memory task (left, sham rTMS treatment to DLPFC; right, active treatment to DLPFC). Modified, with permission, from Barr et al. (150). (B) Potential molecular mechanism through which rTMS might induce plasticity. Synaptic activation of L-Type voltage-gated calcium channel (VGCC) by rTMS leads to increased intracellular calcium initiating a signaling cascade causing activation of the transcription factor cAMP-response element binding protein (CREB) by phosphorylation, a hallmark of long-term potentiation (LTP)/long-term depression (LTD). Examples of downstream changes in gene expression and the effect these genes have on mediating neuronal plasticity are listed. Red, green, and yellow stars correspond to factors shown to be associated with schizophrenia, modulated by rTMS, and involved in mediating LTP or LTD, respectively. BA, Brodmann area; BDNF, brainderived neurotrophic factor; CaM, Calmodulin; CaMKII, CaM kinases II; DNMT3A, DNA (cytosine-5-)-methyltransferase 3 alpha; GABAAR, γ-aminobutyric acid (GABA) A receptor; GATA2, GATA binding protein 2; MECP2, methyl CpG binding protein 2 (Rett syndrome); miR-132, microRNA 132; NMDAR, N-methyl-Daspartic acid receptor; p250GAP, ARHGAP32 Rho GTPase activating protein 32; TrkB, TrkB receptor.

(n = 13 active; n = 12 sham) that received 20-Hz stimulation to the DLPFC (Brodmann area 46/6) had improved performance on the 3back condition of the N-back working memory task (143). Moreover, working memory performance in the active treatment schizophrenia group normalized to that of healthy control subjects (143). In contrast, a 3-week sham-controlled 10-Hz rTMS trial to the left posterior medial frontal gyrus in schizophrenia patients (n ¼ 13 active; n ¼ 12 sham) and control subjects (n ¼ 11 active; n ¼ 11 sham) reported no significant effect of treatment or treatment  diagnostic interaction in the 2-back condition (144). The disparity of results between these studies could be due to a number of factors. First, rTMS-induced differences in gamma oscillations are reported to be more pronounced in the 3-back working memory task (133); thus, treatment might be specific to www.sobp.org/journal

high working memory load. Second, rTMS treatment of working memory might be more efficacious when targeted to Brodmann area 46/9. Last, 4 weeks of 20-Hz rTMS stimulation (in contrast to 3 weeks of 10 Hz) might be a more effective mode of treatment. Anodal direct current stimulation (tDCS) treatment has been previously associated with improvement in global cognitive function, attention, and enhancement of working memory [for review, see (145)]. A single study has examined anodal tDCS for treatment of working memory dysfunction in schizophrenia patients (n ¼ 12) and reported improvements in reaction time but not accuracy (146). Transcranial alternating current (tACS) can induce or disrupt theta phase-coupling and therefore might play a role in working memory function. In healthy subjects, tACS artificially induced frontoparietal phase coupling leading to

T.A. Lett et al. improved working memory, whereas desynchonization impaired working memory (147). These early results suggest tDCS and tACS target DLPFC functioning and connectivity, and thus, these treatments warrant further investigation. In major depressive disorder, mixed results are observed, although depressive patients are not as cognitively impaired as schizophrenia patients, and working memory has not been the primary outcome measure in any study (148). Therefore, results in major depressive disorder patients might not generalize to schizophrenia.

Conclusions Several adjunctive pharmacological agents have shown promising results, yet no agent has demonstrated efficacy in large clinical trials. Cognitive remediation therapy fairly consistently shows improved cognition in schizophrenia, although the effects seem to depend on domain. For example, CRT has large effect on social cognition (effect size is approximately .65), whereas metaanalyses reveal more moderate effects on working memory (effect size is approximately .35). Thus, CRT might be most effective in conjunction with other working memory treatments, such as rTMS, to produce large and durable effects whereby the DLPFC and related circuitry would be activated by rTMS and engaged by CRT concomitantly. Furthermore, cognitive enhancement drugs could enhance the efficacy of rTMS treatment of working memory. It could be speculated that GABAA receptor agonists, such as MK-0777, that affect gamma oscillatory tone could act in concert with rTMS activation of the DLPFC to specifically target local GABA signaling and coupling to other brain regions. There are convergent lines of evidence suggesting that rTMS to the DLPFC might be efficacious treatment for working memory deficits at multiple levels, including: synaptic (e.g., GABA signaling); cellular (e.g., GABA interneurons); neurophysiological (e.g., inhibition); neural network (e.g., gamma oscillations); and functional neuroanatomy (e.g., DLPFC). Therefore, rTMS treatment for working memory deficits in schizophrenia should garner more research, both as an investigative to tool to understand how dysfunction might occur and as a powerful mechanism to induce neuroplasticity. This work was supported by the Canadian Institutes of Health Research Clinician Scientist Award (ZJD, ANV); National Alliance for Research on Schizophrenia and Depression (ANV), Ontario Mental Health Foundation (ZJD, ANV) and the Centre for Addiction and Mental Health, the Brain and Behaviour Research Foundation, and the Centre for Addiction and Mental Health Foundation and the Campbell Institute, thanks to the Temerty Family, Grant Family, Kimel Family, Koerner New Scientist Award, and Paul E. Garfinkel New Investigator Catalyst Award. ZJD received external funding through Neuronetics and Brainsway and Aspect Medical and a travel allowance through Pfizer and Merck. ZJD has also received speaker funding through Sepracor and AstraZeneca and served on the advisory board for Hoffmann-La Roche Limited. JLK has received honoraria from Eli Lilly, Roche, and Novartis. TAL, ANV, and BL report no biomedical financial interests or potential conflicts of interest. Supplementary material cited in this article is available online at http://dx.doi.org/10.1016/j.biopsych.2013.07.026.

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